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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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DARZALEX - MMY2004 (GRIFFIN) Study

Last Updated: 02/04/2025

Click on the following links to related sections within the document: GRIFFIN (MMY2004) Study Overview, Part 1: Results, Part 2: Primary and Updated Analyses Results, and Part 2: Final Analysis Results.
Abbreviations: AE, adverse event; ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; CrCl, creatinine clearance; DLT, doselimiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; HDT, high-dose therapy; IMWG, International Myeloma Working Group; IRR, infusion-related reaction; IV, intravenous; MM, multiple myeloma; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NGS, next-generation sequencing; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, lenalidomide; Rd, lenalidomide and dexamethasone; sCR, stringent complete response; TEAE, treatment-emergent AE; VGPR, very good partial response; VRd, bortezomib, lenalidomide, and dexamethasone.
^aVoorhees (2017).¹ ^bVoorhees (2019).² ^cVoorhees (2020).³ ^d21-day cycles. ^e28-day cycles. ^fVoorhees (2021).⁴ ^gLaubach (2021).⁵ ^hIncludes the preferred terms of peripheral neuropathy and peripheral sensory neuropathy. ⁱVoorhees (2023).⁶ ^jThere were no grade 4/5 IRRs.

SUMMARY

DARZALEX is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of multiple myeloma (MM). Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
GRIFFIN was a 2-part, phase 2 study that evaluated the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) in patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT).¹^-³
- Part 1: Voorhees et al (2021)⁴ reported the final analysis of the safety run-in cohort (N=16) of the GRIFFIN study with a median follow-up of 40.8 months. By the end of DVRd consolidation, 56.3% patients achieved stringent complete response (sCR), and 50.0% were minimal residual disease (MRD) negative (10^-5threshold). After maintenance, 93.8% patients achieved sCR, and 81.3% patients were MRD negative (10^-5threshold). Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 93.8% of patients. One death from progressive disease (PD) occurred in the patient who did not achieve sCR.
- Part 2: Voorhees et al (2020) presented the primary analysis of the randomized portion of this study (n=207).²^,³ Voorhees et al (2023)⁶ reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation. The median duration of followup was 49.6 months. In the D-VRd vs VRd arm, respectively, sCR was achieved in 67% vs 48% of patients (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.223.89; 2-sided P=0.0079) and complete response or better (≥CR) in 83% vs 60% of patients (P=0.0005). At the end of the study, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and VRd arms, respectively, who were previously MRD positive at the end of the consolidation phase, converted to MRD negative (10^-5). In the DVRd vs VRd arm, the most common (≥10%) grade 3/4 TEAEs were neutropenia (46% vs 23%), lymphopenia (23% in both arms), leukopenia (17% vs 8%), thrombocytopenia (16% vs 9%), pneumonia (12% vs 14%), and hypophosphatemia (10% vs 11%).
Rodriguez et al (2022)⁷ presented (at the 58th American Society of Clinical Oncology [ASCO] Annual Meeting) a post hoc analysis of the GRIFFIN study at a median follow-up of 38.6 months that assessed the sustained MRD-negativity (lasting ≥6 or ≥12 months) in clinically relevant subgroups as well as among patients with ≥CR. Rates of sustained MRD-negativity (10^-5) lasting ≥6 or ≥12 months were higher with D-VRd vs VRd in all clinically relevant subgroups. Similar trends were observed when measured at a higher MRD sensitivity threshold of 10^-6, although some variability was observed.
Nooka et al (2024)⁸ reported updated post hoc analysis results by race at the time of final analysis in the overall population with ~2 years of additional follow-up. The median duration of follow-up was 49.6 months. In the D-VRd vs VRd arm, the rate of sCR was 92.9% vs 38.9% in Black patients and 65.1% vs 50.0% in White patients, the rate of MRD-negativity (at 10^-5 threshold) was 64.3% vs 22.2% in Black patients and 65.9% vs 31.6% in White patients, and the estimated 48-month progression-free survival (PFS) rate was 79.1% vs 64.6% in Black patients and 89.4% vs 74.2% in White patients. The most common grade 3/4 TEAEs were neutropenia (D-VRd vs VRd: Black, 50.0% vs 22.2%; White, 47.0% vs 17.6%) and lymphopenia (Black, 28.6% vs 38.9%; White, 22.9% vs 16.2%). No deaths due to TEAEs were reported among Black patients in either arm, and 1 death due to pneumonia was reported among White patients in the DVRd arm.
Chari et al (2024)⁹ reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study. The MRD-negativity rates (10^-5) were higher in the D-VRd arm vs the VRd arm in patients ≥65 years (67.9% vs 17.9%, respectively), with high-risk cytogenetic abnormalities ([HRCAs]; 54.8% vs 32.4%, respectively), and with gain/amp(1q21) (61.8% vs 28.6%, respectively). The hazard ratio (HR) point estimates for PFS favored the D-VRd vs VRd arm in patients ≥65 years (HR, 0.29; 95% CI, 0.06-1.48), with HRCAs (HR, 0.38; 95% CI, 0.14-1.01), and with gain/amp1(1q21) (HR, 0.42; 95% CI, 0.14-1.27). In patients aged ≥65 years, grade 3/4 TEAEs were reported in 88.9% vs 77.8% of patients in the D-VRd vs VRd arm. TEAEs leading to discontinuation of ≥1 treatment component were higher in D-VRd vs VRd, 37.0% vs 25.9% respectively.
Callander et al (2024)¹⁰ reported post hoc analysis results evaluating the clinical efficacy of DARZALEX-based quadruplet therapies including DARZALEX + carfilzomib + lenalidomide + dexamethasone (D-KRd) and D-VRd in transplant-eligible patients with NDMM with HRCAs from the MASTER and GRIFFIN studies, respectively. In GRIFFIN, in patients with 0, 1 and ≥2 HRCAs, respectively, ≥CR was achieved by 90.9%, 78.8%, and 61.5%, the 24-month PFS rate was 96.7%, 93.8%, and 64.2%, and MRD-negativity (10^-5) was reported in 76.1%, 55.9%, and 61.5%. In GRIFFIN, 1 patient with 1 HRCA and 4 patients with ≥2 HRCAs died of PD.
Sborov et al (2022)¹¹ conducted a post hoc analysis to evaluate the risk and incidence of vascular thrombotic events (VTEs) in patients receiving D-VRd vs VRd in the GRIFFIN study. At a median follow-up of 38.6 months, VTEs were reported in 10.1% (n=10) of patients in the D-VRd arm and 15.7% (n=16) of patients in the VRd arm. The most common any-grade VTEs were deep vein thrombosis (DVRd, 2.0%; VRd, 6.9%), pulmonary embolism (D-VRd, 2.0%; VRd, 3.9%), and embolism classified as unspecified vessel type and mixed arterial and venous (D-VRd, 2.0%; VRd, 2.9%). Among patients experiencing VTEs, clinical response deepened over time and response rates were higher in the D-VRd vs VRd arm after 2 years of maintenance.
Silbermann et al (2023)¹² presented (at the 20th International Myeloma Society [IMS] Annual Meeting and Exposition) a post hoc analysis of the GRIFFIN study that evaluated patient-reported outcomes (PROs) during the maintenance therapy phase. During this phase, the proportion of patients reporting “not at all” or “a little” in the symptoms of hip pain increased from 69% to 85% from baseline to maintenance month 24 in the D-VRd/D-R arm and decreased from 83% to 78% in the VRd/R arm. Additionally, the proportion of patients reporting “not at all” or “a little” trouble taking a long walk increased from 61% to 85% from baseline to maintenance month 24 in the D-VRd/D-R arm and from 61% to 87% in the VRd/R arm.
Silbermann et al (2022)¹³ presented (at the 64th ASH Annual Meeting and Exposition) the final analysis of PROs from the GRIFFIN study (median follow-up, 49.6 months). Greater reductions in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) pain symptoms and fatigue symptoms scores were reported in the D-VRd vs VRd arm. Similar improvements were reported both in the D-VRd and VRd arm in EORTC QLQ-C30 global health status (GHS) and physical functioning scores, EuroQol 5-dimensional descriptive system (EQ-5D-5L) visual analog scale (VAS) and utility scores, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item (EORTC QLQ-MY20) disease symptoms and future perspective scores. The time to worsening of EORTC QLQ-C30 GHS score was 30 months higher in the DVRd vs VRd arm.
Chhabra et al (2023)¹⁴ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes after frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. In GRIFFIN, the median cluster of differentiation 34 positive (CD34⁺)cell yield in the D-VRd vs VRd arm was 8.3×10⁶ cells/kg vs 9.4×10⁶ cells/kg, respectively. For each regimen, a numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (D-VRd, 8.8×10⁶ cells/kg vs 7.1×10⁶ cells/kg, P=0.10; VRd, 10.5×10⁶ cells/kg vs 9.4×10⁶ cells/kg, P=0.20; respectively).¹²
Rodriguez-Otero et al (2024)¹⁵ presented (at the 21^st IMS Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of D-VRd vs VRd in patients aged ≥65 years. Patients treated with D-VRd showed a 44% reduction in the risk of disease progression or death vs VRd (HR, 0.56; 95% CI, 0.31-1.01; P=0.05). At a median follow-up of 47.5 months and 49.6 months, the median PFS was not reached in the PERSEUS and GRIFFIN groups, respectively. A higher overall MRD-negativity rate (10^-5) of 66.4% vs 41.7% and a sustained MRD-negativity rate (10^-5; ≥12 months) of 52.5% vs 26.1% was observed in the D-VRd vs VRd groups, respectively. There were no new safety concerns observed, and the overall safety profile of patients aged ≥65 years was comparable to the pooled patient population irrespective of age. A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients aged ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%). The frequency of TEAEs that resulted in discontinuation of ≥1 study drug was similar between treatment groups in patients aged ≥65 years and in all patients.

PRODUCT LABELING

DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf.

CLINICAL DATA

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742)¹^-³ was a 2-part, randomized, active-controlled, phase 2 United States (US) study that evaluated the safety and efficacy of D-VRd in patients with NDMM eligible for HDT and ASCT.

Study Design/Methods

Of note, the data presented utilized the abbreviation “RVd”, which has been replaced with “VRd” in the summary below to remain consistent throughout this scientific response.
Phase 2, randomized, open-label, active comparator-controlled, multicenter study.
The study enrolled 16 patients in the safety run-in phase, which assessed potential dose-limiting toxicities (DLTs) during cycle 1, and 207 patients in the randomized phase 2 portion.
DLTs were defined as reported adverse events (AEs) of:
- Grade 4 neutropenia lasting >7 days
- Grade 4 thrombocytopenia lasting >7 days despite transfusion support
- Grade ≥3 nonhematological toxicity, except:
  - Grade 3 nausea, vomiting, or diarrhea that can be controlled within 48 hours with maximal supportive care
  - Grade 3 hyperglycemia that can be controlled within 48 hours with supportive care
  - Asymptomatic grade ≥3 electrolyte disturbances that can be controlled with repletion within 24 hours
  - Grade 3 maculopapular rash attributable to lenalidomide
- Infusion-related reactions (IRRs):
  - Any grade 4 IRR occurring within 48 hours of infusion of DARZALEX
  - Any grade 3 IRR occurring within 48 hours of infusion of DARZALEX that does not resolve with a reduced infusion rate or temporarily stopping the infusion, as well as administration of supportive care and symptomatic therapy such as a steroid and an antihistamine
The safety run-in phase consisted of an induction phase (cycles 1-4; 21-day cycles), followed by ASCT, followed by a consolidation phase (cycles 5-6; 21-day cycles), that was initiated 60-100 days after ASCT, followed by a maintenance phase (cycles 7-32; 28-day cycles).
- From the induction phase through the consolidation phase, patients received:
  - DARZALEX 16 mg/kg intravenously (IV) weekly in cycles 1-4 and every 3 weeks in cycles 5-6
  - Lenalidomide 25 mg orally (PO) on days 1-14
  - Bortezomib 1.3 mg/m² subcutaneously (SC) on days 1, 4, 8, and 11
  - Dexamethasone 40 mg PO weekly (20 mg PO on days 1, 2, 8, 9, 15, and 16)
- During the maintenance phase, patients received:
  - DARZALEX 16 mg/kg IV every 4 weeks or 8 weeks.
  - Lenalidomide 10 mg PO daily on days 1-21, then 15 mg PO daily beginning cycle 10 (if no tolerability issues)
  - Dexamethasone 20 mg PO every 8 weeks on days 1, 2, 8, 9, 15, and 16
- One interim safety analysis was performed as planned for the safety run-in patients after treated for ≥4 cycles or discontinued study participation.
Following successful completion of the safety run-in phase, in part 2 of the study patients were randomized 1:1 to an induction phase (D-VRd or VRd [cycles 1-4; 21-day cycles]), followed by ASCT, followed by a consolidation phase (D-VRd or VRd [cycles 56; 21-day cycles]), followed by a maintenance phase (DARZALEX + lenalidomide or lenalidomide monotherapy [cycles 7-32; 28-day cycles]), following the dosing illustrated above, +/- DARZALEX.
A data review committee was established to review safety data after 8, 12, and 16 patients in the safety run-in phase completed cycle 1, and to determine if the study should proceed to the randomized phase 2 portion or stop.
Key inclusion criteria: age 18-70 years; documented MM per International Myeloma Working Group (IMWG) 2015 criteria; eligible for HDT/ASCT; Eastern Cooperative Oncology Group performance score of 0 to 2; adequate organ function; no prior systemic therapy for MM; measurable disease; creatinine clearance (CrCl) ≥30 mL/min
Primary objective: determine if the addition of DARZALEX to VRd will increase the sCR rate by the end of the post-ASCT consolidation therapy
Primary endpoints: sCR (by end of post-ASCT consolidation)
Secondary endpoints: MRD (10^-5 via next-generation sequencing [NGS]), CR, overall response rate (ORR), ≥VGPR, duration of response (DOR), time to CR or sCR, PFS, and overall survival (OS)

Part 1: Safety Run-in Phase Final Analysis

Voorhees et al (2021)⁴ reported the final analysis of the safety run-in cohort of the GRIFFIN study.

Results

Baseline Characteristics

Demographics and baseline characteristics are presented in Table: Baseline Characteristics.
Median follow-up was 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.
All patients in the safety run-in phase (N=16) completed induction therapy, stem cell mobilization, ASCT, consolidation, and entered maintenance therapy.
A total of 87.5% (n=14) of patients completed study therapy, and 2 (12.5%) discontinued the therapy because of PD (n=1) or AE (n=1; neuralgia or thrombocytopenia) during maintenance therapy.
Stem cell collection and neutrophil and platelet engraftment are present in Table: Stem Cell Collection and Transplantation.

Baseline Characteristics⁴

Characteristic	D-VRd (n=16)
Age, years
Median (range)	62.5 (46-65)
<65 years, n (%)	14 (87.5)
≥65 years, n (%)	2 (12.5)
Sex, n (%)
Male	8 (50.0)
Female	8 (50.0)
Race, n (%)
White	11 (68.8)
Black or African American	4 (25.0)
Asian	1 (6.3)
ECOG PS, n (%)^a
0	3 (18.8)
1	10 (62.5)
2	3 (18.8)
ISS disease stage, n (%)^b
I	12 (75.0)
II	2 (12.5)
III	2 (12.5)
Cytogenetic risk profile, n (%)^c
Standard	12 (75.0)
High risk	4 (25.0)
Median (range) time since diagnosis of MM, months	1.6 (0-5)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MM, multiple myeloma; t, translocation. ^aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. ^bISS disease stage is based on the combination of serum β₂-microglobulin and albumin levels. Higher stages indicate more advanced disease. ^cCytogenetic risk was assessed by fluorescence in situ hybridization (locally tested); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) in those patients with cytogenetic risk data available.

Stem Cell Collection and Transplantation⁴

Parameter	D-VRd (n=16)
Median (range) CD34⁺ yield, ×10⁶ cells/kg	8.05 (3.5-17.6)
Median (range) CD34⁺ cells transplanted, ×10⁶ cells/kg	4.72 (2.2-6.0)
Patients receiving plerixafor for mobilization, n (%)	9 (56.3)
Patients receiving cyclophosphamide, n (%)	0
Median (maximum) days to neutrophil (0.5×10⁹/L) engraftment,^a	14
Median (maximum) days to platelet (20×10⁹/L) engraftment,^b	13.5
Abbreviations: CD34⁺,cluster of differentiation 34 positive; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone. ^aFor neutrophil engraftment, there were 15 evaluable patients. ^bFor platelet engraftment, there were 16 evaluable patients.

Safety

During cycle 1, 3 of 16 patients developed 4 DLTs: fatigue, gastroenteritis, hypotension, and pneumonitis. All DLTs were grade 3 and none resulted in treatment discontinuation during induction or consolidation therapy.
One patient had a TEAE leading to discontinuation of study treatment.
Fourteen (87.5%) patients experienced any-grade infections and 5 (31.3%) patients experienced grade 3/4 infections.
- During the maintenance phase, 31.3% (n=5) of patients experienced any-grade infections, the most common being upper respiratory tract infections. One (6.3%) patient experienced a grade 3/4 infection (pneumonia and bronchitis).
Grade 1/2 IRRs occurred in 31.3% (n=5) of patients. IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.
Eleven (68%) patients experienced a serious AE. For the incidences of grade 3/4 TEAEs, please see Table: Most Common Grade 3/4 TEAEs.

Most Common Grade 3/4 TEAEs⁴

Events, n (%)	D-VRd (n=16)
Events, n (%)	Grade 3/4^a
Total	15 (93.8)
Most commonly occurring
Neutropenia	7 (43.8)
Pneumonia	5 (31.3)
Lymphopenia	5 (31.3)
Thrombocytopenia	4 (25.0)
Hypertension	3 (18.8)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone, TEAE, treatment-emergent adverse event. ^aNo grade 5 TEAEs were reported.

