Summary

• DARZALEX for intravenous (IV) use + DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for use in combination with carfilzomib, lenalidomide, and dexamethasone (D-KRd) for the treatment of patients with multiple myeloma (MM). Janssen does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• Bhutani et al (2022)^1,2 reported (at the 64th American Society of Hematology [ASH] Annual Meeting and Exposition) the results of an interim analysis from stage 1 of an ongoing minimal residual disease (MRD)-driven, single center, phase 2 study of D-KRd in patients with newly diagnosed multiple myeloma (NDMM). At the end of induction complete response (≥CR) + stringent complete response (sCR) was reported in 15/23 (65%) patients, of whom, 52% had sCR. The MRD-negativity rate (next-generation sequencing [NGS]) was 70% (10⁵ threshold) and 43.5% (10^-6 threshold). The most common (>10%) Grade ≥3 treatment-emergent adverse events (TEAEs) were hypophosphatemia (30.4%), hypertension (13%), and neutropenia (13%).
• Touzeau et al (2024)³ reported the results from a multicenter, single-arm, open-label, phase 2 study evaluating the efficacy and safety of D-KRd induction and consolidation plus tandem transplant in patients with high-risk transplant-eligible patients with NDMM (N=50). The overall response rate (ORR) by the end of induction was 95%, and 53% of patients achieved MRDnegativity after induction at 10^-5 sensitivity threshold. At a median follow-up duration of 33 months, the 30-month overall survival (OS) and progression-free survival (PFS) rates were 91% and 80%, respectively. Grade 3 to 4 D-KRd induction/consolidation-related adverse events (AEs) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%).
• Derman et al (2021)⁴ presented (at the 65th ASH Annual Meeting & Exposition) efficacy and safety results of patients with NDMM treated with extended D-KRd without autologous stem cell transplant (ASCT) regardless of transplant eligibility at a median follow-up of 10 months. Derman et al (2024)⁵ reported the efficacy and safety results of patients with NDMM treated with 24 cycles of D-KRd without ASCT at a median follow-up of 27 months. The primary endpoint of sCR and/or NGS MRD-negative response (at a threshold of <10^-5) after 8 cycles of DKRd was achieved in 75% (30/40) of patients. Notable grade ≥3 AEs were lymphopenia (36%), thrombocytopenia (26%), and neutropenia (21%).
• Costa et al (2019)⁶ presented the results of an ongoing phase 2 study (MASTER) evaluating the efficacy and safety of D-KRd induction followed by autologous hematopoietic cell transplantation (AHCT) and MRD-adapted consolidation therapy for patients with NDMM at a median follow-up of 7.4 months. Costa et al (2023)⁷ reported the results from the final analysis of the MASTER study (N=123) at a median follow-up of 42.2 months. The overall MRDnegative remission rate (NGS; <10⁵ threshold) in MRD-evaluable patients at any point in treatment was 81% (95% confidence interval [CI], 73-88). The 3-year PFS rate was 88% (95% CI, 78-95) for patients with standard-risk (0 high-risk cytogenetic abnormalities [0 HRCA]), 79% (95% CI, 67-88) for patients with high-risk (1 HRCA), and 50% (95% CI, 30-70) for patients with ultra high-risk (≥2 HRCAs) cytogenetic abnormalities. The 3-year OS rate was 94% (95% CI, 88-98) for patients with 0 HRCA, 92% (95% CI, 86-96) for patients with 1 HRCA, and 75% (95% CI, 63-85) for patients with ≥2 HRCAs. The most common grade 3 TEAEs (≥5%) were neutropenia (29%), lymphopenia (15%), hypertension (11%), anemia (9%), fatigue (9%), thrombocytopenia (7%), hypophosphatemia (7%), bone pain (6%), and leukopenia (5%).

