Summary

• DARZALEX for intravenous (IV) use 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 is a 2-part, phase 2 study evaluating the safety and efficacy of DARZALEX (D) when administered in combination with VRd in patients with newly diagnosed MM (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 DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) consolidation, 56.3% patients achieved stringent complete response (sCR), and 50% were minimal residual disease (MRD) negative (10^-5 threshold). After maintenance, 93.8% patients achieved sCR, and 81.3% patients were MRD negative (10^-5 threshold). 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)³ presented the primary analysis of the randomized portion of this study (n=207). Voorhees et al (2023)⁵ 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 follow-up 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], 1.22-3.89; 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 D-VRd 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%).
  • Sborov et al (2022)⁶ conducted a post-hoc analysis to evaluate the risk and incidence of vascular thrombotic events (VTE) 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 (D-VRd, 2%; VRd, 6.9%), pulmonary embolism (D-VRd, 2%; VRd, 3.9%), and embolism classified as unspecified vessel type and mixed arterial and venous (D-VRd, 2%; 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.
  • Chhabra et al (2023)⁷ conducted a post hoc analysis to evaluate stem cell mobilization, collection yields, and hematopoietic recovery following ASCT after frontline DARZALEX- and lenalidomide-containing quadruplet induction in patients with NDMM in the GRIFFIN and MASTER studies. In the GRIFFIN study, 175 patients (D-VRd, n=95; VRd, n=80) underwent stem cell mobilization, with a median duration of 27 days after completing D-VRd induction therapy and 24 days after completing VRd induction therapy. Among patients who underwent mobilization and stem cell collection in the D-VRd vs VRd arm, 2% vs 6% of recipients did not achieve the center-specific, minimally required cluster of differentiation (CD)34+ cell yield in the initial mobilization attempt, respectively. Among patients who underwent mobilization, plerixafor use was more prevalent in those receiving D-VRd (72%) compared with those receiving VRd (55%). The median total CD34+ cell collection after D-VRd vs VRd induction was 8.3×10⁶/kg (range, 2.6-33.0×10⁶/kg) vs 9.4×10⁶/kg (range, 4.1-28.7×10⁶/kg), respectively. The median collection duration in the D-VRd vs VRd arm was 2 days vs 1 day, respectively. Among individuals who underwent mobilization, 99% vs 98% of patients in the D-VRd vs VRd arm underwent ASCT using median CD34+ cell doses of 4.2×10⁶/kg vs 4.8×10⁶/kg, respectively.
• PERSEUS (MMY3014) is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with lenalidomide and DARZALEX FASPRO (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for ASCT.⁸
  • Sonneveld et al (2023)⁸ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. At a median follow-up duration of 47.5 months (range, 0-54.4), 14.1% (50/355) of patients in the D-VRd arm vs 29.1% (103/354) of patients in the VRd arm experienced disease progression or death (hazard ratio [HR], 0.42; 95% CI, 0.30-0.59; P<0.0001), respectively. Overall ≥CR, 87.9% vs 70.1% (P<0.0001) and overall MRD-negativity 75.2% vs 47.5% (P<0.0001) were higher with D-VRd vs VRd. The most common grade 3/4 adverse events (AEs) in the D-VRd vs VRd arm were neutropenia (62.1% vs 51%), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%).
  • Sonneveld et al (2024)⁹ presented (at the 21^st International Myeloma Society [IMS] Annual Meeting) the stem cell yield and ASCT results for transplant-eligible patients with NDMM from the PERSEUS study who received D-VRd vs VRd induction prior to HDT or ASCT. Of the 640 patients who underwent stem cell collection (D-VRd, n=326 vs VRd, n=314), a high percentage of patients in both groups (D-VRd, 98.2% vs VRd, 99.4%) had sufficient stem cells collected for ASCT (≥2×10⁶/kg cells). Although the D-VRd vs VRd group had a numerically lower median number of collected CD34⁺ stem cells (5.52×10⁶/kg vs 7.44×10⁶/kg), the percentage of patients who underwent ASCT was similar in both groups (89.7% vs 87%). After completion of 6 treatment cycles, 58 patients (29 in each treatment group) received ASCT, with 100% hematopoietic reconstitution and comparable engraftment times in both groups.
  • Bertamini et al (2024)¹⁰ presented (at the 66^th American Society of Hematology [ASH] Annual Meeting) results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTCs) as a biomarker in transplant-eligible patients with NDMM. D-VRd vs VRd significantly improved patient outcomes, across both high and low CTC levels (P<0.0001). D-VRd vs VRd improved MRD-negativity rates (≥CR; 10^–5 and 10^–6 sensitivities) and sustained MRD-negativity rates (≥CR; 10^-5 and 10^–6 sensitivities; ≥12 months) in patients with both high and low CTC levels. D-VRd vs VRd improved progression-free survival (PFS) in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in outcomes for patients with high cytogenetic risk combined with high CTC levels. Further, D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).
• CEPHEUS (MMY3019) is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.^11-13
  • Usmani et al (2025)¹³ reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall MRD-negativity (10^-5 sensitivity with ≥CR) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; OR, 2.37; 95% CI, 1.58-3.55; P<0.0001). Similarly, the sustained MRD-negativity (10^-5 sensitivity; ≥12 months) rate was significantly higher in the D-VRd vs VRd arm (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4; P<0.0001). The overall ≥CR rate was significantly higher with D-VRd vs VRd (81.2% vs 61.6%; OR, 2.73; 95% CI, 1.71-4.34; P<0.0001). Further, D-VRd significantly improved the PFS (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005) with 43% reduction in the risk of progression or death vs VRd. The overall survival (OS) rate favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24). Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). The overall safety data were consistent with the established safety profile of each individual drug.
  • Zweegman et al (2024)¹⁴ presented (at the 66^th ASH Annual Meeting) an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for a stem cell transplant (SCT) or transplant deferred. The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10^–5 and 10^–6 sensitivities) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD-negativity (10^–6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free. Analyses of MRD-negativity (with ≥CR) rates in D-VRd vs VRd were generally consistent across prespecified subgroups.
• PLEIADES is an ongoing, phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care treatment regimens in patients with MM. Specifically with transplant-eligible NDMM DARZALEX FASPRO + VRd (D-VRd) for patients with transplant-eligible NDMM (n=67).^15-18 Results specifically to the D-VRd cohort are summarized.
• Several subgroup analyses regarding the use of DARZALEX and DARZALEX FASPRO in combination with VRd in patients with MM were identified. These analyses are listed in the References section for your information.^19-25