Efficacy

At a median follow-up of 40.8 months (range, 20.6-43.0), disease progression occurred in 3 patients.
Median time to first response was 0.77 months (range, 0.1-2.1), and median DOR was not estimable.
Median time to ≥CR was 7.36 months (range, 2.8-18.5), and median duration of ≥CR was not estimable.
Estimated 24-months PFS and OS rates was 93.8%.
Estimated 36-month PFS and OS rates were 78.1% and 93.8%, respectively.
MRD-negativity rates at 10^-5 sensitivity threshold and 10^-6 sensitivity threshold, respectively:
- By end of D-VRd induction: 18.8% (n=3) vs 0%.
- By end of D-VRd consolidation: 50% (n=8) vs 0%.
- At the last follow-up: 81.3% (n=13) vs 31.3% (n=5)
MRD-negativity rates of 10^-5 were sustained for ≥12 months in 8 (50.0%) patients.
Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort.

Updated Response Rates Over Time for the Safety Run-in Cohort^a,⁴

Patients, %	By End of D-VRd Induction	By End of D-VRd Consolidation	By Last Follow-up D-R Maintenance
sCR	-	56.3	93.8
CR	12.5	12.5	-
≥CR	12.5	68.8	93.8
VGPR	56.3	31.3	6.3
PR	31.3	-	-
Abbreviations: CR, complete response; ≥CR, complete response or better; D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. Response data are shown for the response-evaluable population (N=16). ^aPercentages do not add up to 100% due to rounding.

Part 2: Randomized Phase

Voorhees et al (2020)²^,³^,¹⁶ presented the primary analysis and updated analysis of the randomized portion of this study. Kaufman et al (2020)¹⁷ presented a 1-year update of the safety and efficacy results at the 62nd ASH Annual Meeting & Exposition in December 2020. Laubach et al (2021)⁵ presented updated efficacy and safety results after 2 years of maintenance therapy in the GRIFFIN study. Voorhees et al (2023)⁶ reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation.

Results

Baseline Characteristics

A total of 207 patients were randomized (D-VRd, n=104; VRd, n=103).
The median follow-up was 13.5 months in the primary analysis and 22.1 months in the updated analysis.
Ninety percent of patients in the D-VRd arm underwent ASCT compared to 76% in the VRd arm (ASCT rate lower due to early discontinuations).
Baseline patient characteristics are summarized in Table: Patient Demographics in the Randomized Phase (ITT).

Patient Demographics in the Randomized Phase (ITT)³

Characteristic	D-VRd (n=104)	VRd (n=103)
Age
Median (range), years	59 (29-70)	61 (40-70)
≥65 years	28 (26.9)	28 (27.2)
Male, n (%)	58 (55.8)	60 (58.3)
ECOG PS,^a n (%)	n=101	n=102
0	39 (38.6)	40 (39.2)
1	51 (50.5)	52 (51)
2	11 (10.9)	10 (9.8)
ISS stage,^b n (%)
I	49 (47.1)	50 (48.5)
II	40 (38.5)	37 (35.9)
III	14 (13.5)	14 (13.6)
Baseline CrCl, n (%)
30-50 mL/minute	9 (8.7)	9 (8.7)
>50 mL/minute	95 (91.3)	94 (91.3)
Cytogenetic profile,^c n (%)	n=98	n=97
Standard risk	82 (83.7)	83 (85.6)
High risk	16 (16.3)	14 (14.4)
Time since diagnosis of MM	n=103	n=102
Median (range), months	0.7 (0-12)	0.9 (0-61)
Abbreviations: CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone. ^aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. ^bISS disease stage is based on the combination of serum-β₂-microglobulin and albumin levels. Higher stages indicate more advanced disease. ^cCytogenetic risk was assessed by fluorescence in situ hybridization, high risk was defined as the presence of del17p, t(4:14), or t(14:16) among patients with available cytogenetic risk data.

Efficacy

The primary endpoint was met with D-VRd improving the sCR rate by end of consolidation (D-VRd vs VRd: 42.4% vs 32.0%; OR, 1.57; 95% CI, 0.87-2.82; 1-sided P=0.068). The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1.
A significantly higher proportion of patients achieved an ORR following consolidation in the D-VRd arm vs the VRd arm (99.0% vs 91.8%; 2-sided P=0.0160).
The rate of ≥VGPR was 90.9% with D-VRd vs 73.2% with VRd.
The rate of ≥CR was 51.5% with D-VRd vs 42.3% with VRd.
The percentage of patients achieving ≥CR at the end of induction, ASCT, consolidation, and clinical cutoff in the D-VRd arm was 19.2%, 27.3%, 51.5%, and 79.8%, respectively, vs 13.4%, 19.6%, 42.3%, and 60.8% in the VRd arm.
MRD (10^-5 via NGS) among patients achieving ≥CR greater with D-VRd vs VRd: 58.8% vs 24.4% (OR, 4.65; 95% CI, 1.76-12.28; P=0.0014).
In the intent-to-treat (ITT) population, 51% of patients in the D-VRd arm achieved postASCT MRD-negativity vs 20.4% of patients in the VRd arm, regardless of response (OR, 4.70; 95% CI, 2.38-9.28; P<0.0001). Additional MRD results are presented in Table: Post-consolidation MRD-Negativity.
Median stem cell yield (D-VRd vs VRd): 8.2 vs 9.4×10⁶ cells

Post-consolidation MRD-Negativity³

MRD-Negative Status (10^-5),^a n (%); ITT	D-VRd (n=104)	VRd (n=103)	OR (95% CI)^b	P value^c
MRD negative regardless of response	53/104 (51.0)	21/103 (20.4)	4.07 (2.18-7.59)	<0.0001
MRD negative with CR or better	49/104 (47.1)	19/103 (18.4)	3.89 (2.07-7.33)	<0.0001
In patients achieving CR or better	49/69 (62.0)	19/59 (32.2)	3.57 (1.72-7.44)	0.0006
MRD-evaluable population	53/77 (68.8)	21/65 (32.3)	4.47 (2.19-9.11)	<0.0001
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. ^aThe threshold of MRD-negativity was defined as 1 tumor cell per 10⁵ white cells. MRD status is based on assessment of bone marrow aspirates by NGS in accordance with International Myeloma Working Group criteria. MRD assessments occurred in patients who had both baseline (with clone identified/calibrated) and postbaseline MRD (with negative, positive, or indeterminate result) samples taken (DVRd, n=71; VRd, n=55). Patients with a missing or inconclusive assessment were considered MRD positive. ^bMantel-Haenszel estimate of the common OR for stratified tables is used. The stratification factors are ISS stage (I, II, III) and CrCl (30-50 mL/min or >50 mL/min) at randomization. An OR >1 indicates an advantage for the DARZALEX group. ^cP values were calculated from the Fisher’s exact test.

At the median follow-up of 22.1 months, D-VRd achieved higher sCR (62.6% vs 45.4%; OR, 1.98; 95% CI, 1.12-3.49; 2-sided P=0.0177), CR (17.2% vs 15.5%), and ≥CR (79.8% vs 60.8%; OR, 2.53; 95% CI, 1.33-4.81; 2-sided P=0.0045) vs VRd.
In the ITT population, median PFS and OS were not reached (NR) in the D-VRd and VRd arms. In the D-VRd and VRd arms, respectively (Kaplan-Meier estimates):
- 12-month PFS rates were 96.9% and 95.3%.
- 24-month PFS rates were 95.8% and 89.8%.
- 12-month OS rates were 99.0% and 97.9%.
- 24-month OS rates were 95.8% and 93.4%.
DARZALEX did not impact time to engraftment and hematopoietic reconstitution (Table: Stem Cell Collection and Transplantation).

Stem Cell Collection and Transplantation¹⁶

Parameter	D-VRd	VRd
Median (range) stem cell yield, ×10⁶ CD34⁺ cells/kg^a,b	8.2 (3-33)	9.4 (4-29)
Median stem cells transplanted, ×10⁶ CD34⁺ cells/kg^c	4.2	4.8
Patients receiving plerixafor for mobilization, n (%)^d	66 (70)	45 (56)
Patients receiving cyclophosphamide, n (%)^d	5 (5)	4 (5)
Median (max) days to neutrophil engraftment (0.5×10⁹/L)	12 (31)	12 (23)
Median (max) days to platelet engraftment (20×10⁹/L)	13 (31)	12 (23)
Abbreviations: CD34⁺,cluster of differentiation 34 positive; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; max, maximum; VRd, bortezomib + lenalidomide + dexamethasone. ^aAmong patients who underwent peripheral blood stem cell apheresis (D-VRd, n=93; VRd, n=80). ^bOne patient in the D-VRd arm had a stem cell yield <3×10⁶ cells/kg; no patients in either arm had a stem cell yield <2×10⁶ cells/kg. ^cAmong patients receiving transplant (D-VRd, n=94; VRd, n=78). ^dAmong patients who underwent mobilization (D-VRd, n=95; VRd, n=80). Patients underwent stem cell mobilization with G-CSF with or without plerixafor, according to institutional standards; if unsuccessful, cyclophosphamide-based mobilization was permitted.

Safety

In the updated safety and efficacy analysis, any-grade infections occurred in 91% of patients in the D-VRd arm and 62% of patients in the VRd arm, the most common being grade 1/2 upper respiratory tract infections; grade 3/4 infections were seen in 23% of patients in the D-VRd arm vs 22% of patients in the VRd arm.
Pneumonia was reported in 13% of patients in the D-VRd arm and 15% of patients in the VRd arm.
TEAEs are summarized in Table: Most Common TEAEs.

Most Common TEAEs^a,³^,¹⁶

TEAEs, n (%)	D-VRd (n=99)		VRd (n=102)
TEAEs, n (%)	Any-Grade	Grade 3/4	Any-Grade	Grade 3/4
Hematologic
Neutropenia	57 (57.6)	41 (41.4)	36 (35.3)	22 (21.6)
Thrombocytopenia	43 (43.4)	16 (16.2)	36 (35.3)	9 (8.8)
Leukopenia	36 (36.4)	16 (16.2)	29 (28.4)	7 (6.9)
Anemia	35 (35.4)	9 (9.1)	33 (32.4)	6 (5.9)
Lymphopenia	30 (30.3)	23 (23.2)	28 (27.5)	22 (21.6)
Nonhematologic
Fatigue	68 (68.7)	6 (6.1)	62 (60.8)	6 (5.9)
Upper respiratory tract infection	62 (62.6)	1 (1.0)	45 (44.1)	2 (2.0)
Peripheral neuropathy^b	59 (59.6)	7 (7.1)	74 (72.5)	8 (7.8)
Diarrhea	59 (59.6)	7 (7.1)	51 (50.0)	4 (3.9)
Constipation	51 (51.5)	2 (2.0)	40 (39.2)	1 (1.0)
Cough	50 (50.5)	0	27 (26.5)	0
Nausea	49 (49.5)	2 (2.0)	50 (49.0)	1 (1.0)
Pyrexia	45 (45.5)	2 (2.0)	28 (27.5)	3 (2.9)
Insomnia	42 (42.4)	2 (2.0)	31 (30.4)	1 (1.0)
Back pain	36 (36.4)	1 (1.0)	34 (33.3)	4 (3.9)
Edema peripheral	34 (34.3)	2 (2.0)	35 (34.3)	3 (2.9)
Arthralgia	33 (33.3)	0	33 (32.4)	2 (2.0)
IRRs	42 (42.4)	6 (6)^c	-	-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. ^aAny-grade TEAEs are listed that occurred in ≥30% of patients in either arm. The safety analysis population included all randomized patients who received ≥1 dose of study treatment; analysis was according to treatment received. ^bIncludes patients with neuropathy peripheral and peripheral sensory neuropathy. ^cNo grade 4 IRRs were reported.

Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)⁶ reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation.

Results

Patient Characteristics

At the time of the final analysis, all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from the study.
The median duration of follow-up was 49.6 months (interquartile range [IQR], 47.452.1).
By the final analysis, 25% of patients in the D-VRd arm and 51% in the VRd arm discontinued treatment. See Table: Patient Disposition.
The median duration of treatment in the D-VRd and VRd arms was 32.5 months (IQR, 31.133.4) and 27.5 months (IQR, 2.932.7), respectively.
- In the D-VRd arm, among the 90 patients who received DARZALEX and lenalidomide maintenance therapy, 21% (n=19) switched from DARZALEX to DARZALEX FASPRO and received ≥1 cycle of DARZALEX FASPRO (median number, 3.0 [IQR, 3.05.0]).

Patient Disposition⁶

Patients, n	D-VRd (n=104)	VRd (n=103)
Treated with maintenance therapy	90	70
Completed maintenance therapy	74	48
Discontinued treatment during maintenance therapy	16	22
AE	6	7
PD	3	8
Patient withdrawal	2	4
Lost to follow-up	2	0
Death	1	1
Other	2	2
Discontinued treatment by final analysis	26	53
Abbreviations: AE, adverse event; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone.

Efficacy

At the final analysis, among response-evaluable patients in the D-VRd (n=100) vs VRd (n=98) arm, respectively, sCR was achieved in 67% vs 48% of patients (OR, 2.18; 95% CI, 1.223.89; 2-sided P=0.0079) and ≥CR in 83% vs 60% of patients (P=0.0005). Response data over time are summarized in Table: Summary of Response Over Time.⁶^,¹⁸

Summary of Response Over Time⁶

Timepoint, %	D-VRd						VRd
Timepoint, %	sCR	CR	≥CR	VGPR	PR	SD/PD/ NE	sCR	CR	≥CR	VGPR	PR	SD/PD/ NE
End of induction^a	12	7	19	53	26	2	7	6	13	43	35	8
End of post-ASCT consolidation^a	42	9	52	39	8	1	32	10	42	31	19	8
Final analysis^b	67	16	83	13	3	1	48	12	60	17	14	8
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. Rates shown are the number of patients with each type of response divided by the response-evaluable population.^aResponse rates were from the primary analysis cutoff (median follow-up, 13.5 months) and the responseevaluable population comprised 196 patients (D-VRd, n=99; VRd, n=97). ^bResponse rates were also evaluated at the time of the final analysis (median follow-up 49·6 months; IQR 47·452·1), and the response-evaluable population comprised 198 patients (D-VRd, n=100; VRd, n=98).

The response duration among patients in the D-VRd vs VRd arm is presented in Table: Response Survival Duration Among Patients in the D-VRd vs VRd Arm.

Response Duration Among Patients in the D-VRd vs VRd Arm⁶

Parameter	D-VRd	VRd
Median duration to first response (ORR), months (95% CI)	0.8 (0.8-0.8)	0.8 (0.8-1.0)
Median duration to sCR, months (95% CI)	10.2 (8.8-13.0)	14.3 (9.2-21.7)
HR (95% CI)	1.26 (0.86-1.83)
P value	0.2339
Median duration to ≥VGPR, months (95% CI)	2.2 (2.12.7)	3.0 (2.2-6.3)
Median duration to ≥CR, months (95% CI)	8.9 (7.99.4)	9.6 (8.4-12.2)
Median DOR	NR	NR
Estimated 48-month DOR, % (95% CI)	89 (79.994.3)	71 (55.8-81.4)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; DOR, duration of response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reached; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.

Among patients who achieved partial response or better (≥PR), 9% (n/N=9/99) in the D-VRd arm and 18% (n/N=16/90) in the VRd arm subsequently had PD (See Table: Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance).

Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance⁶^,¹⁸

Parameter	D-VRd	VRd	P value
Response,^a n	100	98	-
ORR, n (%)	99 (99)	90 (92)	0.016^b
≥CR	83 (83)	59 (60)	0.0005^b
CR	16 (16)	12 (12)	-
sCR	67 (67)	47 (48)	0.0079^b
≥VGPR	96 (96)	76 (78)	0.0002^b
VGPR	13 (13)	17 (17)	-
PR	3 (3)	14 (14)	-
SD, n (%)	1 (1)	8 (8)	-
PD, n (%)	0	0	-
MRD negative
ITT population, n	104	103	-
10^-5sensitivity, n (%)	67 (64)	31 (30)	<0.0001^c
OR (95% CI)	4.23 (2.35-7.62)
10^-6 sensitivity, n (%)	37 (36)	16 (16)	0.0013^c
OR (95% CI)	2.95 (1.52-5.75)
In patients achieving ≥CR, n	83	59	-
10^-5 sensitivity, n (%)	64 (77)	28 (47)	0.0004^c
10^-6 sensitivity, n (%)	35 (42)	14 (24)	0.031^c
Durable MRD negativity
Lasting ≥12 months, n	104	103	-
10^-5 sensitivity, n (%)	46 (44)	14 (14)	<0.0001^c
OR (95% CI)	5.00 (2.50-9.99)
10^-6 sensitivity, n (%)	10 (10)	4 (4)	0.16^c
OR (95% CI)	2.48 (0.76-8.07)
Abbreviations: CI, confidence interval; CR, complete response; ≥CR, complete response or better; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; MRD, minimal residual disease; NGS, next-generation sequencing; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.The predefined per protocol final analysis occurred after all patients completed ≥1 year of long-term follow-up after the end-of-study treatment, died, or withdrew from study participation, whichever occurred first.^aResponse rate is based on the response-evaluable population, which included randomized patients who had a confirmed diagnosis of MM, had measurable disease at baseline, received ≥1 dose of study treatment, and had ≥1 postbaseline disease assessment. The response-evaluable population for the primary analysis included 99 patients in the D-VRd group and 97 patients in the VRd group.^bP value was calculated using the Cochran-Mantel-Haenszel Chi-square test stratified by ISS disease stage (I, II, or III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.^cP value was calculated using Fisher’s exact test.

By the end of the 2-year maintenance therapy, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and VRd arms, respectively, who were previously MRD positive at the end of the consolidation phase, converted to MRD negative (10^-5). MRD-negativity rates continuously improved over time and were consistently higher in the D-VRd vs VRd arm. See Table: Summary of MRD-Negativity Rates Over Time (ITT Population).