• Callander et al (2024)⁸ reported post hoc analysis results evaluating the clinical efficacy of the DARZALEX-based quadruplet therapies D-KRd and DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in transplant-eligible patients with NDMM with HRCAs from the MASTER and GRIFFIN studies, respectively. In the MASTER study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.6%, 89.1%, and 70.8%; the estimated 24-month PFS rate was 92.4%, 95.7%, and 65.5%; and MRD-negativity (10^-5) was reported in 80.0%, 86.4%, and 83.3%. In MASTER study, 2 patients with 0 HRCA died a sudden death and 1 patient with ≥2 HRCAs died of reasons unrelated to the treatment.
• Giri et al (2022)⁹ presented (at the 64th ASH Annual Meeting and Exposition) a post hoc subgroup analysis of MASTER study according to age group (≥70 years vs <70 years). In patients aged ≥70 years vs <70 years, rate of MRD-surveillance (MRDSURE) was 61% vs 74%, 3-year PFS rate was 86.3% vs 80.3%, and 3-year OS rate was 95.8% vs 88.7%, respectively. In patients aged ≥70 years vs <70 years, grade ≥3 AEs were reported in 79% vs 69%, respectively.
• Chhabra et al (2023)¹⁰ 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 MASTER study, the median duration for stem cell collection was 2 days. The median cluster of differentiation 34 positive (CD34⁺)cell yield in the D-KRd arm was 6.0×10⁶ cells/kg. The median CD34⁺ stem cell yields after upfront vs rescue plerixafor in the D-KRd arm of the MASTER study was 6.2×10⁶ cells/kg vs 5.2×10⁶ cells/kg (P=0.25).¹²
• Landgren et al (2020)¹¹ reported the final results of a phase 2 study (at the 62nd ASH Annual Meeting & Exposition) evaluating weekly (QW) D-KRd combination therapy in patients with NDMM (N=41) at a median follow-up of 21.3 months. In the absence of ASCT, 71% of patients achieved MRD-negativity. No additional grade ≥3 toxicities were observed with QW D-KRd therapy compared to standard-of-care biweekly carfilzomib, lenalidomide, and dexamethasone (KRd).
• Chari et al (2017)¹² reported the results of a phase 1b study evaluating the safety and efficacy of DARZALEX in combination with various treatment regimens, including KRd, for the treatment of MM. After a median follow-up of 16.1 months in patients in the DKRd arm (N=22) who completed 8 cycles of treatment (n=15), sCR was reported in 27%, ≥CR in 27%, very good partial response or better (≥VGPR) in 87%, and partial response or better (≥PR) in 100% of patients. TEAEs which occurred in ≥30% of patients receiving D-KRd included lymphopenia, thrombocytopenia, anemia, leukopenia, and neutropenia. Infusion-related reactions (IRRs) occurred in 27% of patients receiving DKRd.^12,13

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 DATA

Phase 2 Study of D-KRd in Patients With NDMM

Bhutani et al (2022)^1,2 reported an interim analysis from stage 1 of an ongoing, MRDdriven, single center, phase 2 study of D-KRd in patients with NDMM.

Study Design/Methods

• Patients aged ≥18 years old with NDMM who had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, left ventricular ejection fraction (LVEF) ≥45%, creatinine clearance (CrCl) ≥30 mL/min were included.²
• Patients with NDMM who were both eligible and ineligible for transplant were allowed to receive 1 cycle of nonprotocol therapy (if deemed necessary) and then 7 or 8 cycles of induction therapy with D-KRd (total 8 induction cycles).¹
• MRD assessment was performed by both NGS and next-generation flow cytometry (NGF) at the end of induction cycle 8, after ASCT, and after every 4 cycles of consolidation (maximum 12 cycles).^1,2
• Post-induction treatment was determined by an MRD-driven algorithm, using MRD (NGS, 10^-5) to assign patients to 1 of the following 3 study groups^1,2:
  • Group A (MRD-negative after induction): received lenalidomide maintenance therapy deferring ASCT, if transplant eligible
  • Group B (MRD-positive, transplant eligible): underwent ASCT, received KRd consolidation (maximum 12 cycles), followed by lenalidomide maintenance
  • Group C (MRD-positive after 8 cycles of induction, transplant ineligible): received KRd consolidation (maximum 12 cycles), followed by lenalidomide maintenance
• Patients were allowed to proceed to lenalidomide maintenance if they achieved MRDnegative status at any protocol-specified timepoint.¹
• Primary endpoint: rate of ≥CR after 8 cycles of D-KRd induction in patients with NDMM²
• Key secondary endpoints: ORR, post-induction rate of MRD-negative response, duration of response (DOR), time to next treatment (TNT), PFS, and OS²