PRODUCT LABELING

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

CLINICAL STUDIES

DARZALEX Phase 2 Study

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742) is an ongoing, 2-part, open-label, multicenter, phase 2, randomized, active-controlled United States (US) study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.^1-3

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.
• 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 endpoint: sCR (by end of post-ASCT consolidation)
• Secondary endpoints: MRD (10^-5 via next-generation sequencing [NGS]), CR, overall response rate (ORR), very good partial response or better (≥VGPR)

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) 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.

Safety

• During cycle 1, three of 16 patients developed 4 dose-limiting toxicities (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 infusion-related reactions (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 (68.6%) patients experienced a serious AE. For the incidences of grade 3/4 TEAEs, see Table: Most Common Grade 3/4 TEAEs.

Efficacy

• At a median follow-up of 40.8 months (range, 20.6-43), disease progression occurred in 3 patients.
• Median time to first response was 0.77 months (range, 0.1-2.1), and median duration of response 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-month PFS and OS rate 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 was sustained for ≥12 months in 8 (50%) patients.
• Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort.

Part 2: Randomized Phase

Voorhees et al (2020)^2,3,26 presented the primary analysis and updated analysis of the randomized portion of this study. Kaufman et al (2020)²⁷ presented a 1-year update of safety and efficacy results at the 62nd ASH Annual Meeting & Exposition in December 2020. Laubach et al (2021)²⁸ presented updated efficacy and safety results after 2 years of maintenance therapy in the GRIFFIN Study. Voorhees et al (2023)⁵ 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 demographics are summarized in Table: Patient Demographics in the Randomized Phase (ITT).

Efficacy

• Primary endpoint met with D-VRd improving the sCR rate by end of consolidation (D-VRd vs VRd: 42.4% vs 32%; 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 group vs the VRd group (99% 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 intention-to-treat (ITT) population, 51% of patients in the D-VRd arm achieved post-ASCT 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 in Table: Post-Consolidation MRD-Negativity.
• Median stem cell yield (D-VRd vs VRd): 8.2 vs 9.4 x 10⁶ cells.