Summary of MRD-Negativity Rates Over Time (ITT Population)^a,⁶^,¹⁸

Timepoint, %	D-VRd		VRd
Timepoint, %	MRD-Negativity (10^-5)	MRD-Negativity (10^-6)	MRD-Negativity (10^-5)	MRD-Negativity (10^-6)
End of induction	22	1	8	0
Post-ASCT consolidation	50	11	20	3
End of study	64	36	30	16
Abbreviations: ASCT, autologous stem cell transplant; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone.^aMRD was evaluated by NGS using the clonoSEQ assay. MRD assessments occurred at the first evidence of suspected CR or sCR, after induction (but before stem cell collection), after consolidation, and after 12 and 24 months of maintenance, regardless of response.

No patient in either treatment arm with sustained MRD-negativity 10^-5 lasting ≥12 months became MRD positive later.
The median time to MRD-negativity in the D-VRd vs VRd arm at sensitivity thresholds of 10^-5 and 10^-6, respectively, was 8.5 vs 34.6 months (HR, 2.70; 95% CI, 1.72-4.23; P<0.0001) and 33.9 months vs NR (HR, 1.93; 95% CI, 1.05-3.54; P=0.031).
Efficacy and survival outcomes are summarized in Table: Efficacy and Survival Outcomes (ITT Population).

Efficacy and Survival Outcomes (ITT Population)⁶^,¹⁸

Parameter	D-VRd	VRd
Median PFS, months	NR	NR
3-year PFS rate, %	89	80.7
4-year PFS rate, %	87.2	70
PFS HR (95% CI); P value	0.45 (0.21-0.95); 0.032
Median PFS in patients who received lenalidomide therapy as per SoC after study completion, months	NR	NR
4-year PFS rate in patients who received SoC lenalidomide therapy after study completion, %	96	80
Median PFS in patients who did not receive lenalidomide therapy as per SoC after study completion, months	NR	NR
4-year PFS rate in patients who did not receive SoC lenalidomide therapy after study completion, %	100	86
Median OS, months	NR	NR
3-year OS rate, %	92.7	92.2
4-year OS rate, %	92.7	92.2
OS HR (95% CI); P value	0.90 (0.31-2.56); 0.84^a
Disease progression or death, n/N (%)	11/104 (11)	18/103 (17)
HR (95% CI)	0.45 (0.21-0.95)
P value	0.032
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; ITT, intention-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival; SoC, standard of care; VRd, bortezomib + lenalidomide + dexamethasone.^aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, and III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.An HR <1 indicates an advantage for D-VRd. P value is based on the log-rank test stratified with ISS staging and baseline CrCl at randomization.

Safety

Among safety-evaluable patients in the D-VRd (n=99) vs VRd (n=102) arms, grade 3/4 TEAEs occurred in 86% (n=85) vs 79% (n=81), respectively.
In the D-VRd vs VRd arm, serious TEAEs occurred in 46% (n=46) vs 52% (n=53) of patients, respectively.
- The most common serious TEAEs included pneumonia (15% vs 14%) and pyrexia (11% vs 10%).
TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33% [n=33]; VRd, 31% [n=32]). One patient in each arm died due to TEAEs unrelated to study treatment.
Any-grade infections were more common in the D-VRd vs VRd arm (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment arms for grade 3/4 infections (D-VRd, 29%; VRd, 26%) and infections leading to treatment discontinuation (D-VRd, 2%; VRd, 3%).
- During maintenance therapy (cycle 7 and onwards) in the DVRd vs VRd arm, any-grade infections occurred in 35% (n/N=31/89) vs 32% (n/N=23/71) of patients and grade 3/4 infections occurred in 18% (n=16) vs 21% (n=15) of patients.
- In the D-VRd vs VRd arm, Coronavirus Disease 2019 (COVID-19) infectioSns were reported in 5% (n=5) vs 2% (n=2) of patients, respectively. Of these, 1 patient in each arm had a grade 3 COVID-19-related event (including 1 serious event in the D-VRd arm).
TEAEs occurring in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.
During maintenance therapy, second primary malignancies with first onset after the start of maintenance therapy were reported in 4% (n/N=4/89) evaluable patients in the DVRd arm and 4% (n/N=3/71) evaluable patients in the VRd arm.
A total of 14 (D-VRd, n=7; VRd, n=7) patients died, of whom 9 (D-VRd, n=5; VRd, n=4) patients died due to PD.
There were 39% (n=39) IRRs reported at the initial infusion, 2% (n=2) IRRs at the second infusion, and 14% (n=14) IRRs at the subsequent infusions.¹⁸

Most Common TEAEs in the Safety Population^a,⁶^,¹⁸

TEAEs, n (%)	D-VRd (n=99)			VRd (n=102)
TEAEs, n (%)	Grade 1/2	Grade 3	Grade 4	Grade 1/2	Grade 3	Grade 4
Hematologic
Anemia	28 (28)	9 (9)	0	27 (26)	5 (5)	1 (1)
Thrombocytopenia	28 (28)	4 (4)	12 (12)	27 (26)	4 (4)	5 (5)
Leukopenia	22 (22)	8 (8)	9 (9)	22 (22)	6 (6)	2 (2)
Neutropenia	17 (17)	32 (32)	14 (14)	18 (18)	21 (21)	2 (2)
Lymphopenia	8 (8)	13 (13)	10 (10)	6 (6)	20 (20)	3 (3)
Nonhematologic
Hypokalemia	24 (24)	3 (3)	1 (1)	24 (24)	3 (3)	0
Hypocalcemia	17 (17)	0	0	12 (12)	2 (2)	1 (1)
Pneumonia^b	11 (11)	11 (11)	1 (1)	4 (4)	14 (14)	0
Hyperkalemia	6 (6)	1 (1)	0	1 (1)	0	1 (1)
Cellulitis	6 (6)	0	1 (1)	3 (3)	1 (1)	0
Hypophosphatemia	5 (5)	9 (9)	1 (1)	6 (6)	11 (11)	0
Hyperuricemia	4 (4)	0	0	6 (6)	0	1 (1)
Acute kidney injury	2 (2)	2 (2)	2 (2)	4 (4)	3 (3)	0
Atrial fibrillation	1 (1)	0	1 (1)	3 (3)	0	0
Increased blood creatine phosphokinase	1 (1)	0	0	0	0	1 (1)
Atrial tachycardia	1 (1)	0	0	0	0	1 (1)
Sepsis	0	1 (1)	2 (2)	0	1 (1)	0
Drug reaction with eosinophilia and systemic symptoms	0	0	0	0	1 (1)	1 (1)
Septic shock	0	0	0	0	0	1 (1)
Cerebrovascular accident	0	0	0	0	0	1 (1)
Systemic inflammatory response syndrome	0	0	0	0	0	1 (1)
Death	0	0	0	0	0	0
IRRs^c	49 (49)	7 (7)	0	-	-	-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. ^aThe maximum intensity for each preferred term is listed, and TEAEs are listed for all grade 4 or 5 events and any grade 3 events occurring in ≥10% of patients in either treatment arm (corresponding grade 1-2 events are listed).^bOne grade 5 event was recorded in the D-VRd group.^cThere were no grade 4/5 IRRs. Data pertaining to IRRs are not available for the VRd arm.

Post Hoc Analysis of Sustained MRD-Negativity

Rodriguez et al (2022)⁷ presented a post hoc analysis of the GRIFFIN study that assessed the sustained MRD-negativity (lasting ≥6 or ≥12 months) in clinically relevant subgroups as well as among patients with ≥CR.

Study Design/Methods

Sustained MRD-negativity (≥2 MRD-negative results in the bone marrow ≥6 or ≥12 months apart without any positive result in between) was evaluated in the ITT population.
This post hoc analysis included all patients who completed 2 years of maintenance therapy or discontinued treatment.

Results

Patient Characteristics

Overall, the ITT population consisted of 104 patients in the D-VRd arm and 103 in the VRd arm.
The baseline characteristics in the ITT population and based on duration of MRD-negativity (10^-5) are summarized in Table: Demographics and Baseline Disease Characteristics Based on Duration of MRD-negativity (10^-5) in the ITT Population.

Demographics and Baseline Disease Characteristics Based on Duration of MRD-Negativity (10^-5) in the ITT Population⁷

Characteristic	D-VRd			VRd
	ITT (n=104)	MRD-Negative (10^-5) Patients		ITT (n=103)	MRD-Negative (10^-5) Patients
	ITT (n=104)	≥6 mo (n=50)	≥12 mo (n=46)	ITT (n=103)	≥6 mo (n=15)	≥12 mo (n=13)
Median age (range), years	59 (29-70)	60 (29-70)	60 (29-70)	61 (40-70)	57 (40-68)	58 (40-68)
<65 years, n (%)	76 (73)	34 (68)	32 (70)	75 (73)	12 (80)	10 (77)
≥65 years, n (%)	28 (27)	16 (32)	14 (30)	28 (27)	3 (20)	3 (23)
Sex, n (%)
Male	58 (56)	26 (52)	24 (52)	60 (58)	8 (53)	7 (54)
Female	46 (44)	24 (48)	22 (48)	43 (42)	7 (47)	6 (46)
Race, n (%)	n=103	n=50	n=46	n=103	n=15	n=13
White	85 (83)	43 (86)	39 (85)	76 (74)	13 (87)	11 (85)
Black or African American	14 (14)	6 (12)	6 (13)	18 (17)	1 (7)	1 (8)
Asian	0	0	0	2 (2)	0	0
Other/multiple/unknown	4 (4)	1 (2)	1 (2)	7 (7)	1 (7)	1 (8)
ECOG PS, n (%)^a	n=101	n=50	n=46	n=102	n=15	n=13
0	39 (39)	20 (40)	20 (43)	40 (39)	5 (33)	5 (38)
1	51 (50)	23 (46)	19 (41)	52 (51)	8 (53)	6 (46)
2	11 (11)	7 (14)	7 (15)	10 (10)	2 (13)	2 (15)
ISS disease stage, n (%)^b
I	49 (47)	23 (46)	20 (43)	50 (49)	5 (33)	3 (23)
II	40 (38)	20 (40)	20 (43)	37 (36)	8 (53)	8 (62)
III	14 (13)	7 (14)	6 (13)	14 (14)	2 (13)	2 (15)
Missing	1 (1)	0	0	2 (2)	0	0
Cytogenetic profile, n (%)^c	n=98	n=48	n=45	n=97	n=15	n=13
Standard risk	82 (84)	44 (92)	42 (93)	83 (86)	13 (87)	11 (85)
High risk	16 (16)	4 (8)	3 (7)	14 (14)	2 (13)	2 (15)
Revised cytogenetic profile, n (%)^c	n=98	n=48	n=45	n=97	n=15	n=13
Standard risk	56 (57)	33 (69)	31 (69)	60 (62)	8 (53)	7 (54)
High risk	42 (43)	15 (31)	14 (31)	37 (38)	7 (47)	6 (46)
gain 1q	34 (35)	14 (29)	13 (29)	28 (29)	5 (33)	4 (31)
t(14;20)	1 (1)	0	0	1 (1)	0	0
Abbreviations: del, deletion; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; mo, months; MRD, minimal residual disease; t, translocation; VRd, bortezomib + lenalidomide + dexamethasone. ^aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. ^bISS disease stage is based on the combination of serum β₂-microglobulin and albumin levels. Higher stages indicate more advanced disease. ^cCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data, while revised high risk was defined as the presence of del17p, t(4;14), t(14;16), t(14;20), or gain 1q (≥3 copies of chromosome 1q21) among those patients.

Sustained MRD-Negativity

Sustained MRD-negativity rates lasting ≥6 months were higher with D-VRd vs VRd among all clinically relevant subgroups, patients who achieved ≥CR and sCR at a sensitivity threshold of 10^-5,and most of the high-risk subgroups at a sensitivity threshold of 10^-6; see Table: Subgroup Analysis of Rates of Sustained MRD-Negativity Lasting ≥6 Months at the 10^-5 or 10^-6 Sensitivity Thresholds.
Similarly, sustained MRD-negativity rates lasting ≥12 months were higher with D-VRd vs VRd among all subgroups at a sensitivity threshold of 10^-5and most subgroups (except for the revised high cytogenetic risk group, including gain 1q) at a sensitivity threshold of 10^-6; see Table: Subgroup Analysis of Rates of Sustained MRD-Negativity Lasting ≥12 Months at the 10^-5 or 10^-6 Sensitivity Thresholds.

Subgroup Analysis of Rates of Sustained MRD-Negativity Lasting ≥6 Months at the 10^-5 or 10^-6 Sensitivity Thresholds⁷

Parameter	MRD-Negativity Lasting ≥6 Months, n/N (%)
	Sensitivity Threshold of 10^-5		Sensitivity Threshold of 10^-6
	D-VRd	VRd	D-VRd	VRd
ITT (overall)	50/104 (48.1)	15/103 (14.6)	17/104 (16.3)	5/103 (4.9)
OR (95% CI)	5.18 (2.64-10.17)		3.66 (1.30-10.32)
Age
<65 years	34/76 (44.7)	12/75 (16.0)	11/76 (14.5)	3/75 (4.0)
OR (95% CI)	4.25 (1.98-9.14)		4.06 (1.09-15.20)
≥65 years	16/28 (57.1)	3/28 (10.7)	6/28 (21.4)	2/28 (7.1)
OR (95% CI)	11.11 (2.71-45.61)		3.55 (0.65-19.37)
ISS disease stage
I	23/49 (46.9)	5/50 (10.0)	6/49 (12.2)	1/50 (2.0)
OR (95% CI)	7.96 (2.70-23.47)		6.84 (0.79-59.06)
II	20/40 (50.0)	8/37 (21.6)	9/40 (22.5)	2/37 (5.4)
OR (95% CI)	3.63 (1.34-9.84)		5.08 (1.02-25.33)
III	7/14 (50.0)	2/14 (14.3)	2/14 (14.3)	2/14 (14.3)
OR (95% CI)	6.00 (0.97-37.30)		1.00 (0.12-8.31)
Cytogenetic risk^a
High	4/16 (25.0)	2/14 (14.3)	0/16	0/14
OR (95% CI)	2.00 (0.31-13.06)		NE (NE-NE)
Standard	44/82 (53.7)	13/83 (15.7)	17/82 (20.7)	5/83 (6.0)
OR (95% CI)	6.23 (2.99-12.99)		4.08 (1.43-11.66)
Revised cytogenetic risk^a
High	15/42 (35.7)	7/37 (18.9)	5/42 (11.9)	3/37 (8.1)
OR (95% CI)	2.38 (0.84-6.72)		1.53 (0.34-6.90)
Standard	33/56 (58.9)	8/60 (13.3)	12/56 (21.4)	2/60 (3.3)
OR (95% CI)	9.33 (3.73-23.29)		7.91 (1.68-37.17)
Gain 1q^a	14/34 (41.2)	5/28 (17.9)	5/34 (14.7)	3/28 (10.7)
OR (95% CI)	3.22 (0.99-10.52)		1.44 (0.31-6.62)
≥CR	48/82 (58.5)	14/59 (23.7)	17/82 (20.7)	5/59 (8.5)
OR (95% CI)	4.54 (2.16-9.54)		2.82 (0.98-8.16)
sCR	43/66 (65.2)	10/46 (21.7)	16/66 (24.2)	5/46 (10.9)
OR (95% CI)	6.73 (2.84-15.98)		2.62 (0.89-7.77)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; del, deletion; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; sCR, stringent complete response; t, translocation; VRd, bortezomib + lenalidomide + dexamethasone. ^aCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data, while revised high risk was defined as the presence of del17p, t(4;14), t(14;16), t(14;20), or gain 1q (≥3 copies of chromosome 1q21) among those patients.

Subgroup Analysis of Rates of Sustained MRD-Negativity Lasting ≥12 Months at the 10^-5 or 10^-6 Sensitivity Thresholds⁷

Parameter	MRD-Negativity Lasting ≥12 Months, n/N (%)
	Sensitivity Threshold of 10^-5		Sensitivity Threshold of 10^-6
	D-VRd	VRd	D-VRd	VRd
ITT (overall)	46/104 (44.2)	13/103 (12.6)	10/104 (9.6)	4/103 (3.9)
OR (95% CI)	5.46 (2.68-11.10)		2.48 (0.76-8.07)
Age
<65 years	32/76 (42.1)	10/75 (13.3)	7/76 (9.2)	2/75 (2.7)
OR (95% CI)	4.73 (2.11-10.59)		3.70 (0.74-18.44)
≥65 years	14/28 (50.0)	3/28 (10.7)	3/28 (10.7)	2/28 (7.1)
OR (95% CI)	8.33 (2.04-34.07)		1.56 (0.24-10.14)
ISS disease stage
I	20/49 (40.8)	3/50 (6.0)	4/49 (8.2)	0/50
OR (95% CI)	10.80 (2.95-39.60)		NE (NE-NE)
II	20/40 (50.0)	8/37 (21.6)	6/40 (15.0)	2/37 (5.4)
OR (95% CI)	3.63 (1.34-9.84)		3.09 (0.58-16.38)
III	6/14 (42.9)	2/14 (14.3)	0/14	2/14 (14.3)
OR (95% CI)	4.50 (0.72-28.15)		NE (NE-NE)
Cytogenetic risk^a
High	3/16 (18.8)	2/14 (14.3)	0/16	0/14
OR (95% CI)	1.38 (0.20-9.77)		NE (NE-NE)
Standard	42/82 (51.2)	11/83 (13.3)	10/82 (12.2)	4/83 (4.8)
OR (95% CI)	6.87 (3.19-14.82)		2.74 (0.82-9.13)
Revised cytogenetic risk^a
High	14/42 (33.3)	6/37 (16.2)	1/42 (2.4)	2/37 (5.4)
OR (95% CI)	2.58 (0.87-7.64)		0.43 (0.04-4.91)
Standard	31/56 (55.4)	7/60 (11.7)	9/56 (16.1)	2/60 (3.3)
OR (95% CI)	9.39 (3.64-24.23)		5.55 (1.14-26.95)
Gain 1q^a	13/34 (38.2)	4/28 (14.3)	1/34 (2.9)	2/28 (7.1)
OR (95% CI)	3.71 (1.05-13.15)		0.39 (0.03-4.59)
≥CR	44/82 (53.7)	12/59 (20.3)	10/82 (12.2)	4/59 (6.8)
OR (95% CI)	4.54 (2.10-9.78)		1.91 (0.57-6.41)
sCR	39/66 (59.1)	8/46 (17.4)	9/66 (13.6)	4/46 (8.7)
OR (95% CI)	6.86 (2.77-16.99)		1.66 (0.48-5.75)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; del, deletion; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; sCR, stringent complete response; t, translocation; VRd, bortezomib + lenalidomide + dexamethasone. ^aCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data,while revised high risk was defined as the presence of del17p, t(4;14), t(14;16), t(14;20), or gain 1q (≥3 copies of chromosome 1q21) among those patients.