Results

Patient Characteristics

• Stage 1 futility analysis criteria were met in November 2021, and stage 2 enrollment is actively ongoing.¹
• At data cutoff, 30/39 patients have been enrolled.¹ Overall, 23 patients were enrolled in stage 1.² The demographics and characteristics of stage 1 patients are presented in Table: Demographics and Other Characteristics (Stage 1).
• All patients completed 8 total cycles of induction therapy.²

Efficacy

• At the end of induction, ≥CR was achieved in 15/23 (65%) patients, with sCR in 52% and VGPR in 30%.^1,2 See Table: Response Rates With D-KRd.
• The MRD-negativity rate by NGS was 70% at the 10^-5 and 43.5% at the 10^-6 sensitivity level.²
• The MRD-negativity rate by NGF was 83% at the 10^-5 and 47% at the 10^-6 sensitivity level in 23 and 19 evaluable patients, respectively; 43% of bone marrow specimens tested by NGF were hemodiluted.^1,2
• Concordance of MRD by NGS/NGF at 10^-5 was 16/23 (69.6% in agreement and 30.4% in disagreement; Cohen's kappa, 0.183).^1,2
• Concordance of MRD by NGS/NGF at 10^-6 was 12/19 (63.2% in agreement and 36.8% in disagreement; Cohen's kappa, 0.257).^1,2
• Stem cell collection for eligible patients (n=22) was performed upon completion of induction; 5 patients failed to collect optimal target (≥3 x 10⁶ CD34⁺ cells/kg) during their first mobilization attempt after 8 cycles of induction.^1,2

Safety

• There were no treatment discontinuations due to toxicity reported.²
• There were no treatment-related mortality reported during stage 1.¹ See Table: Safety Profile of DKRd.

Phase 2 Study of D-KRd in Transplant-Eligible Patients With NDMM

Touzeau et al (2024)³ reported the results from a multicenter, single-arm, open-label, phase 2 (Intergroupe Francophone du Myelomé [IFM] 2018-04; clinicaltrials.gov identifier: NCT03606577) study evaluating the efficacy and safety of D-KRd induction and consolidation plus tandem transplant in patients with high-risk transplant-eligible patients with NDMM.

Study Design/Methods

• Key inclusion criteria: age ≤65 years, previously untreated symptomatic NDMM (measurable paraprotein in the serum [≥0.5 g/dL] or urine [>0.2 g/24 h]), transplant-eligible, ECOG PS ≤2, adequate renal function, and presence of at least 1 high-risk cytogenetics (t[4;14], del17p, t[14;16]).
• Key exclusion criteria: human immunodeficiency virus, hepatitis B virus and hepatitis C virus positivity, history of other malignancy (other than basal cell carcinoma and carcinoma of the cervix in situ), and grade ≥2 peripheral neuropathy (National Cancer Institute Common Toxicity Criteria [NCI-CTCAE] version 4.0).
• Patients received 28-day cycles of the following treatment:
  • Induction phase (cycles 1-6, 28-day cycles each):
    • DARZALEX: 16 mg/kg IV QW during cycles 1-2 on days 1, 8, 15, and 22; and every 2 weeks (Q2W) during cycles 3-6 on days 1 and 15.
    • Carfilzomib: 20 or 36 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of each cycle
    • Lenalidomide: 25 mg orally (PO) on days 1-21
    • Dexamethasone: 20 mg PO on days 1, 2, 8, 9, 15, 16, 22, and 23
  • Stem cell harvest:
    • Stem cell harvest was planned following the completion of cycle 6
    • Prior to the harvest, patients received high-dose cyclophosphamide (3 g/m²) in combination with granulocyte colony-stimulating factor (G-CSF) at a dose of 5 µg/kg, administered according to local practices. The target cell yield for collection was 5×10⁶ CD34⁺ cells per kg
  • First transplant:
    • Patients who achieved adequate stem cell collection proceeded to ASCT using melphalan (200 mg/m²) as the conditioning regimen
  • Consolidation phase (cycles 7-10, 28-day cycles each):
    • DARZALEX: 16 mg/kg IV Q2W on days 1 and 15
    • Carfilzomib: 56 mg/m² IV on days 1, 8, and 15
    • Lenalidomide: 15 mg PO for cycle 7 on days 1-21; and 25 mg on days 1-21 for cycles 8-10
    • Dexamethasone: 40 mg PO QW on days 1, 8, 15, and 22
  • Second transplant:
    • After the consolidation therapy, patients who remained progression-free underwent a second ASCT with melphalan 200 mg/m².
  • Maintenance phase (up to 2 years):
    • DARZALEX: 16 mg/kg IV every 8 weeks (Q8W)
    • Lenalidomide: 10 mg on days 1-21 (28-day cycle)
• Primary objective: feasibility of the treatment regimen with rate of patients who completed second ASCT as primary endpoint.
• Key secondary endpoints: response rates (overall response [OR], PR, VGPR, CR, and sCR) and MRD at each step of the program, quality of stem cell harvest, PFS, OS, and safety.
• All patients were followed until death or end of the study.
• Safety was monitored until 30 days after the last dose of the study drug, except for secondary malignancies (monitored continuously during follow-up).
• Toxicities were graded according to the NCI-CTCAE, version 4.03.