• 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.
• MRD-negativity rates in the D-VRd and VRd arms, respectively (10^-5 sensitivity threshold):
  • D-VRd (n=104) and VRd (n=103) (ITT): MRD-negative: 51% vs 20.4% (P<0.0001); MRD-negative & ≥CR: 47.1% vs 18.4% (P<0.0001)
    • ≥CR: D-VRd (n=79) and VRd (n=59): MRD-negative: 62% vs 32.2% (P=0.0006)
    • MRD evaluable: D-VRd (n=77) and VRd (n=65): MRD-negative: 68.8% vs 32.3% (P<0.0001)
• In the ITT population, median PFS and OS were not reached 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% 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).

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. See Table: Most Common TEAEs.
  • Pneumonia was reported in 13% of patients in the D-VRd arm and 15% of patients in the VRd arm. See Table: Most Common TEAEs.

Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)⁵ 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], 47.4-52.1).
• 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, 31.1-33.4) and 27.5 months (IQR, 2.9-32.7), 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 [IQR, 3-5]).

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, 1.22-3.89; 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.^5,29

• 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.

• Among patients who achieved ≥partial response (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).

• 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).

• 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 not reached (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).

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 D-VRd 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) infections 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 of 89 (4%) evaluable patients in the D-VRd arm and 3 of 71 (4%) 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 [39%] IRRs reported at the initial infusion, 2 [2%] IRRs at the second infusion, and 14 [14%] IRRs at the subsequent infusions.²⁹

Post Hoc Analysis of the Incidence of VTE in the GRIFFIN Study

Sborov et al (2022)⁶ 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), and
  • 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 subcutaneous (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.

Efficacy

• Among patients with VTEs, the median total number of treatment cycles was 32 (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.

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% (n=5)
    • Cycles 18+: 3.6% (n=3) vs 1.7% (n=1)
• In the D-VRd vs VRd arm, the median SAVED score in patients in the ITT population was 0 (range, 0 to 3) vs 0 (range, -3 to 4) and in patients experiencing VTE was 0 (range, 0-3) vs 0.5 (range, 0-4).
• 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, anti-thrombosis 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% (n=8) vs 93.8% (n=15) of patients who developed VTE.
  • Overall, 60% (n=6) of patients in the D-VRd arm and 68.8% (n=11) of patients in the VRd arm were receiving anti-thrombosis prophylaxis during the first onset of VTE.

Post Hoc Analysis for Stem Cell Mobilization Yields

Chhabra et al (2023)⁷ conducted a post hoc analysis to evaluate stem cell mobilization, collection yields, and hematopoietic recovery following ASCT after frontline DARZALEX- and lenalidomide-containing quadruplet induction in patients with NDMM from the GRIFFIN and MASTER studies.

Study Design/Methods

• In the GRIFFIN study, patients at 35 US sites underwent stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) with or without plerixafor (upfront/rescue) after 4 induction cycles (12 weeks) of D-VRd or VRd. If plerixafor-facilitated mobilization was unsuccessful, cyclophosphamide-based mobilization was permitted. After mobilization, patients received melphalan 200 mg/m², followed by ASCT. A summary of patients from the GRIFFIN study who underwent stem cell mobilization has been presented in Table: Summary of Patients From the GRIFFIN Study Who Underwent Stem Cell Mobilization.
  • The upfront plerixafor usage strategy comprised planned use of plerixafor, irrespective of blood CD34+ count on day 4 of G-CSF administration.
  • The rescue plerixafor usage strategy comprised “just in time” use of plerixafor based on peripheral blood CD34+ count after G-CSF administration.

Results

Patient Characteristics

• Among the 207 randomized patients in the GRIFFIN study, 91% (95 of 104) in the D-VRd group and 78% (80 of 103) in the VRd group underwent stem cell mobilization. Baseline characteristics of patients who received D-VRd and VRd in the GRIFFIN study based on upfront and rescue plerixafor received are presented in Table: Baseline Characteristics of Patients Who Received D-VRd and VRd in the GRIFFIN Study.
• Among the mobilized patients in the D-VRd vs VRd arm, 99% (94 of 95) vs 98% (78 of 80) underwent ASCT, respectively.

Stem Cell Mobilization

• The median duration of stem cell collection was 2 days for patients receiving D-VRd and 1 day for patients receiving VRd. See Table: Summary of ASCT and Stem Cell Mobilization in the GRIFFIN Study.
• Among patients who underwent mobilization, plerixafor use was more prevalent in those receiving D-VRd (72%) compared with those receiving VRd (55%).