PFS by Sustained MRD-Negativity

Median PFS by MRD-negativity (at sensitivity thresholds of 10^-5 and 10^-6) lasting for ≥6 or ≥12 months was NR in any arm.
- Among patients who achieved durable MRD-negativity at a sensitivity threshold of 10^-5, PFS was consistently better in the D-VRd vs VRd arm.
PFS was improved in all arms who achieved sustained MRD-negativity lasting ≥6 or ≥12 months compared with patients who did not achieve sustained MRD-negativity, underlying the importance of achieving this surrogate endpoint.
Among all patients with sustained MRD-negativity, 1 patient in the D-VRd arm had subsequent disease progression, and 1 patient in the VRd arm died (cause unknown). Both these patients had high cytogenic risk at baseline.

Subgroup Analysis of the GRIFFIN Study in Black vs White Patients

Nooka et al (2020)¹⁹ presented a subgroup analysis from the randomized portion of the GRIFFIN study, evaluating the differences in safety and efficacy of D-VRd vs VRd for Black and White patients at a median follow-up of 22.1 months. Nooka et al (2022) reported 2 updated results in this subgroup analysis at the median follow-up of 27.4 months²⁰ and 38.6 months²¹.The results presented by Nooka et al (2024)⁸ regarding the updated post hoc analysis categorized by race during the final analysis in the general population, with approximately ~2 years of additional follow-up at a median follow-up duration of 49.6 months, are outlined as follows:

Study Design/Methods

The study design is consistent with the randomized portion of the GRIFFIN Study Design/Methods.
This analysis was conducted at the time of final analysis, with an additional ~2-year follow-up.
Patients self-reported race and ethnicity.

Results

Patient Characteristics

Of the 207 randomized patients included in the study, 15.5% were Black (D-VRd, n=14; VRd, n=18), 77.8% were White (D-VRd, n=85; VRd, n=76), 1% were Asian (VRd, n=2), 1.5% reported “other” race (D-VRd, n=2; VRd, n=1), 0.5% reported multiple races (VRd, n=1), and 3.4% reported unknown race (D-VRd, n=2; VRd, n=5).
- Additionally, 7.2% were Hispanic or Latino (D-VRd, n=9; VRd, n=6), 89.4% were non-Hispanic or Latino (D-VRd, n=92; VRd, n=93), and 3.4% did not know or did not report ethnicity (D-VRd, n=3; VRd, n=4).
The median duration of follow-up was 49.6 months.
The baseline patient and disease characteristics are presented in Table: Baseline Patient and Disease Characteristics According to Race.
Treatment exposure and duration have been summarized in Table: Summary of Treatment Duration and Exposure According to Race.

Baseline Patient and Disease Characteristics According to Race^a,²²

Characteristic	Black		White
Characteristic	D-VRd (n=14)	VRd (n=18)	D-VRd (n=85)	VRd (n=76)
Median age (range), years	58.5 (29-67)	57.0 (48-67)	59.0 (35-70)	61.5 (41-70)
Sex, n (%)
Male	5 (35.7)	8 (44.4)	52 (61.2)	46 (60.5)
Female	9 (64.3)	10 (55.6)	33 (38.8)	30 (39.5)
Median weight (range), kg	82.6 (66.0-147.5)	93.8 (57.0-123.8)	78.4 (48.8-158.6)	82.4 (37.4-150.1)
Median height (range), cm	168.3 (152.0-190.5)	168.9 (154.9-190.0)	171.3 (152.4-203.2)	173.0 (150.6-200.0)
BMI
Median (range), kg/m²	30.7 (23.5-40.6)	31.4 (23.8-43.8)	26.5 (19.7-41.4)	27.3 (15.8-45.0)
≥30 kg/m², n (%)	7 (50.0)	11 (61.1)	29 (34.1)	20 (26.3)
Comorbidities
Median (range) number of comorbidities^b	7.0 (3-13)	5.5 (1-38)	7.0 (1-24)	7.0 (1-27)
Diabetes mellitus, n (%)	3 (21.4)	4 (22.2)	9 (10.6)	7 (9.2)
Pre-existing neuropathies, n (%)^c	4 (28.6)	3 (16.7)	4 (4.7)	12 (15.8)
ECOG PS score, n (%)^d	n=13	n=18	n=84	n=75
0	6 (46.2)	7 (38.9)	32 (38.1)	30 (40.0)
1	6 (46.2)	10 (55.6)	42 (50.0)	37 (49.3)
2	1 (7.7)	1 (5.6)	10 (11.9)	8 (10.7)
Type of myeloma, n (%)^e	n=13	n=18	n=82	n=74
IgG	8 (61.5)	11 (61.1)	46 (56.1)	40 (54.1)
IgA	1 (7.7)	2 (11.1)	17 (20.7)	16 (21.6)
IgD	0	0	1 (1.2)	1 (1.4)
IgM	0	0	1 (1.2)	0
Light chain	3 (23.1)	4 (22.2)	17 (20.7)	14 (18.9)
Biclonal	1 (7.7)	1 (5.6)	0	3 (4.1)
ISS disease stage, n (%)^f
I	9 (64.3)	11 (61.1)	40 (47.1)	37 (48.7)
II	3 (21.4)	4 (22.2)	32 (37.6)	27 (35.5)
III	2 (14.3)	3 (16.7)	12 (14.1)	10 (13.2)
Missing	0	0	1 (1.2)	2 (2.6)
Cytogenetic risk, n (%)^g	n=14	n=16	n=80	n=73
Standard risk	11 (78.6)	14 (87.5)	68 (85.0)	63 (86.3)
High risk	3 (21.4)	2 (12.5)	12 (15.0)	10 (13.7)
del(17p)	2 (14.3)	0	6 (7.5)	6 (8.2)
t(4;14)	1 (7.1)	2 (12.5)	6 (7.5)	3 (4.1)
t(14;16)	0	0	1 (1.3)	2 (2.7)
Revised cytogenetic risk, n (%)^h	n=14	n=16	n=80	n=73
Standard risk (0 HRCAs)	10 (71.4)	9 (56.3)	44 (55.0)	46 (63.0)
High risk	4 (28.6)	7 (43.8)	36 (45.0)	27 (37.0)
gain/amp(1q21)	2 (14.3)	4 (25.0)	30 (37.5)	23 (31.5)
t(14;20)	0	1 (6.3)	1 (1.3)	0
1 HRCA	3 (21.4)	6 (37.5)	28 (35.0)	20 (27.4)
≥2 HRCAs	1 (7.1)	1 (6.3)	8 (10.0)	7 (9.6)
Abbreviations: BMI, body mass index; D-VRd, DARZALEX + lenalidomide + bortezomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; Ig, immunoglobulin; ISS, International Staging System; VRd, lenalidomide + bortezomib + dexamethasone. ^aDemographic and clinical characteristics were taken from electronic case report forms completed by study sites.^bMedian (range) number of comorbidities was calculated from data of patients with medical histories available in which comorbidities were reported, which included 32 Black patients (D-VRd, n=14; VRd, n=18) and 153 White patients (DVRd, n=81; VRd, n=72). A value of “0” was not automatically applied in the event a medical history did not report the presence of a comorbidity. ^cNeuropathies included peripheral sensory neuropathy, neuralgia, peripheral neuropathy, and/or diabetic neuropathy. ^dECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. ^eType of myeloma by immunofixation or serum free light-chain assay. ^fISS disease stage is based on the combination of serum β₂-microglobulin and albumin levels. Higher stages indicate more advanced disease. ^gCytogenetic risk was assessed by FISH (local testing); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) among patients with available cytogenetic risk data. ^hRevised cytogenetic risk was assessed by FISH testing; revised high risk was defined as ≥1 of the following: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).

Summary of Treatment Duration and Exposure According to Race^a,²²

Parameter	Black		White
Parameter	D-VRd (n=14)	VRd (n=18)	D-VRd (n=83)	VRd (n=74)
Median duration of therapy (range), months	32.3 (19.4-36.9)	26.5 (2.6-35.3)	32.5 (1.1-37.7)	31.1 (0.5-36.3)
Median dose intensity (range)
D (mg/kg/cycle)^b	20.3 (19.4-22.7)	-	20.3 (18.9-48.5)	-
R (mg/cycle)^c	245.5 (136.6-311.7)	253.6 (102.2-350.0)	245.0 (71.7-350.0)	274.2 (85.5-350.0)
V (mg/m²/cycle)^d	4.8 (3.1-5.1)	4.8 (3.6-5.3)	5.0 (2.8-5.4)	4.8 (2.5-5.4)
d (mg/cycle)^e	38.4 (33.4-73.3)	114.2 (40.0-120.0)	36.8 (26.6-113.3)	111.7 (44.5-120.0)
Cycle delays, n (%)	9 (64.3)	10 (55.6)	52 (62.7)	34 (45.9)
D	9 (64.3)	-	50 (60.2)	-
R	7 (50.0)	9 (50.0)	43 (51.8)	34 (45.9)
V	1 (7.1)	5 (27.8)	16 (19.3)	14 (18.9)
d	8 (57.1)	5 (27.8)	38 (45.8)	17 (23.0)
Dose adjusted, n (%)
D	9 (64.3)	-	39 (47.0)	-
R	7 (50.0)	11 (61.1)	43 (51.8)	32 (43.2)
V	4 (28.6)	6 (33.3)	17 (20.5)	14 (18.9)
d	1 (7.1)	1 (5.6)	9 (10.8)	12 (16.2)
Abbreviations: D, DARZALEX; d, dexamethasone; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; R, lenalidomide; V, bortezomib; VRd, bortezomib + lenalidomide + dexamethasone. ^aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment. ^bDose intensity (mg/kg/cycle) was calculated as the sum of total doses (mg/kg) received in all cycles divided by the number of treatment cycles on D. ^cDose intensity (mg/cycle) was calculated as the sum of total doses (mg) received in all cycles divided by the number of treatment cycles on R. ^dDose intensity (mg/m²/cycle) was calculated as the sum of total doses (mg/m²) received in all cycles divided by the number of treatment cycles on V. ^eDose intensity (mg/cycle) was calculated as the sum of total doses (mg) received in all cycles divided by the number of treatment cycles on d.

Efficacy

Among Black vs White patients, efficacy response rates were evaluable in 32 vs 155, and MRD-negativity was evaluable in 32 vs 161. The efficacy outcomes are summarized in Table: Response, MRD, and Survival Outcomes According to Race.
D-VRd reduced the risk of disease progression or death compared with VRd by 55% (HR, 0.45; 95% CI, 0.21-0.95) in the overall population.
- The risk of disease progression or death was reduced by 61% in Black patients (HR, 0.39; 95% CI, 0.07-2.24; P=0.2767) vs 53% in White patients (HR, 0.47; 95% CI, 0.19-1.18; P=0.1003) in the D-VRd vs VRd arm.

Response, MRD, and Survival Outcomes According to Race^a, ⁸^,²²

Parameter	Black		White
Parameter	D-VRd	VRd	D-VRd	VRd
Response evaluable population, n	14	18	83	72
≥CR, n (%)	14 (100)	10 (55.6)	67 (80.7)	44 (61.1)
OR (95% CI)	NE (NE-NE)		2.66 (1.29-5.49)
sCR, n (%)	13 (92.9)	7 (38.9)	54 (65.1)	36 (50.0)
OR (95% CI)	20.43 (2.17-192.64)		1.86 (0.98-3.55)
≥VGPR, n (%)	14 (100)	16 (88.9)	79 (95.2)	53 (73.6)
OR (95% CI)	NE (NE-NE)		7.08 (2.28-21.98)
PR, %	-	5.6	3.6	18.1
SD/PD/NE, %	-	5.6	1.2	8.3
MRD-evaluable population^b, n	14	18	85	76
MRD at 10^-5 threshold, n (%)	9 (64.3)	4 (22.2)	56 (65.9)	24 (31.6)
OR (95% CI)	6.30 (1.33-29.94)		4.18 (2.16-8.09)
MRD at 10^-6 threshold, n (%)	4 (28.6)	2 (11.1)	33 (38.8)	11 (14.5)
OR (95% CI)	3.20 (0.49-20.81)		3.75 (1.73-8.13)
Estimated 48-month PFS rate, %	79.1	64.6	89.4	74.2
Abbreviations: CI, confidence interval; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; NE, not evaluable; NGS, next-generation sequencing; OR, odds ratio; PD, progressive disease; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aPercentages may not add to 100 due to rounding. ^bThe threshold of MRD negativity was defined as 1 tumor cell per 10⁵ or per 10⁶ white cells. MRD status is based on the assessment of bone marrow aspirates by NGS in accordance with International Myeloma Working Group criteria. Bone marrow aspirates were assessed at baseline, at first evidence of suspected CR or sCR (including patients with ≥VGPR and suspected daratumumab interference), at the end of induction and consolidation, and after 1 and 2 years (±3 weeks) of maintenance, regardless of response.

Safety

TEAEs are summarized in Table: Most common (≥30%) TEAEs in Black or White patients.
The most common serious TEAE was pneumonia in both Black (D-VRd, 21.4%; VRd, 16.7%) and White patients (D-VRd, 13.3%; VRd, 14.9%).
Study treatment was discontinued among Black (D-VRd, 28.6% [n=4]; VRd, 61.1% [n=11]) and White patients (D-VRd, 22.4% [n=19]; VRd, 47.4% [n=36]).
- Primary reasons for treatment discontinuation were progressive disease (Black: DVRd, 0% [n=0]; VRd, 22.2% [n=4]; White: 8.2% [n=7]; 11.8% [n=9]) and adverse events (Black: DVRd, 14.3% [n=2]; VRd, 11.1% [n=2]; White: DVRd, 5.9% [n=5]; VRd, 13.2% [n=10]).
TEAEs that led to study treatment discontinuation of ≥1 component of study combination therapy occurred in 64.3% vs 38.9% of Black and 28.9% vs 25.7% of White patients in the D-VRd vs VRd arm. Summary of TEAEs leading to study treatment discontinuation according to race is presented in Table: Summary of TEAEs Leading to Discontinuation of Study Treatment According to Race Occurring in ≥2 Patients in Any Treatment Group or Those Attributed to Neuropathy-Related Events.
No deaths were reported in Black patients during the whole duration of the study (treatment period and post-treatment observation combined); 12 deaths were reported in White patients (D-VRd, n=6; VRd, n=6) due to PD (D-VRd, n=4; VRd, n=4) and AEs (D-VRd, n=2 [1 event occurred outside the reporting interval, which was >30 days after the last dose of study treatment]; VRd, n=2 [both events occurred outside the reporting interval]).
No deaths due to TEAEs were reported among Black patients in either arm, and 1 death due to pneumonia was reported among White patients in the D-VRd arm.