Results

Patient Characteristics

• Overall, 50 patients with symptomatic transplant-eligible patients with NDMM were enrolled between July 2019 and March 2021 from 11 centers in France. The baseline patient and disease characteristics are presented in Table: Baseline Patient and Disease Characteristics.
• Overall, 46 patients (92%) completed induction (2 patients had progressive disease, and 2 patients discontinued due to AE), and 42 patients (84%) underwent ASCT 1 (4 patients had stem cell collection failure).
• Forty (80%) completed consolidation (1 patient withdrew consent, and 1 patient discontinued due to AE), and 36 (72%) completed second transplant (4 patients due to stem cell collection failure). With at least 70% of patients completing second transplant, the study met its primary endpoint. Overall, 14 patients discontinued before maintenance, due to insufficient stem cell harvest (n=8), disease progression (n=5), or AE (n=1). Thirty-six patients entered maintenance. Maintenance was still ongoing in 24 patients, and 6 patients have now completed maintenance.

Efficacy

Response Rates and MRD

• MRD analysis (NGS, at 10^-5 and 10^-6 threshold sensitivity) was performed after induction in 39 of 48 patients, after first transplant in 37 of 42 patients, after consolidation in 32 of 41 patients, and after second transplant in 33 of 36 patients. MRD-negativity rates after induction and before maintenance have been presented in Table: Efficacy Outcomes.

Survival Outcomes

• At a median duration of follow-up of 33 months, 9 patients had disease progression, including 2 patients who discontinued the study due to stem-cell collection failure (n=1) or AE (n=1).
• Two patients had disease progression during the induction phase, and 5 patients had disease progression during maintenance (4 patients achieved MRD negativity at 10^–6 before maintenance).
• Among 3 patients with primary plasma cell leukemia, 1 patient had an early disease progression during induction, and 2 patients were still progression-free and in the maintenance phase.

Stem Cell Collection

• Stem cells were collected in 27 patients after cycle 6 of induction, with a median CD34⁺ cell yield of 6.1×10⁶ per kg (range, 0-16×10⁶).
  • Of these, 6 patients had insufficient stem-cell harvest and proceeded to tandem transplant. Therefore, the study protocol was amended to collect stem-cells after cycle 3 of induction.
  • Twenty-one patients had a stem-cell collection after cycle 3, with a median CD34⁺ cell yield of 8.3×10⁶ per kg (range, 4.1×10⁶ to 26×10⁶).
    • Of these, 2 patients had a stem-cell harvest insuffcient for proceeding to tandem transplant.