CD34+ Stem Cell Yield

• The median CD34+ stem cell yield in the D-VRd vs VRd arm was 8.3×10⁶ cells/kg vs 9.4×10⁶ cells/kg, respectively, and was numerically higher for patients who received upfront plerixafor vs 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). See Table: Summary of ASCT and Stem Cell Mobilization in the GRIFFIN Study.

Stem Cell Remobilization

• Remobilization occurred in 2% (2/95) vs 6% (5/80) of patients in the D-VRd vs VRd arm, respectively. See Table: Summary of ASCT and Stem Cell Mobilization in the GRIFFIN Study.
• Of the mobilized patients, 9 (D-VRd, n=5; VRd, n=4) received cyclophosphamide.

Transplantation and Hematologic Recovery

• In total, 3 mobilized patients did not undergo ASCT (at the discretion of the principal investigator and due to AE sequelae and patient withdrawal).
• In the D-VRd vs VRd arm, 94 vs 78 patients underwent ASCT with a median transplanted CD34+ cell dose of 4.2×10⁶/kg vs 4.8×10⁶/kg, respectively. See Table: Summary of ASCT and Stem Cell Mobilization in the GRIFFIN Study.
• In the D-VRd vs VRd arm, neutrophil recovery was achieved in 100% of mobilized patients after ASCT at a median duration of 12 days (range, 3-31) vs 12 days (range, 2-23), respectively.
• Platelet recovery in the D-VRd vs VRd arm occurred at a median duration of 13 vs 12 days, respectively.

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; clinicaltrials.gov identifier: NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in D-VRd group or lenalidomide in VRd arm in patients with NDMM eligible for ASCT. Sonneveld et al (2023)⁸ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT.

Study Design/Methods

• A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.
  • Stratification was done based on the International Staging System (ISS) disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).
• Dosing:
  • Induction and consolidation: Total duration of induction and consolidation treatment was 6 cycles. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO- 1800 mg once weekly (QW) in cycles 1-2 and every 2 weeks (Q2W) in cycles 3-4
      • SC bortezomib-1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • Oral (PO) lenalidomide-25 mg on days 1-21 of each cycle
      • PO/IV dexamethasone-40 mg on days 1-4 and days 9-12 of each cycle
    • VRd:
      • SC bortezomib-1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
      • PO lenalidomide-25 mg daily on days 1-21 of each cycle
      • PO/IV dexamethasone-40 mg on days 1-4 and days 9-12 of each cycle
  • Maintenance: Total duration of maintenance (≥24 months) was cycle 7 until PD. Each cycle was 28 days.
    • D-VRd:
      • DARZALEX FASPRO-1800 mg SC every 4 weeks
      • PO lenalidomide-10 mg until PD or unacceptable toxicity
      • Patients who achieved sustained MRD for 12 months after ≥24 months of maintenance discontinued DARZALEX FASPRO, but continued PO lenalidomide until PD or unacceptable toxicity. Once they experienced loss of MRD-negativity or CR, they restarted DARZALEX FASPRO
      • Patients who did not achieve sustained MRD for 12 months after ≥24 months of maintenance continued DARZALEX FASPRO and PO lenalidomide
    • VRd:
      • PO lenalidomide-10 mg daily until PD or unacceptable toxicity
• Primary endpoint: PFS.
• Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.
• Other secondary endpoints: ORR, ≥VGPR, sCR, duration of MRD-negativity.

Results

Patient Characteristics

• A total of 709 patients were randomized into the D-VRd (n=355) and VRd (n=354) arms.
• Demographics and baseline clinical characteristics of the ITT population are presented in Table: Demographics and Baseline Clinical Characteristics of the ITT Population.
• A total of 698 patients (D-VRd, n=351; VRd, n=347) received ≥1 dose of treatment.
• As of the clinical data cutoff date of August 1, 2023, 322 (91.7%) vs 300 (86.5%) patients in the D-VRd vs VRd arm, who started the induction phase continued into the maintenance phase, respectively.
  • A total of 207/322 patients in the D-VRd arm who were receiving maintenance treatment discontinued DARZALEX FASPRO per protocol after receiving ≥24 months of maintenance treatment and achieving ≥CR and sustained MRD-negativity for ≥12 months.
• A total of 315 (89.7%) vs 302 (87%) patients in the D-VRd vs VRd arm received ASCT, respectively.
• The median duration of treatment and median relative dose intensities are presented in Table: Duration of Treatment and Relative Dose Intensities During Induction/Consolidation/Maintenance Treatment in the Safety Population.
• The median duration of follow-up was 47.5 months (range, 0-54.4).