Most common (≥30%) TEAEs in Black or White patients^a,⁸

Adverse Event, n (%)	Black				White
	D-VRd (n=14)		VRd (n=18)		D-VRd (n=83)		VRd (n=74)
	Any Grade	Grade 3/4	Any Grade	Grade 3/4	Any Grade	Grade 3/4	Any Grade	Grade 3/4
Hematologic
Neutropenia	8 (57.1)	7 (50.0)	6 (33.3)	4 (22.2)	54 (65.1)	39 (47.0)	26 (35.1)	13 (17.6)
Anemia	8 (57.1)	2 (14.3)	7 (38.9)	3 (16.7)	29 (34.9)	7 (8.4)	22 (29.7)	3 (4.1)
Thrombocytopenia	6 (42.9)	4 (28.6)	7 (38.9)	2 (11.1)	38 (45.8)	12 (14.5)	26 (35.1)	6 (8.1)
Leukopenia	6 (42.9)	3 (21.4)	8 (44.4)	1 (5.6)	32 (38.6)	14 (16.9)	17 (23.0)	4 (5.4)
Lymphopenia	5 (35.7)	4 (28.6)	9 (50.0)	7 (38.9)	26 (31.3)	19 (22.9)	16 (21.6)	12 (16.2)
Nonhematologic
Upper respiratory tract infection	11 (78.6)	0	9 (50.0)	0	55 (66.3)	4 (4.8)	38 (51.4)	2 (2.7)
Constipation	9 (64.3)	0	7 (38.9)	0	40 (48.2)	2 (2.4)	28 (37.8)	1 (1.4)
Peripheral oedema	9 (64.3)	0	9 (50.0)	0	27 (32.5)	2 (2.4)	27 (36.5)	3 (4.1)
Peripheral neuropathy/peripheral sensory neuropathy	8 (57.1)	1 (7.1)	12 (66.7)	1 (5.6)	53 (63.9)	5 (6.0)	58 (78.4)	6 (8.1)
Nausea	8 (57.1)	1 (7.1)	9 (50.0)	1 (5.6)	42 (50.6)	1 (1.2)	37 (50.0)	0
Fatigue	8 (57.1)	1 (7.1)	8 (44.4)	0	61 (73.5)	6 (7.2)	45 (60.8)	5 (6.8)
Headache	7 (50.0)	0	2 (11.1)	0	26 (31.3)	5 (6.0)	17 (23.0)	1 (1.4)
Vomiting	7 (50.0)	1 (7.1)	5 (27.8)	0	25 (30.1)	2 (2.4)	21 (28.4)	0
Arthralgia	7 (50.0)	1 (7.1)	5 (27.8)	0	31 (37.3)	0	28 (37.8)	2 (2.7)
Cough	7 (50.0)	0	5 (27.8)	0	45 (54.2)	0	21 (28.4)	0
Insomnia	7 (50.0)	0	2 (11.1)	0	37 (44.6)	2 (2.4)	26 (35.1)	1 (1.4)
Rash maculopapular	6 (42.9)	1 (7.1)	2 (11.1)	0	18 (21.7)	2 (2.4)	19 (25.7)	2 (2.7)
Pyrexia	6 (42.9)	0	3 (16.7)	0	41 (49.4)	3 (3.6)	26 (35.1)	2 (2.7)
Diarrhea	6 (42.9)	0	6 (33.3)	0	59 (71.1)	7 (8.4)	46 (62.2)	4 (5.4)
Decreased appetite	6 (42.9)	0	2 (11.1)	0	18 (21.7)	0	8 (10.8)	0
Back pain	5 (35.7)	0	9 (50.0)	0	35 (42.2)	2 (2.4)	22 (29.7)	3 (4.1)
Pain in extremity	5 (35.7)	0	7 (38.9)	0	17 (20.5)	1 (1.2)	15 (20.3)	0
Myalgia	5 (35.7)	0	4 (22.2)	0	21 (25.3)	0	15 (20.3)	2 (2.7)
Hypokalemia	5 (35.7)	0	6 (33.3)	1 (5.6)	23 (27.7)	4 (4.8)	16 (21.6)	2 (2.7)
Dizziness	4 (28.6)	0	7 (38.9)	0	19 (22.9)	0	15 (20.3)	0
Dysgeusia	4 (28.6)	0	6 (33.3)	0	19 (22.9)	0	12 (16.2)	0
Dyspnea	3 (21.4)	0	6 (33.3)	2 (11.1)	21 (25.3)	2 (2.4)	21 (28.4)	2 (2.7)
Hyperglycemia	1 (7.1)	0	6 (33.3)	0	11 (13.3)	2 (2.4)	11 (14.9)	1 (1.4)
Muscle spasms	3 (21.4)	0	2 (11.1)	0	26 (31.3)	2 (2.4)	15 (20.3)	1 (1.4)
Abbreviations: D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, lenalidomide + bortezomib + dexamethasone.^aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.^bIRRs (not shown in table) occurred in 28.6% of Black patients and 53.0% of White patients who received D-VRd; 1 (7.1%) Black patient and 6 (7.2%) White patients had grade 3 IRRs (none were grade 4 or 5).

Summary of TEAEs Leading to Discontinuation of Study Treatment According to Race Occurring in ≥2 Patients in Any Treatment Group or Those Attributed to Neuropathy-Related Events^a^,^b^,²²

Black
	D-VRd (n=14)					VRd (n=18)
	Discontinuation of					Discontinuation of
	Any Study Treatment	D	R	V	d	Any Study Treatment	R	V	d
Patients with TEAEs leading to study treatment discontinuation, n (%)	9 (64.3)	1 (7.1)	2 (14.3)	8 (57.1)	1 (7.1)	7 (38.9)	2 (11.1)	5 (27.8)	1 (5.6)
Occurring in ≥2 patients or attributable to neuropathy-related events
Peripheral sensory neuropathy	3 (21.4)	0	0	3 (21.4)	0	4 (22.2)	0	4 (22.2)	0
Neuralgia	2 (14.3)	0	0	2 (14.3)	0	1 (5.6)	1 (5.6)	0	0
Hypoesthesia	1 (7.1)	0	0	1 (7.1)	0	0	0	0	0
Peripheral neuropathy	1 (7.1)	0	1 (7.1)	1 (7.1)	0	0	0	0	0
Paresthesia	0	0	0	0	0	1 (5.6)	0	1 (5.6)	0
White
	D-VRd (n=83)					VRd (n=74)
	Discontinuation of					Discontinuation of
	Any study treatment	D	R	V	d	Any study treatment	R	V	d
Patients with TEAEs leading to study treatment discontinuation, n (%)	24 (28.9)	5 (6.0)	12 (14.5)	15 (18.1)	7 (8.4)	19 (25.7)	11 (14.9)	12 (16.2)	9 (12.2)
Occurring in ≥2 patients or attributable to neuropathy-related events
Peripheral sensory neuropathy	8 (9.6)	0	0	8 (9.6)	0	3 (4.1)	1 (1.4)	3 (4.1)	1 (1.4)
Neuralgia	2 (2.4)	0	0	2 (2.4)	0	2 (2.7)	0	2 (2.7)	0
Neutropenia	2 (2.4)	0	2 (2.4)	0	0	0	0	0	0
Rash	2 (2.4)	0	2 (2.4)	0	0	0	0	0	0
Peripheral neuropathy	1 (1.2)	0	0	1 (1.2)	0	4 (5.4)	2 (2.7)	3 (4.1)	2 (2.7)
Fall	0	0	0	0	0	1 (1.4)	0	1 (1.4)	0
Abbreviations: D, daratumumab; d, dexamethasone; D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; R, lenalidomide; TEAE, treatment-emergent adverse event; V, bortezomib; VRd, lenalidomide + bortezomib + dexamethasone.^aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment. ^bNeuropathy-related events included peripheral sensory neuropathy, neuralgia, paresthesia, peripheral neuropathy, hypoesthesia, and/or falls.

Final Analysis in Clinically Relevant Subgroups

Chari et al (2024)⁹^,²³ reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study (median follow-up, 49.6 months).

Study Design/Methods

This final analysis was conducted after all patients completed ≥1 year of follow-up after concluding study treatment, died, or withdrew.

Results

Efficacy

MRD-negativity (10^-5) rates favored the D-VRd vs VRd arm across all subgroups at the time of final analysis. See Table: Final Analysis of MRD-negativity (10^-5) Rates by the End of the GRIFFIN Study.
A final analysis of sCR rates were higher for D-VRd vs VRd for most subgroups. See Table: Final Analysis of sCR by the End of the GRIFFIN Study.
MRD-negativity (10^-5) rates favored the D-VRd vs VRd arm across all subgroups among patients who achieved a best response ≥CR by the end of the study. See Table: Final Analysis of MRD-negativity (10^-5) Rates Among Patients with a Best Response of ≥CR by the End of the GRIFFIN Study.
D-VRd was associated with higher rates of sustained MRD-negativity (10^-5) lasting ≥12 months across all subgroups. See Table: Final Analysis of Rates of Sustained MRD-negativity (10^-5) lasting ≥12 months.
- No patients who achieved sustained MRD-negativity (10^-5) lasting ≥12 months developed PD.
Among MRD-evaluable patients who achieved MRD-negativity (10^-5) at any time, 2 (both with ≥2 HRCAs) patients in the D-VRd arm and 5 (0 HRCA, n=2; 1 HRCA, n=3) patients in the VRd arm developed PD.
- Two patients from the D-VRd arm and 3 patients from the VRd arm, who initially achieved MRD-negativity, developed PD after they became MRD positive again. The remaining 2 patients from the VRd arm developed PD while they continued to be MRD negative; however, MRD was not evaluated around the time of PD.
At a median follow-up of 49.6 months, the HR point estimates for PFS among all subgroups with cytogenetic abnormalities favored the D-VRd vs VRd arm, except for patients with ≥2 HRCAs. See Table: Final Analysis of PFS in the GRIFFIN Study.
- Median PFS was not reached for either treatment group among patients with 0 HRCA, and the PFS HR was 0.39 (95% CI, 0.10-1.51) for D-VRd vs VRd.
- Median PFS was not reached for D-VRd and was 47.9 months for VRd among patients with 1 HRCA, and the PFS HR was 0.19 (95% CI, 0.05-0.75) for D-VRd vs VRd.
- Median PFS was 33.9 months for D-VRd and was not reached for VRd among patients with ≥2 HRCAs, (HR, 1.65; 95% CI, 0.30-9.18).
- PFS was not reached for D-VRd and was 47.9 months for VRd among patients with gain/amp(1q21), with or without HRCAs, and the PFS HR was 0.42 (95% CI, 0.14-1.27) for D-VRd vs VRd.
Within the functionally high-risk subgroup of patients with a best response of <VGPR by the end of induction, more D-VRd vs VRd patients had revised high cytogenetic risk and 1 HRCA at baseline, and similar proportions had ≥2 HRCAs.
- Revised high risk: 48.3% (n=14/29) vs 32.6% (n=14/43), D-VRd vs VRd respectively.
- 1 HRCA: 37.9% (n=11/29) vs 23.3% (n=10/43), D-VRd vs VRd respectively.
- ≥2 HRCAs: 10.3% (n=3/29) vs 9.3% (n=4/43), D-VRD vs VRd respectively.
Among patients who did not achieve MRD-negativity (10^-5)by the end of consolidation, the proportion of patients with revised high cytogenetic risk, 1 HRCA, and ≥2 HRCAs was higher for D-VRd vs VRd at baseline.
- Revised high risk: 52.1% (n=25/48) vs 34.2% (n=26/76), D-VRd vs VRd respectively.
- 1 HRCA: 39.6% (n=19/48) vs 25.0% (n=19/76), D-VRd vs VRd respectively.
- ≥2 HRCAs: 12.5% (n=6/48) vs 9.2% (n=7/76), D-VRd vs VRd respectively.

Final Analysis of MRD-negativity (10^-5) Rates by the End of the GRIFFIN Study⁹

Subgroup	D-VRd, n/N (%)	VRd, n/N (%)	OR (95% CI)^a
ITT (overall)	67/104 (64.4)	31/103 (30.1)	4.23 (2.35-7.62)
Baseline characteristic
Age ≥65 years	19/28 (67.9)	5/28 (17.9)	9.71 (2.78-33.92)
ISS stage III disease	10/14 (71.4)	5/14 (35.7)	4.50 (0.91-22.15)
Cytogenetic risk
High cytogenetic risk^b	7/16 (43.8)	4/14 (28.6)	1.94 (0.42-8.92)
Revised high cytogenetic risk^c	23/42 (54.8)	12/37 (32.4)	2.52 (1.01-6.32)
0 HRCA^c	42/56 (75.0)	19/60 (31.7)	6.47 (2.87-14.60)
1 HRCA^c	17/32 (53.1)	11/29 (37.9)	1.85 (0.67-5.15)
≥2 HRCAs^c	6/10 (60.0)	1/8 (12.5)	10.50 (0.91-121.39)
Gain/amp(1q21)^d	21/34 (61.8)	8/28 (28.6)	4.04 (1.38-11.81)
Gain/amp(1q21) + 1 HRCA^c	6/9 (66.7)	0/6	NE (NE-NE)
Gain/amp(1q21) isolated^e	15/25 (60.0)	8/22 (36.4)	2.62 (0.81-8.55)
Best response to therapy
<VGPR after induction	17/30 (56.7)	8/44 (18.2)	5.88 (2.05-16.86)
≥VGPR after induction	50/70 (71.4)	22/54 (40.7)	3.64 (1.72-7.70)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21). ^dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) did not have any other HRCAs.

Final Analysis of sCR by the End of the GRIFFIN Study²³

Subgroup	D-VRd, n/N (%)	VRd, n/N (%)	OR (95% CI)^a
Response evaluable (overall)^b	67/100 (67.0%)	47/98 (48.0%)	2.18 (1.22-3.89)
Baseline characteristic
Age ≥65 years	17/27 (63.0)	11/27 (40.7)	2.47 (0.83-7.39)
ISS stage III disease	9/14 (64.3)	8/13 (61.5)	1.13 (0.24-5.37)
Cytogenetic risk
High cytogenetic risk^c	8/16 (50.0)	5/13 (38.5)	1.60 (0.36-7.07)
Revised high cytogenetic risk^d	23/41 (56.1)	20/36 (55.6)	1.02 (0.42-2.52)
0 HRCA^d	43/55 (78.2)	26/58 (44.8)	4.41 (1.94-10.04)
1 HRCA^d	18/31 (58.1)	17/28 (60.7)	0.90 (0.32-2.54)
≥2 HRCAs^d	5/10 (50.0)	3/8 (37.5)	1.67 (0.25-11.07)
Gain/amp(1q21)^e	19/33 (57.6)	16/28 (57.1)	1.02 (0.37-2.82)
Gain/amp(1q21) + 1 HRCA^d	5/9 (55.6)	2/6 (33.3)	2.50 (0.29-21.40)
Gain/amp(1q21) isolated^f	14/24 (58.3)	14/22 (63.6)	0.80 (0.24-2.63)
Best response to therapy
<VGPR by the end of induction	20/30 (66.7)	10/44 (22.7)	6.80 (2.41-19.16)
≥VGPR by the end of induction	47/70 (67.1)	37/54 (68.5)	0.94 (0.44-2.01)
MRD status
Not MRD^- by the end of consolidation	24/48 (50.0)	32/78 (41.0)	1.44 (0.70-2.96)
MRD^- by the end of consolidation	43/52 (82.7)	15/20 (75.0)	1.59 (0.46-5.51)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; OR, odds ratio; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd. ^bThis analysis included patients from the response evaluable population, which included all randomized patients who had measurable disease (confirmed MM diagnosis), received ≥1 dose of study treatment, and had ≥ postbaseline disease assessment^cHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16). ^dRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21). ^ePatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]). ^fPatients with isolated gain/amp(1q21) did not have any other HRCAs.

Final Analysis of MRD-negativity (10^-5) Rates Among Patients with a Best Response of ≥CR by the End of the GRIFFIN Study⁹

Subgroup	D-VRd, n/N (%)	VRd, n/N (%)	OR (95% CI)^a
Patients with best response of ≥CR^b	64/83 (77.1)	28/59 (47.5)	3.70 (1.77-7.72)
Baseline characteristic
Age ≥65 years	18/23 (78.3)	5/14 (35.7)	6.48 (1.48-28.34)
ISS stage III disease	10/13 (76.9)	4/8 (50.0)	3.33 (0.50-22.14)
Cytogenetic risk
High cytogenetic risk^c	6/10 (60.0)	4/7 (57.1)	1.13 (0.16-7.99)
Revised high cytogenetic risk^d	21/30 (70.0)	12/23 (52.2)	2.14 (0.69-6.63)
0 HRCA^d	41/49 (83.7)	16/35 (45.7)	6.09 (2.22-16.68)
1 HRCA^d	16/24 (66.7)	11/20 (55.0)	1.64 (0.48-5.56)
≥2 HRCAs^d	5/6 (83.3)	1/3 (33.3)	10.0 (0.40-250.42)
Gain/amp(1q21)^e	19/25 (76.0)	8/17 (47.1)	3.56 (0.95-13.37)
Gain/amp(1q21) + 1 HRCA^d	5/6 (83.3)	0/2	NE (NE-NE)
Gain/amp(1q21) isolated^f	14/19 (73.7)	8/15 (53.3)	2.45 (0.58-10.33)
Best response to therapy
<VGPR by the end of induction	16/22 (72.7)	7/15 (46.7)	3.05 (0.77-12.14)
≥VGPR by the end of induction	48/61 (78.7)	21/44 (47.7)	4.04 (1.73-9.48)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; OR, odds ratio; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd. ^bThis analysis included patients from the response evaluable population, which included all randomized patients who had measurable disease (confirmed MM diagnosis), received ≥1 dose of study treatment, and had ≥ postbaseline disease assessment^cHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16). ^dRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21). ^ePatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]). ^fPatients with isolated gain/amp(1q21) did not have any other HRCAs.

Final Analysis of Rates of Sustained MRD-negativity (10^-5) lasting ≥12 months⁹

Subgroup	D-VRd, n/N (%)	VRd, n/N (%)	OR (95% CI)^a
ITT (overall)	46/104 (44.2)	14/103(13.6)	5.0 (2.50-9.99)
Baseline characteristic
Age ≥65 years	14/28 (50.0)	3/28 (10.7)	8.33 (2.04 (34.07)
ISS stage III disease	6/14 (42.9)	2/14 (14.3)	4.50 (0.72-28.15)
Cytogenetic risk
High cytogenetic risk^b	3/16 (18.8)	2/14 (14.3)	1.38 (0.20-9.77)
Revised high cytogenetic risk^c	14/42 (33.3)	6/37 (16.2)	2.58 (0.87-7.64)
0 HRCA^c	31/56 (55.4)	8/60 (13.3)	8.06 ((3.24-20.06)
1 HRCA^c	12/32 (37.5)	5/29 (17.2)	2.88 (0.87-9.56)
≥2 HRCAs^c	2/10 (20.0)	1/8 (12.5)	1.75 (0.13-23.70)
Gain/amp(1q21)^d	13/34 (38.2)	4/28 (14.3)	3.71 (1.05-13.15)
Gain/amp(1q21) + 1 HRCA^c	2/9 (22.2)	0/6	NE (NE-NE)
Gain/amp(1q21) isolated^e	11/25 (44.0)	4/22 (18.2)	3.54 (0.93-13.51)
Best response to therapy
<VGPR by the end of induction	13/30 (43.3)	3/44 (6.8)	10.45 (2.64-41.41)
≥VGPR by the end of induction	33/70 (47.1)	11/54 (20.4)	3.49 (1.55-7.85)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21). ^dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) did not have any other HRCAs.

Final Analysis of PFS in the GRIFFIN Study⁹

Subgroup	D-VRd		VRd		HR (95% CI)^a
Subgroup	n/N	Median PFS, Months	n/N	Median PFS, Months	HR (95% CI)^a
ITT (overall)	11/104	NR	18/103	NR	0.45 (0.21-0.95)
Baseline characteristic
Age ≥65 years	2/28	NR	5/28	NR	0.29 (0.06-1.48)
ISS stage III disease	2/14	NR	6/14	33.1	0.23 (0.05-1.13)
Cytogenetic risk
High cytogenetic risk^b	5/16	NR	5/14	36.1	0.54 (0.15-1.88)
Revised high cytogenetic risk^c	7/42	NR	10/37	47.9	0.38 (0.14-1.01)
0 HRCA^c	3/56	NR	7/60	NR	0.39 (0.10-1.51)
1 HRCA^c	3/32	NR	8/29	47.9	0.19 (0.05-0.75)
≥2 HRCAs^c	4/10	33.9	2/8	NR	1.65 (0.30-9.18)
Gain/amp(1q21)^d	6/34	NR	7/28	47.9	0.42 (0.14-1.27)
Gain/amp(1q21) + 1 HRCA^c	4/9	33.9	2/6	38.7	0.81 (0.15-4.47)
Gain/amp(1q21) isolated^e	2/25	NR	5/22	47.9	0.21 (0.04-1.09)
Best response to therapy
<VGPR by the end of induction	3/30	NR	9/44	NR	0.29 (0.08-1.07)
≥VGPR by the end of induction	8/70	NR	9/54	NR	0.58 (0.22-1.51)
MRD status
Not MRD^- by the end of consolidation	9/52	NR	14/82	NR	0.82 (0.35-1.89)
MRD^- by the end of consolidation	2/52	NR	4/21	NR	0.17 (0.03-0.92)
Not MRD^- by the end of 2 yrs of maintenance	8/37	NR	12/72	NR	1.04 (0.43-2.56)
MRD^- by the end of 2 yrs of maintenance	3/67	NR	6/31	NR	0.21 (0.05-0.86)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; NR, not reached; PFS, progression-free survival; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-VRd. ^bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16). ^cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21). ^dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]). ^ePatients with isolated gain/amp(1q21) did not have any other HRCAs.

Safety

A summary of the most common (>30%) TEAEs in the safety analysis population separated by age <65 years and ≥65 years is provided in Table: Most Common (>30%) any grade TEAEs by Age (<65 years and ≥65 year).
Among patients aged <65 years (84.7% vs 80.0%) and ≥65 years (88.9% vs 77.8%), the rates of grade 3/4 TEAEs were slightly higher for D-VRd vs VRd.
The incidence of serious TEAEs was lower in D-VRd vs VRd among patients <65 years, 41.7% vs 56.0% respectively.
The incidence of serious TEAEs was higher in the D-VRd vs VRd among patients ≥65 years, 59.3% vs 40.7% respectively.
The discontinuation of ≥1 therapeutic agent due to TEAEs were comparable between patients aged <65 years (D-VRd, 31.9% vs VRd, 33.3%) and higher for D-VRd vs VRd in patients ≥65 years (D-VRd, 37.0% vs 25.9%).
- The most common TEAE leading to discontinuation of ≥1 drug was peripheral neuropathy for patients <65 years (D-VRd, 11.1% vs VRd, 13.3%) and ≥65 years (D-VRd, 18.5% vs VRd, 11.1%).
The incidence of TEAEs leading to lenalidomide dose reduction was higher for D-VRd vs VRd (<65 years: D-VRd, 33.3% vs VRd, 28.0%; ≥65 years: D-VRd, 59.3% vs VRd, 33.3%) among patients aged <65 and ≥65 years.
- The most common TEAE leading to lenalidomide dose reduction was neutropenia for patients <65 years (D-VRd, 15.3% vs VRd, 5.3%) and ≥65 years (D-VRD, 22.2% vs VRd, 14.8%).
Two deaths due to a TEAE occurred and were considered unrelated to study treatment.
- <65 years (VRd, n=1; cause unknown)
- ≥65 years (D-VRd, n=1; pneumonia)

Most Common (>30%)^a any grade TEAEs by Age (<65 years and ≥65 year)⁹

Most common TEAEs, n (%)	<65 years		≥65 years
Most common TEAEs, n (%)	D-VRd (n=72)	VRd (n=75)	D-VRd (n=27)	VRd (n=27)
Hematologic
Neutropenia	47 (65.3)	29 (38.7)	16 (59.3)	12 (44.4)
Thrombocytopenia	30 (41.7)	24 (32.0)	14 (51.9)	12 (44.4)
Leukopenia	29 (40.3)	21 (28.0)	10 (37.0)	9 (33.3)
Anemia	25 (34.7)	25 (33.3)	12 (44.4)	8 (29.6)
Lymphopenia	23 (31.9)	23 (30.7)	8 (29.6)	6 (22.2)
Nonhematologic
Upper respiratory tract infection	51 (70.8)	37 (49.3)	16 (59.3)	14 (51.9)
Diarrhea	48 (66.7)	39 (52.0)	18 (66.7)	17 (63.0)
Fatigue	48 (66.7)	45 (60.0)	23 (85.2)	18 (66.7)
Peripheral neuropathy^b	41 (56.9)	56 (74.7)	21 (77.8)	22 (81.5)
Nausea	38 (52.8)	37 (49.3)	14 (51.9)	14 (51.9)
Constipation	37 (51.4)	29 (38.7)	14 (51.9)	13 (48.1)
Insomnia	36 (50.0)	25 (33.3)	9 (33.3)	6 (22.2)
Cough	35 (48.6)	26 (34.7)	18 (66.7	5 (18.5)
Pyrexia	34 (47.2)	27 (36.0)	14 (51.9)	6 (22.2)
Back pain	30 (41.7)	29 (38.7)	11 (40.7)	7 (25.9)
Arthralgia	27 (37.5)	26 (34.7)	12 (44.4)	12 (44.4)
Headache	27 (37.5)	18 (24.0)	6 (22.2)	6 (22.2)
Muscle spasms	26 (36.1)	11 (14.7)	4 (14.8)	9 (33.3)
Vomiting	25 (34.7)	21 (28.0)	7 (25.9)	8 (29.6)
Peripheral edema	24 (33.3)	25 (33.3)	12 (44.4)	12 (44.4)
Hypokalemia	19 (26.4)	20 (26.7)	9 (33.3)	7 (25.9)
Pain in extremity	19 (26.4)	13 (17.3)	3 (11.1)	9 (33.3)
Dyspnea	14 (19.4)	24 (32.0)	10 (37.0)	7 (25.9)
Dizziness	15 (20.8)	16 (21.3)	8 (29.6)	9 (33.3)
Pneumonia	14 (19.4)	16 (21.3)	10 (37.0)	2 (7.4)
Dysgeusia	14 (19.4)	14 (18.7)	9 (33.3)	5 (18.5)
Abbreviations: D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; VRd, lenalidomide + bortezomib + dexamethasone.^aIncludes TEAEs occurring in ≥30% of patients aged <65 years or ≥65 years in either treatment group from the safety analysis population (all randomized patients who received ≥1 dose of study treatment).^bIncludes preferred terms neuropathy peripheral and peripheral sensory neuropathy.

Analysis of Transplant-Eligible Patients With HRCAs From MASTER and GRIFFIN Studies

Callander et al (2024)¹⁰ reported post hoc analysis results evaluating the clinical efficacy of DARZALEX-based quadruplet therapies D-KRd and D-VRd in transplant-eligible patients with NDMM with HRCAs from the MASTER (median follow-up of 31.1 months) and GRIFFIN (median follow-up of 49.6 months) studies, respectively. Results specific to GRIFFIN are summarized below.

Study Design/Methods

Patients with HRCA included ≥1 genetic abnormality: del17p, t(4;14), t(14;16), t(14;20), and/or gain/amp(1q21) (≥3 copies of chromosome 1q21).

Results

Patient Characteristics

Among patients receiving DARZALEX-based treatment in the GRIFFIN (N=120 [randomized phase, n=104; safety run-in, n=16]) study, a total of 67 (55.8%), 34 (28.3%) and 13 (10.8%) patients, respectively, had 0 HRCA, 1 HRCA and 2+ HRCA cytogenetic risk.
Baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics in Patients who Received D-VRd in GRIFFIN.

Baseline Patient and Disease Characteristics in Patients who Received D-VRd in GRIFFIN^a,¹⁰

Characteristic	Standard-Risk 0 HRCA (n=67)	High-Risk 1 HRCA (n=34)	Ultra-High-Risk ≥2 HRCAs (n=13)	Total (n=114)
Median age (range), years	59.0 (34-70)	59.5 (29-70)	62.0 (49-70)	60.0 (29-70)
Sex, n (%)
Male	37 (55.2)	18 (52.9)	9 (69.2)	64 (56.1)
Female	30 (44.8)	16 (47.1)	4 (30.8)	50 (43.9)
ISS disease stage,^b n (%)
I	42 (62.7)	13 (38.2)	5 (38.5)	60 (52.6)
II	20 (29.9)	17 (50.0)	4 (30.8)	41 (36.0)
III	5 (7.5)	4 (11.8)	4 (30.8)	13 (11.4)
Cytogenetic abnormality,^c n (%)
del(17p)	0	4 (11.8)	8 (61.5)	12 (10.5)
t(4;14)	0	3 (8.8)	5 (38.5)	8 (7.0)
t(14;16)	0	0	1 (7.7)	1 (0.9)
Gain/amp(1q21)	0	26 (76.5)	12 (92.3)	38 (33.3)
t(14;20)	0	1 (2.9)	0	1 (0.9)
Median duration of study treatment,^d months
Induction/consolidation^e	8.1	8.1	7.4	8.1
Maintenance	24.4	24.2	23.9	24.2
Abbreviations: ASCT, autologous stem cell transplantation; del, deletion; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, international staging system; t, translocation. ^aFor GRIFFIN, the D-VRd group included patients from the randomized phase (n=104) and the safety run-in phase (n=16). Patients were grouped by HRCA: 0 HRCA (n=67), 1 HRCA (n=34), or ≥2 HRCAs (n=13). 6 patients were not evaluable for cytogenetic abnormalities.^bISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.^cCytogenetic risk was assessed by fluorescence in situ hybridization (local testing).^dStudy duration is reported for treated patients for induction/consolidation (0 HRCA, n=66; 1 HRCA, n=32; ≥2 HRCAs, n=13; total, n=111) and maintenance (0 HRCA, n=62; 1 HRCA, n=29; ≥2 HRCAs, n=10; total, n=101).^eDuration of study treatment is from initiation of therapy to completion of consolidation therapy, including ASCT.

Efficacy

Efficacy outcomes are summarized in Table: Efficacy Outcomes by Cytogenetic Risk Status in the GRIFFIN Study.

Efficacy Outcomes by Cytogenetic Risk Statusin the GRIFFIN Study^a,¹⁰

Parameter	Standard-Risk 0 HRCA (n=67)	High-Risk 1 HRCA (n=34)	Ultra-High-Risk ≥2 HRCAs (n=13)
≥CR,^b %	90.9	78.8	61.5
24-month PFS rate, %	96.7	93.8	64.2
36-month PFS rate, %	96.7	90.5	53.5
48-month PFS rate, %	93.7	90.5	53.5
MRD negative
Evaluable population, n	67^c	34^c	13^c
10^-5sensitivity, %	76.1	55.9	61.5
10^-6sensitivity, %	44.8	26.5	15.4
In patients achieving ≥CR, n	60	26	8
10^-5sensitivity, %	83.3	69.2	87.5
Durable MRD-negativity lasting ≥12 months
Evaluable population, n	67^c	34^c	13^c
10^-5sensitivity, %	53.7	38.2	30.8
MRD (10^-5) conversion rate
Evaluable population, n	67^c	34^c	13^c
MRD-positive by the end of induction and then became MRD-negative, %	49.3	41.2	38.5
MRD-positive by the end of consolidation and then became MRD-negative, %	19.4	11.8	23.1
Median time to MRD-negativity (10^-5),^c months	8.5	8.6	19.6
Abbreviations: ≥CR, complete response or better; HRCA, high-risk cytogenetic abnormality; MRD, minimal residual disease; PFS, progression-free survival. ^aHRCAs include any of the following genetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21) (≥3 copies of chromosome 1q21). Patients were grouped into categories: standard risk (0 HRCA), high risk (1 HRCA), or ultra-high risk (≥2 HRCAs). ^bEvaluable patients in GRIFFIN were the response-evaluable population (0 HRCA, n=66; 1 HRCA, n=33; ≥2 HRCAs, n=13).^cFor GRIFFIN, the D-R group included patients from the randomized phase (n=104) and the safety run-in phase (n=16). Patients were grouped by HRCA: 0 HRCA (n=67), 1 HRCA (n=34), or ≥2 HRCAs (n=13). 6 patients were not evaluable for cytogenetic abnormalities.

Safety

In the GRIFFIN study, 8 patients died while on D-VRd therapy (0 HRCA, n=2 [due to adverse event (bronchopneumonia) and PD]; 1 HRCA, n=1 [due to PD]; ≥2 HRCAs, n=4 [all due to PD]; not evaluable for cytogenetics, n=1 [due to respiratory failure]).

Post Hoc Analysis of the Incidence of VTE

Sborov et al (2022)¹¹ conducted a post hoc analysis to evaluate the risk and incidence of VTE in patients receiving D-VRd vs VRd in the GRIFFIN study.

Study Design/Methods

The risk of VTE was assessed using the SAVED risk assessment model (<2 points, low risk; >2 points, high risk), as described below:
- Surgery within 90 days (S; +2)
- Asian race (A; -3)
- History of VTE (V; +3)
- Eighty (age ≥80 years; E; +1)
- Dexamethasone dose (D; +2 for high, +1 for standard)
All patients received VTE prophylaxis with at least aspirin ≥162 mg/day. Patients with increased risk of VTE received prophylaxis with enoxaparin 40 mg/day SC or other low-molecular-weight heparin (LMWH) at an equivalent dose and frequency. Vitamin K antagonists, factor Xa inhibitors, or direct thrombin inhibitors could be used at the treating physician's discretion.

Results

Patient Characteristics

Overall, 207 patients were included (ITT population: D-VRd, n=104; VRd, n=103; safety population: D-VRd, n=99; VRd, n=102).
The median duration of follow-up was 38.6 months.
The Baseline patient and disease characteristics in patients who did or did not experience VTEs are summarized in Table: Demographic and Baseline Disease Characteristics Among Patients Who Did or Did Not Experience VTEs.

Demographic and Baseline Disease Characteristics Among Patients Who Did or Did Not Experience VTEs¹¹

Characteristic	Patients who experienced VTEs			Patients who did not experience VTEs
Characteristic	Total (n=26)	D-VRd (n=10)	VRd (n=16)	Total (n=181)	D-VRd (n=94)	VRd (n=87)
Age, years
Median (range)	57.5 (35-70)	54.0 (35-70)	59.5 (47-70)	60.0 (29-70)	59.5 (29-70)	61.0 (40-70)
<65, n (%)	17 (65.4)	7 (70.0)	10 (62.5)	134 (74.0)	69 (73.4)	65 (74.7)
≥65, n (%)	9 (34.6)	3 (30.0)	6 (37.5)	47 (26.0)	25 (26.6)	22 (25.3)
Male, n (%)	19 (73.1)	8 (80.0)	11 (68.8)	99 (54.7)	50 (53.2)	49 (56.3)
Weight, kg	n=26	n=10	n=16	n=179	n=92	n=87
Median (range)	87.1 (62.0-148.5)	81.9 (63.6-141.5)	88.2 (62.0-148.5)	80.4 (37.4-158.6)	78.9 (48.8-158.6)	82.7 (37.4-150.1)
ECOG PS score, n (%)	n=26	n=10	n=16	n=177	n=91	n=86
0	3 (11.5)	1 (10.0)	2 (12.5)	76 (42.9)	38 (41.8)	38 (44.2)
1	17 (65.4)	7 (70.0)	10 (62.5)	86 (48.6)	44 (48.4)	42 (48.8)
2	6 (23.1)	2 (20.0)	4 (25.0)	15 (8.5)	9 (9.9)	6 (7.0)
ISS disease stage, n (%)^a
I	13 (50.0)	6 (60.0)	7 (43.8)	86 (47.5)	43 (45.7)	43 (49.4)
II	13 (50.0)	4 (40.0)	9 (56.3)	64 (35.4)	36 (38.3)	28 (32.2)
III	0	0	0	28 (15.5)	14 (14.9)	14 (16.1)
Missing	0	0	0	3 (1.7)	1 (1.1)	2 (2.3)
Type of measurable disease, n (%)^b
Serum and urine	4 (15.4)	1 (10.0)	3 (18.8)	33 (18.2)	22 (23.4)	11 (12.6)
Free light chain	3 (11.5)	2 (20.0)	1 (6.3)	23 (12.7)	13 (13.8)	10 (11.5)
Serum only	14 (53.8)	4 (40.0)	10 (62.5)	99 (54.7)	49 (52.1)	50 (57.5)
Urine only	5 (19.2)	3 (30.0)	2 (12.5)	22 (12.2)	9 (9.6)	13 (14.9)
Not evaluable	0	0	0	4 (2.2)	1 (1.1)	3 (3.4)
Bone marrow involvement (% plasma cells, bone marrow biopsy/aspirate), n (%)^c
<10	3 (11.5)	1 (10.0)	2 (12.5)	13 (7.2)	9 (9.6)	4 (4.6)
10-59	9 (34.6)	4 (40.0)	5 (31.3)	88 (48.6)	42 (44.7)	46 (52.9)
≥60	14 (53.8)	5 (50.0)	9 (56.3)	73 (40.3)	40 (42.6)	33 (37.9)
Missing	0	0	0	7 (3.9)	3 (3.2)	4 (4.6)
Time from MM diagnosis to randomization	n=26	n=10	n=16	n=179	n=93	n=86
Median (range), months	0.8 (0-3)	0.4 (0-3)	0.9 (0-2)	0.8 (0-61)	0.7 (0-12)	0.9 (0-61)
Cytogenetic profile, n (%)^d	n=25	n=10	n=15	n=170	n=88	n=82
Standard risk, n (%)	21 (84.0)	8 (80.0)	13 (86.7)	144 (84.7)	74 (84.1)	70 (85.4)
High risk, n (%)	4 (16.0)	2 (20.0)	2 (13.3)	26 (15.3)	14 (15.9)	12 (14.6)
del17p	4 (16.0)	2 (20.0)	2 (13.3)	10 (5.9)	6 (6.8)	4 (4.9)
t(4;14)	1 (4.0)	0	1 (6.7)	13 (7.6)	8 (9.1)	5 (6.1)
t(14;16)	0	0	0	4 (2.4)	1 (1.1)	3 (3.7)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone; VTEs, vascular thrombotic events. ^aBased on the combination of serum β₂-microglobulin and albumin. ^bIncludes IgD, IgM, IgE, and biclonal. ^cHighest value by biopsy or aspirate. ^dCytogenetic risk was based on local fluorescence in situ hybridization or karyotype analysis. Patients with high-risk cytogenetics had a del17p, t(4;14) or t(14;16) abnormality; a patient could be counted in more than 1 subcategory. Patients with standard-risk cytogenetic abnormalities had an absence of high-risk cytogenetic abnormalities.

Efficacy

Among patients with VTEs, the median total number of treatment cycles was 32.0 (range, 20-32) in the D-VRd arm and 30.5 (range, 4-32) in the VRd arm.
The response rates at different timepoints among patients who experienced VTE are summarized in Tables: Response Rates in Patients With VTE and Response Rates in Patients With VTE at the First Onset of VTE.

Response Rates in Patients With VTE¹¹

Parameter, %	D-VRd (n=10)				VRd (n=16)
Parameter, %	End of Induction	End of ASCT	End of Consolidation	After 2 Years of Maintenance	End of Induction	End of ASCT	End of Consolidation	After 2 Years of Maintenance
≥CR	20.0	20.0	50.0	90.0	25.0	31.3	31.3	68.8
sCR	10.0	10.0	40.0	70.0	18.8	25.0	25.0	56.3
CR	10.0	10.0	10.0	20.0	6.3	6.3	6.3	12.5
VGPR	50.0	60.0	50.0	10.0	50.0	50.0	56.3	18.8
PR	30.0	20.0	-	-	25.0	18.8	12.5	12.5
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone; VTE, vascular thrombotic event.

Response Rates in Patients With VTE at the First Onset of VTE¹¹

Parameter, %	D-VRd (n=10)	VRd (n=16)
≥CR	50.0	31.3
sCR	30.0	25.0
CR	20.0	6.3
VGPR	30.0	43.8
PR	20.0	12.5
SD/PD/NE	-	12.5
Abbreviations: CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone; VTE, vascular thrombotic event.

Safety

In the D-VRd vs VRd arm, VTEs occurred in 10.1% (n=10) vs 15.7% (n=16) of patients in the safety analysis population. See Table: VTEs in the Safety Analysis Population.
The median time to first onset of VTE was 305 days (range, 6-810) in the D-VRd arm and 119 days (range, 21-822) in the VRd arm.
In the D-VRd vs VRd arm, new onset VTEs were reported at the following stages:
- Induction (cycles 1-4): 5.1% (n=5) vs 8.8% (n=9)
- Consolidation (cycles 5-6): 0% (n=0) vs 1.4% (n=1)
- Maintenance:
  - Cycles 7-18: 2.2% (n=2) vs 7.0% (n=5)
  - Cycles 18+: 3.6% (n=3) vs 1.7% (n=1)
In the D-VRd vs VRd arm, the median SAVED score was 0 (range, 0 to 3) vs 0 (range, 3 to 4) in patients in the ITT population and 0 (range, 0-3) vs 0.5 (range, 04) in patients experiencing VTE.
The median number of cardiovascular comorbidities both in patients in the overall population and patients experiencing VTE was 1.
In the D-VRd vs VRd arm, antithrombosis prophylaxis at any time was received by 84.8% (n=84) vs 83.3% (n=85) of patients in the overall safety population and by 80.0% (n=8) vs 93.8% (n=15) of patients who developed VTE.
- Overall, 60.0% (n=6) of patients in the D-VRd arm and 68.8% (n=11) of patients in the VRd arm were receiving antithrombosis prophylaxis during the first onset of VTE.

VTEs in the Safety Analysis Population^a,¹¹

VTE, n (%)	D-VRd (n=99)			VRd (n=102)
VTE, n (%)	Grade 1	Grade 2-4	Total	Grade 1	Grade 2-4	Total
Total number with ≥1 VTE	1 (1.0)	9 (9.1)	10 (10.1)	1 (1.0)	15 (14.7)	16 (15.7)
Embolic and thrombotic events	2 (2.0)	3 (3.0)	5 (5.1)	1 (1.0)	10 (9.8)	11 (10.8)
Deep vein thrombosis	1 (1.0)	1 (1.0)	2 (2.0)	0	7 (6.9)	7 (6.9)
Pulmonary embolism	0	2 (2.0)	2 (2.0)	0	4 (3.9)	4 (3.9)
Embolism venous	0	0	0	1 (1.0)	0	1 (1.0)
Jugular vein thrombosis	0	1 (1.0)	1 (1.0)	0	1 (1.0)	1 (1.0)
Subclavian vein thrombosis	0	1 (1.0)	1 (1.0)	0	0	0
Thrombophlebitis superficial	1 (1.0)	1 (1.0)	2 (2.0)	0	0	0
Unspecified and mixed arterial and venous	0	6 (6.1)	6 (6.1)	1 (1.0)	5 (4.9)	6 (5.9)
Embolism	0	2 (2.0)	2 (2.0)	1 (1.0)	2 (2.0)	3 (2.9)
Cerebral congestion	0	2 (2.0)	2 (2.0)	0	1 (1.0)	1 (1.0)
Cerebrovascular accident	0	0	0	0	1 (1.0)	1 (1.0)
Hemiparesis	0	0	0	0	1 (1.0)	1 (1.0)
Intestinal infarction	0	1 (1.0)	1 (1.0)	0	0	0
Vascular access site thrombosis	0	1 (1.0)	1 (1.0)	0	0	0
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; VRd, bortezomib + lenalidomide + dexamethasone; VTE, vascular thrombotic event. ^aNo grade 5 VTEs were reported in either treatment arm.

PROs During Maintenance Phase of the GRIFFIN Study

Silbermann et al (2023)¹² presented a post hoc analysis of the GRIFFIN study that evaluated PROs during the maintenance therapy phase.

Study Design/Methods

While the patients were on treatment, PROs were assessed using the EORTC QLQ-C30, EORTC QLQ-MY20, and EQ-5D-5L questionnaires on day 1 of cycles 1, 2, and 3 and day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5 and day 21 of cycle 6 (end of post-transplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy.
Selected item-level responses that were evaluated from the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires for pain and physical functioning were as follows:
- Pain in hip
- Trouble taking a long walk
- Need to rest
- Pain in back, arm/shoulder, or chest
- Being tired
- Pain interfering with activities
- Limitations in performing usual activities
Frequency distribution by treatment group and no. of visits were summarized.
Responses were combined into 2 categories: “not at all/a little” and “quite a bit/very much.”

Results

Patient Characteristics

A total of 207 patients were randomized (D-VRd/D-R, n=104; VRd/R, n=103).
The symptoms/impacts of key PRO items at baseline are shown in Table: Baseline PRO Items.

Baseline PRO Items¹²^,²⁴

PRO Items, %	Not At All		A Little		Quite a Bit		Very Much
PRO Items, %	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)
Had pain in hip	35.2	47.6	34.1	35.7	18.2	10.7	12.5	6.0
Trouble taking a long walk	31.8	29.8	29.5	31.0	18.2	21.4	20.5	17.9
Need to rest	26.1	23.8	31.8	45.2	26.1	22.6	15.9	8.3
Had pain in back	19.3	26.2	36.4	29.8	22.7	32.1	21.6	11.9
Had pain in arms/shoulder	59.1	54.8	22.7	27.4	8.0	14.3	10.2	3.6
Had pain in chest	70.5	69.0	23.9	17.9	2.3	9.5	3.4	3.6
Been tired	25.0	23.8	39.8	46.4	27.3	23.8	8.0	6.0
Did pain interfere with activities	34.1	33.3	30.7	27.4	18.2	23.8	17.0	15.5
Limited in work or activities	37.5	40.5	30.7	33.3	19.3	14.3	12.5	11.9
Abbreviations: D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + lenalidomide + bortezomib + dexamethasone; PRO, patient-reported outcome; R, lenalidomide; VRd, lenalidomide + bortezomib + dexamethasone.

Change in PRO Items Over Time

Improvements were observed during the maintenance phase in all the key PRO items when compared with the baseline. See Table: Summary of PROs From Baseline to Maintenance Month 24.

Summary of PROs From Baseline to Maintenance Month 24^a,¹²^,²⁴

PRO Items, %	Baseline		Month 6		Month 12		Month 18		Month 24
PRO Items, %	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)	DVRd/ D-R (n=88)	VRd/ R (n=84)
Had pain in hip (EORTC QLQ-MY20)
Not at all/a little	69	83	86	93	87	72	81	89	85	78
Quite a bit/very much	31	17	14	7	13	29	19	11	15	22
Trouble taking a long walk (EORTC QLQC30)
Not at all/a little	61	61	80	84	80	71	77	74	85	87
Quite a bit/very much	39	39	20	16	20	29	23	26	15	13
Need to rest (EORTC QLQC30)
Not at all/a little	58	69	86	81	79	77	74	74	83	91
Quite a bit/very much	42	31	14	19	22	23	26	26	18	9
Had pain in back (EORTC QLQ-MY20)
Not at all/a little	56	56	80	81	78	74	79	74	80	78
Quite a bit/very much	44	44	20	19	22	26	21	26	21	22
Had pain in arm/shoulder (EORTC QLQ-MY20)
Not at all/a little	82	82	86	93	89	89	91	78	85	96
Quite a bit/very much	18	18	14	7	11	12	9	22	15	4
Had pain in chest (EORTC QLQ-MY20)
Not at all/a little	94	87	98	98	96	97	100	100	100	100
Quite a bit/very much	6	13	2	2	4	3	0	0	0	0
Been tired (EORTC QLQC30)
Not at all/a little	65	70	86	77	82	66	77	67	85	96
Quite a bit/very much	35	30	14	23	18	34	23	33	15	4
Did pain interfere with activities (EORTC QLQC30)
Not at all/a little	65	61	92	88	84	91	88	85	90	100
Quite a bit/very much	35	39	8	12	16	9	12	15	10	0
Limited in work or activities (EORTC QLQC30)
Not at all/a little	68	74	91	91	91	91	88	89	95	96
Quite a bit/very much	32	26	9	9	9	9	12	11	5	5
Abbreviations: D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + lenalidomide + bortezomib + dexamethasone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire Core 30-item; EORTC QLQ-MY20, European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire Multiple Myeloma Module 20-item; PRO, patient-reported outcome; R, lenalidomide; VRd, lenalidomide + bortezomib + dexamethasone.^aDue to rounding, the numbers may not total 100%.

PROs in the GRIFFIN Study

Silbermann et al (2022)¹³ presented the final analysis of PROs from the GRIFFIN study.

Study Design/Methods

The final analysis was conducted after all patients completed ≥1 year of follow-up after completing maintenance therapy.
PROs were assessed using the following questionnaires, and the scores were transformed to values ranging from 0-100:
- EORTC QLQ-C30
  - Functional scales: physical, role, emotional, cognitive, and social functioning
  - GHS scale
  - Symptom scales: fatigue, nausea and vomiting, and pain
  - Single items: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties
- EORTC QLQ-MY20
  - Symptom scales: disease symptoms and AEs of treatment
  - Functional scale: future perspective
  - Single item: body image
- EQ-5D-5L
  - Generic measure of health status
  - Domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression
  - VAS
  - Utility score
PROs were assessed at baseline on day 1 of cycle 1; on day 1 of cycles 2, 3, and 5; on day 21 of cycle 4; at post-ASCT consolidation; and after months 6, 12, 18, and 24 of maintenance.

Results

Patient Characteristics

A total of 207 patients were randomized (D-VRd, n=104; VRd, n=103).
Compliance rates for all PRO questionnaires were as follows:
- At baseline: 81% overall
- At post-ASCT consolidation phase: D-VRd, 63%; VRd, 49%
- At month 24 of maintenance phase: D-VRd, 49%; VRd, 45%
The median duration of follow-up was 49.6 months.
The mean PRO scores at baseline were similar between the 2 arms. See Table: Mean Baseline PRO Scores in the GRIFFIN Study.

Mean Baseline PRO Scores in the GRIFFIN Study¹³

Scale	D-VRd (n=104)	VRd (n=103)
EORTC QLQ-C30 score, mean (SD)
GHS	63.2 (24.3)	65.1 (21.8)
Functional scales
Physical functioning	70.9 (27.2)	72.5 (24.8)
Role functioning	61.7 (34.6)	65.9 (32.4)
Emotional functioning	74.4 (21.5)	73.7 (23.0)
Cognitive functioning	79.9 (27.8)	82.5 (22.7)
Social functioning	67.1 (30.2)	73.0 (28.9)
Symptom scales
Pain	44.1 (34.5)	43.5 (33.4)
Fatigue	39.9 (30.8)	36.1 (26.2)
Nausea/vomiting	7.0 (12.3)	3.6 (10.0)
EORTC QLQ-MY20 score, mean (SD)
Future perspective	52.7 (26.0)	58.2 (25.1)
Body image	75.4 (32.2)	81.4 (28.0)
Disease symptoms	34.3 (24.9)	31.2 (20.9)
Adverse effects of treatment	18.7 (17.9)	15.3 (14.5)
EQ-5D-5L scores, mean (SD)
Utility score	0.7 (0.2)	0.8 (0.2)
VAS	68.0 (21.0)	68.5 (20.0)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; EORTC QLQ-MY20, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item; EQ-5D-5L, EuroQol 5-dimensional descriptive system; GHS, global health status; PRO, patient-reported outcome; SD, standard deviation; VAS, visual analog scale; VRd, bortezomib + lenalidomide + dexamethasone.

PRO Scores

Improvements in least squares (LS) mean PRO scores from baseline are summarized in Table: LS Mean Change From Baseline in PRO Scores at Maintenance Month 24.
Similar improvements were reported in both the arms for EQ-5D-5L utility scores and EORTC QLQ-MY20 future perspective scores.
The time to worsening of EORTC QLQ-C30 GHS score was 30 months higher in the DVRd vs VRd arm (HR, 0.71; 95% CI, 0.46-1.10).
At data cutoff, the median times to worsening of EORTC QLQ-MY20 disease symptoms (HR, 0.75; 95% CI, 0.43-1.30) and EQ-5D-5L utility scores (HR, 0.49; 95% CI, 0.300.81) were NR in the D-VRd arm.
The median time to worsening of EQ-5D-5L VAS was similar in both the arms (HR, 0.86; 95% CI, 0.56-1.33).
In the D-VRd arm, EORTC QLQ-MY20 treatment side effects score worsened after a median duration which was >2 times longer than the VRd arm (HR, 0.82; 95% CI, 0.571.18).

LS Mean Change From Baseline in PRO Scores at Maintenance Month 24¹³

Scale	LS Mean Change From Baseline (95% CI) at Maintenance Month 24
Scale	D-VRd (n=104)	VRd (n=103)
EORTC QLQ-C30
GHS	13.6 (8.4 to 18.9)	9.4 (2.5 to 16.2)
Functional scales
Physical functioning	22.0 (16.5 to 27.6)	12.6 (5.6 to 19.7)
Symptom scales
Pain	-30.4 (-37.9 to -22.9)	-19.7 (-29.4 to -10.1)
Fatigue	-19.1 (-25.6 to -12.5)	-13.1 (-21.5 to -4.7)
EORTC QLQ-MY20
Disease symptoms	-15.5 (-20.7 to -10.3)	-8.2 (-14.8 to -1.6)
EQ-5D-5L scores
VAS	11.5 (6.6 to 16.4)	8.9 (2.4 to 15.4)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item; EORTC QLQ-MY20, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Multiple Myeloma Module 20-item; EQ-5D-5L, EuroQol 5-dimensional descriptive system; GHS, global health status; LS, least squares; PRO, patient-reported outcome; VAS, visual analog scale; VRd, bortezomib + lenalidomide + dexamethasone.

Stem Cell Collection in the GRIFFIN Study

Chhabra et al (2023)¹⁴ conducted a post hoc analysis evaluating the patient characteristics, stem cell mobilization and yields, and transplant outcomes following frontline DARZALEX-based induction therapy in the MASTER and GRIFFIN studies. Results specific to the GRIFFIN study have been summarized below.

Results

Patient Characteristics

Among the 207 patients randomized in the GRIFFIN study, 95/104 (91%) patients in the D-VRd arm and 80/103 (78%) patients in the VRd arm underwent stem cell mobilization. Among the mobilized patients, 99% (94 of 95) in the D-VRd arm and 98% (78 of 80) in the VRd arm underwent ASCT.
The median duration of follow-up was 38.6 months.
The baseline patient demographics and clinical characteristics are summarized in Table: Baseline Characteristics in the GRIFFIN Study.

Baseline Characteristics in the GRIFFIN Study¹⁴

Characteristic	D-VRd				VRd
	All Patients	Received Upfront Plerixafor	Rescue Plerixafor Strategy (n=46)^a		All Patients	Received Upfront Plerixafor	Rescue Plerixafor Strategy (n=49)^a
	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor	Received G-CSF Only	All Patients	Received Upfront Plerixafor	Received Rescue Plerixafor	Received G-CSF Only
Patients who underwent mobilization, n	95	49	19	19	80	31	13	28
Age, years
Median (range)	59 (29-70)	60 (29-70)	55 (35-70)	58 (34-70)	59 (40-70)	59 (47-70)	62 (49-69)	61 (40-68)
<65, n (%)	69 (73)	37 (76)	12 (63)	12 (63)	60 (75)	24 (77)	7 (54)	21 (75)
≥65, n (%)	26 (27)	12 (24)	7 (37)	7 (37)	20 (25)	7 (23)	6 (46)	7 (25)
Male, n (%)	51 (54)	28 (57)	8 (42)	12 (63)	43 (54)	14 (45)	6 (46)	17 (61)
ISS disease stage, n (%)^b
I	46 (48)	22 (45)	10 (53)	10 (53)	38 (48)	16 (52)	4 (31)	13 (46)
II	36 (38)	19 (39)	6 (32)	8 (42)	29 (36)	9 (29)	7 (54)	11 (39)
II	13 (14)	8 (16)	3 (16)	1 (5)	12 (15)	5 (16)	2 (15)	4 (14)
Missing	0	0	0	0	1 (1)	1 (3)	0	0
Cytogenetic risk, n (%)^c	n=91	n=47	n=18	n=18	n=77	n=29	n=13	n=28
Standard risk	75 (82)	38 (81)	13 (72)	18 (100)	66 (86)	24 (83)	12 (92)	23 (82)
High risk	16 (18)	9 (19)	5 (28)	0	11 (14)	5 (17)	1 (8)	5 (18)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; ISS, International Staging System; VRd, bortezomib + lenalidomide + dexamethasone. ^aAmong the mobilized patients in GRIFFIN, 9 (D-VRd, n=5; VRd, n=4) patients received cyclophosphamide, and no accurate information on mobilization regimen used was available for 16 (D-VRd, n=8; VRd, n=8) patients. ^bISS staging is based on the combination of serum β₂-microglobulin and albumin. Higher stages indicate more advanced disease. ^cCytogenetic risk was assessed by fluorescence in situ hybridization (local testing); high cytogenetic risk was defined as the presence of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data.

Summary of ASCT

A higher rate of mobilization was observed in the D-VRd vs Rd arm due to lower rates of discontinuation during induction (D-VRd, 2%; VRd, 7%) and following induction but before mobilization (D-VRd, 3%; VRd, 14%).
A total of 68 (72%) patients in the D-VRd arm and 44 (55%) in the VRd arm received plerixafor either upfront or as a rescue strategy.
A total of 5 patients in the D-VRd arm and 4 in the VRd arm received cyclophosphamide.
A total of 19 (20%) patients in the D-VRd arm and 28 (35%) in the VRd arm received granulocyte colony-stimulating factor (G-CSF) alone.
The median CD34⁺stem cell yield was 8.3×10⁶ cells/kg in the D-VRd arm and 9.4×10⁶ cells/kg in the VRd arm. In both arms, a numerically higher stem cell yield was reported in patients who received upfront plerixafor vs those who received rescue plerixafor (D-VRd, 8.8×10⁶ cells/kg vs 7.1×10⁶ cells/kg, P=0.10; VRd, 10.5×10⁶ cells/kg vs 9.4×10⁶ cells/kg, P=0.20; respectively).
Median number of days for stem cell collection was 2 in patients in the D-VRd arm and 1 in the VRd arm.
Additional data stratified by upfront plerixafor use, rescue plerixafor use, and G-CSF only use are summarized in Table: Summary of ASCT in the GRIFFIN Study.

Summary of ASCT in the GRIFFIN Study^a,¹⁴

Parameter	All Patients		Received Upfront Plerixafor		Rescue Plerixafor Strategy^b
	All Patients		Received Upfront Plerixafor		Received Rescue Plerixafor		Received G-CSF Only
	D-VRd	VRd	D-VRd	VRd	D-VRd	VRd	D-VRd	VRd
Pts who underwent mobilization, n	95	80	49	31	19	13	19	28
Pts who received plerixafor, n	68	44	49	31	19	13	0	0
Mobilization attempts, n (%)
1	89 (94)	74 (93)	46 (94)	28 (90)	19 (100)	12 (92)	17 (89)	27 (96)
2	2 (2)	3 (4)	1 (2)	1 (3)	0	1 (8)	1 (5)	1 (4)
3	0	1 (1)	0	0	0	0	0	0
4	0	1 (1)	0	1 (3)	0	0	0	0
Missing	4 (4)	1 (1)	2 (4)	1 (3)	0	0	1 (5)	0
Median stem cell collection target per ASCT (range), ×10⁶ CD34⁺cells/kg	2.5 (2-4)	2.5 (2-5)	2.5 (2-4)	2.5 (2-5)	2 (2-4)	2.5 (2-4)	2 (2-3)	2 (2-4)
Median duration of stem cell collection (range), days	2 (1-4)	1 (1-4)	2 (1-4)	1 (1-4)	1 (1-3)	2 (1-4)	2 (1-4)	1 (1-4)
Median stem cell yield (range), ×10⁶ CD34⁺cells/kg	8.3 (2.6-33)	9.4 (4.1-28.7)	8.8 (2.6-33)	10.5 (5.5-22.5)	7.1 (4.2-16.7)	9.4 (4.4-17.3)	8.3 (4.4-18.6)	7.6 (4.1-23)
Pts who collected the minimum threshold for ASCT, n (%)	89 (94)	79 (99)	45 (92)	30 (97)	19 (100)	13 (100)	18 (95)	28 (100)
Pts who collected 2x the minimum threshold for ASCT, n (%)	81 (85)	74 (93)	42 (86)	29 (94)	16 (84)	11 (85)	17 (89)	26 (93)
Number of CD34⁺ cells transplanted (10⁶ cells/kg), median (range)	4.2 (2-27.6)	4.8 (1.1-15)	4.3 (2.5-27.6)	4.8 (1.1-15)	4.0 (2.0-8.3)	4.7 (1.7-12.2)	4.3 (2.8-9.3)	4.4 (2.0-13.2)
Median duration from end of induction to apheresis (range), days	27 (0-63)	24 (4-133)	23 (14-48)	25.5 (4-133)	26 (0-36)	23 (14-43)	33 (13-63)	22.5 (12-55)
Pts who completed ASCT, n (%)	94 (99)	78 (98)	49 (100)	31 (100)	18 (95)	13 (100)	19 (100)	26 (93)
Abbreviations: ASCT, autologous stem cell transplant; CD34⁺, cluster of differentiation 34 positive; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; pts, patients; VRd, bortezomib + lenalidomide + dexamethasone.^aAmong the mobilized patients in GRIFFIN, 9 (D-VRd, n=5; VRd, n=4) patients received cyclophosphamide, and no accurate information on mobilization regimen used was available for 16 (D-VRd, n=8; VRd, n=8) patients. ^bPatients who did not receive upfront plerixafor had the treatment plan called “rescue plerixafor strategy.” Rescue plerixafor use was defined as only using plerixafor when deemed necessary “just-in-time” based on pre-apheresis blood CD34⁺ cell count after G-CSF. Patients in the rescue plerixafor strategy group did not receive upfront plerixafor, but received either rescue plerixafor or no plerixafor at all.

Post hoc Analysis of Patients Aged ≥65 Years From the PERSEUS and GRIFFIN Studies

Rodriguez-Otero et al (2024)¹⁵ presented (at the 21^st IMS Annual Meeting) results from a post hoc analysis of the PERSEUS and GRIFFIN studies that evaluated the efficacy and safety of D-VRd vs VRd in 237 patients aged ≥65 years.

Results

Patient Characteristics

Patients aged ≥65 years represented 25.5% of patients from the PERSEUS study (D-VRd, 94 of 355 patients vs VRd, 87 of 354 patients) and 27.1% of patients from the GRIFFIN study (D-VRd, 28 of 104 patients vs VRd, 28 of 103 patients). The baseline demographic and disease characteristics are summarized in Table: Baseline Demographic and Disease Characteristics in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population.
The median duration of treatment was 37.4 months (range: 0.5-52.5) and 32.6 months (range: 0.1-53.0) in the D-VRd and VRd groups, respectively.
The median relative dose intensities were comparable between the D-VRd vs VRd groups for bortezomib (92.9% vs 93.5%) and dexamethasone (95.5% vs 100%) but were relatively lower in the D-VRd group for lenalidomide (75.5% vs 87.7%). The median relative dose intensity for DARZALEX FASPRO in the D-VRd group was 99.7%.
Treatment discontinuation rates were comparable between the D-VRd vs VRd groups for bortezomib (12.5% vs 12.3%) and dexamethasone (3.3% vs 3.5%) but were higher in the D-VRd group for lenalidomide (23.3% vs 17.5%).

Baseline Demographic and Disease Characteristics in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population^a,¹⁵

Characteristic	D-VRd (n=122)	VRd (n=115)
Median age (range), years	67 (65-70)	67 (65-70)
Male, n (%)	76 (62.3)	67 (58.3)
ECOG PS score, n/N (%)
0	66/122 (54.1)	66/114 (57.9)
1	47/122 (38.5)	40/114 (35.1)
2	9/122 (7.4)	8/114 (7.0)
ISS disease stage^b, n (%)
I	51 (41.8)	39 (33.9)
II	32 (26.2)	33 (28.7)
III	11 (9.0)	15 (13.0)
Missing	28 (23.0)	28 (24.3)
Cytogenetic risk^c, n/N (%)
Standard risk	88/119 (73.9)	91/114 (79.8)
High risk	27/119 (22.7)	22/114 (19.3)
del(17p)	17/119 (14.3)	12/114 (10.5)
t(4;14)	10/119 (8.4)	7/114 (6.1)
t(14;16)	2/119 (1.7)	5/114 (4.4)
Indeterminate	4/119 (3.4)	1/114 (0.9)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; VRd, bortezomib, lenalidomide, and dexamethasone.^aPooled ITT population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN.^bISS staging was derived based on the combination of serum β2-microglobulin and albumin.^cHigh risk was defined as ≥1 of the following cytogenetic abnormalities: del(17p), t(4;14), and/or t(14;16) by fluorescence in situ hybridization. Standard risk was defined by the absence of these cytogenetic abnormalities.

Transplant Characteristics

Majority of patients aged ≥65 years who received ≥1 dose of the study treatment (D-VRd, n=120 vs VRd, n=114) underwent stem cell mobilization (93.3% vs 84.2%).
- The median number of CD34⁺ cells collected was sufficient for ASCT in both the treatment groups.
- Two patients from the D-VRd group vs 1 patient from the VRd group had <2×10⁶/kg CD34⁺ stem cells collected.
The proportions of patients who proceeded to ASCT was comparable between the treatment groups (D-VRd, 86.7% vs VRd, 82.5%).
- The median time to engraftment was comparable between the treatment groups (D-VRd, 14 days vs VRd, 13 days).
The stem cell mobilization and ASCT outcomes are summarized in Table: Stem Cell Mobilization and ASCT Outcomes in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Population

Stem Cell Mobilization and ASCT Outcomes in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN Safety Population^a,¹⁵

Characteristic	D-VRd (n=120)	VRd (n=114)
Patients proceeded to stem cell mobilization, n (%)	112 (93.3)	96 (84.2)
Mobilization medication/therapy used, n (%)
G-CSF^b	110 (98.2)	91 (94.8)
Cyclophosphamide	71 (63.4)	51 (53.1)
Plerixafor	59 (52.7)	32 (33.3)
Chemotherapy	2 (1.8)	0 (0)
Other	1 (0.9)	2 (2.1)
Patients with stem cells collected, n (%)	108 (90.0)	95 (83.3)
Total CD34⁺ stem cells collected, median (range), ×10⁶/kg	4.22 (1.80-13.50)	5.76 (1.12-49.50)
Patients who completed melphalan conditioning therapy, n	104	94
Total dose of melphalan conditioning therapy, median (range), mg/m²	193 (59-385)	192 (52-371)
Patients who proceeded to ASCT, n (%)	104 (86.7)	94 (82.5)
Patients with hematopoietic reconstitution, n	103	93
Time to achieve ANC ≥0.5×10⁹/L,^c median (range), days	13 (0-28)	12 (0-34)
Time to achieve platelets ≥20×10⁹/L without transfusion,^c median (range), days	13 (0-33)	12 (1-48)
Time to engraftment,^c,d median (range), days	14 (0-33)	13 (1-48)
Abbreviations: ANC, absolute neutrophil count; ASCT, autologous stem cell transplant; CD, cluster of differentiation; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; VRd, bortezomib, lenalidomide, and dexamethasone.^aPooled safety population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN and received ≥1 dose of study treatment.^bIncluded standardized medications of filgrastim, lenograstim, and G-CSF.^cNumber of days from the ASCT date, excluding patients whose counts did not reach nadir below the set threshold.^dThe date of engraftment post-ASCT was defined as the latest date of ANC ≥0.5×10⁹/L and platelet count ≥20×10⁹/L. Patients with hematopoietic reconstitution were included.

Efficacy

At a median follow-up of 47.5 and 49.6 months, the median PFS was not reached in the PERSEUS and GRIFFIN groups, respectively.
Patients treated with D-VRd showed 44% reduction in the risk of disease progression or death vs VRd (HR, 0.56; 95% CI, 0.31-1.01; P = 0.05).
The estimated 48-month PFS rates were 79.1% and 71.6% for the D-VRd vs VRd groups, respectively.
Higher response rates, overall MRD-negativity rates (10^-5), and sustained negativity rates (10^-5; ≥12 months) were observed in the D-VRd vs VRd groups, respectively, and is presented in Table: Summary of Response Rates and MRD-negativity Rates in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population.

Summary of Response Rates and MRD-negativity Rates in Patients Aged ≥65 Years in the Pooled PERSEUS/GRIFFIN ITT Population^a,¹⁵

Patients, %	D-VRd (n=122)	VRd (n=115)	OR (95% CI)^b	P Value^c
sCR	59.0	49.6	1.49 (0.88-2.53)	0.14
≥CR	82.8	67.0	2.37 (1.28-4.39)	0.005
CR	23.8	17.4	-	-
VGPR	10.7	19.1	-	-
PR	1.6	9.6	-	-
SD/PD/NE	4.9	4.3	-	-
Overall MRD-negativity (10^-5)^d	66.4	41.7	2.75 (1.61-4.71)	0.0002
Sustained MRD-negativity (10^-5) (≥12 months)^e	52.5	26.1	3.2 (1.83-5.58)	<0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone. ^aPooled ITT population included all patients aged ≥65 years who were randomized in PERSEUS or GRIFFIN.^bMantel-Haenszel estimates of the common ORs for stratified tables were used. The stratification factors were ISS disease stage (I vs II vs III) and cytogenetic risk (high risk vs standard/unknown risk).^cP value from the stratified Cochran-Mantel-Haenszel chi-square test.^dMRD-negativity rates were for patients who also achieved ≥CR. MRD was assessed using bone marrow aspirate and evaluated by next-generation sequencing (clonoSEQ assay version 2.0; Adaptive Biotechnologies). ^eSustained MRD-negativity was defined as 2 consecutive MRD measurements ≥12 months apart without an MRD-positive measurement in between.

Safety

There were no new safety concerns observed, and the overall safety profile of patients aged ≥65 years was comparable to the pooled patient population irrespective of age.
A higher incidence of grade 3/4 infections was observed in the D-VRd vs VRd group, with slightly higher rates in patients ≥65 years (36.3% vs 24.8%) than in all patients (29.5% vs 22.5%).
The frequency of TEAEs that resulted in discontinuation of ≥1 study drug was similar between treatment groups in patients aged ≥65 years and all patients. The summary of TEAEs is presented in Table: Summary of TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Population.

Summary of TEAEs in Patients Aged ≥65 Years and All Patients Irrespective of Age in the Pooled PERSEUS/GRIFFIN Safety Population^a,¹⁵

Patients, n (%)	Age (≥65 Years)		All Patients
Patients, n (%)	D-VRd (n=120)	VRd (n=114)	D-VRd (n=450)	VRd (n=449)
Grade 3/4 TEAEs	113 (94.2)	99 (86.8)	406 (90.2)	378 (84.2)
Most common^b
Neutropenia/febrile neutropenia	71 (59.2)	49 (43.0)	282 (62.7)	214 (47.7)
Thrombocytopenia	46 (38.3)	22 (19.3)	118 (26.2)	69 (15.4)
Diarrhea	17 (14.2)	12 (10.5)	44 (9.8)	32 (7.1)
Pneumonia	13 (10.8)	7 (6.1)	49 (10.9)	35 (7.8)
Serious TEAEs	81 (67.5)	60 (52.6)	246 (54.7)	224 (49.9)
Most common^c
Pneumonia	15 (12.5)	9 (7.9)	55 (12.2)	35 (7.8)
Febrile neutropenia	8 (6.7)	5 (4.4)	19 (4.2)	17 (3.8)
Pyrexia	8 (6.7)	2 (1.8)	24 (5.3)	26 (5.8)
Diarrhea	7 (5.8)	4 (3.5)	11 (2.4)	11 (2.4)
Sepsis	6 (5.0)	3 (2.6)	9 (2.0)	10 (2.2)
Fatal TEAEs^d	6 (5.0)	4 (3.5)	14 (3.1)	17 (3.8)
Discontinuation of ≥1 study drug due to TEAEs	49 (40.8)	52 (45.6)	149 (33.1)	136 (30.3)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone. ^aPooled safety population included all patients who were randomized in PERSEUS or GRIFFIN and received ≥1 dose of study treatment.^bGrade 3/4 TEAEs that occurred in ≥10% of patients aged ≥65 years in either treatment group.^cSerious TEAEs that occurred in ≥5% of patients aged ≥65 years in either treatment group.^dFatal TEAEs were considered related to daratumumab in 1 patient aged ≥65 years (squamous cell carcinoma) and in 1 patient aged <65 years (sepsis).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 14 November 2024.

References

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