Safety

• The treatment-related adverse events (TRAEs) are summarized in Table: AEs Reported Through Induction and Consolidation.
• Twenty-one patients (42%) developed coronavirus disease 2019 (COVID-19) infection, mostly grade 1 to 2, except for 3 patients (grade 3 COVID-19 infection).
• Five patients (10%) developed deep vein thrombosis during induction.
• One patient (2%) developed reversible grade 2 carfilzomib-related cardiac insufficiency.
• Treatment discontinuation due to treatment-related toxicity were reported in 4 patients (8%) during induction (COVID-19 infection, n=1; tumor lysis syndrome, n=1), in 1 patient during consolidation (COVID-19 infection), and in 1 patient during maintenance (Human papilloma 2 or John Cunningham [JC] virus infection).
• Dose reduction of KRd occurred in 23 (46%), 37 (74%), and 17 patients (34%), respectively.
• Seven patients died; 5 patients due to myeloma progression and 2 patients due to D-KRd–related AEs (septic shock [n=1, during induction] and JC virus–related progressive multifocal leukoencephalopathy [n=1, during maintenance]).

Phase 2 Study of D-KRd in Patients With NDMM Without ASCT

Derman et al (2021)⁴ reported efficacy and safety results of patients with NDMM treated with extended D-KRd without ASCT regardless of transplant eligibility at a median follow-up of 10 months. Derman et al (2024)⁵ (clinicaltrials.gov identifier: NCT03500445) reported efficacy and safety results of patients with NDMM treated with 24 cycles of D-KRd without ASCT at a median follow-up of 27 months.

Study Design/Methods

• Open-label, single-arm, phase 2 study.⁵
• Patients ≥18 years old with NDMM who had received up to 1 cycle of therapy prior to enrollment were eligible to participate irrespective of ASCT, from two Multiple Myeloma Research Consortium sites in the United States.⁵
• Patients received 24 cycles (28-day cycle) of D-KRd which consisted of the following⁵:
  • DARZALEX 16 mg/kg IV
    • Cycles 1-2 QW
    • Cycles 3-8 Q2W
    • Cycles 9-24 every 4 weeks (Q4W)
  • Carfilzomib
    • 20/36 mg/m² IV: Cycles 1-8 on days 1, 2, 8, 9, 15, and 16
    • 36 mg/m² IV: Cycles 9-24 on days 1, 2, 15, and 16
  • Lenalidomide 25 mg PO
    • Cycles 1-24 on days 1-21 of 28-day cycle
  • Dexamethasone PO
    • 40 mg (20 mg if age >75 years old) QW for cycles 1-8
    • 20 mg QW for cycles 9-24
• Patients could opt for harvesting stem cells after 4-6 cycles of protocol therapy to permit ASCT in the future.⁵
• Primary endpoint: rate of sCR, and/or MRD-negative response (at a threshold of <10^-5 by NGS) after treatment cycle 8.⁵
  • Considerations includes patients who cannot be evaluated for MRD by NGS due to⁵:
    • Unavailable or untraceable clonal sequences.
    • Challenges in accurately distinguishing IgG kappa monoclonal antibody (daratumumab) from IgG kappa paraprotein via serum protein immunofixation.

Results

Patient Disposition and Characteristics

• A total of 42 patients entered the treatment phase between March 2019 and January 2022. The data cutoff date was July 15, 2023. See Table: Patient Demographics and Baseline Characteristics.
  • Among the 42 patients who entered the treatment phase, 21 (50%) reached the end of therapy, 6 (14%) of whom were off all treatment at the data cutoff. See Tables: Patient Disposition and Characteristics of Patients with Disease Progression.
  • Thirty-seven patients (88%) underwent stem cell collection, all with G-CSF and upfront plerixafor with a median of 2 days (range, 1-3) of collection, for a median yield of 8.26×10⁶ CD34⁺ cells/kg (range, 3.1×10⁶ to 17.5×10⁶).
• Before cycle 8, treatment was withdrawn by 2 patients for reasons unrelated to treatment.
• A total of 40 (95%) patients were evaluable for the primary endpoint by the end of cycle 8.

Efficacy

• At a median follow-up duration of 27 months (range, 1.5-52) following 8 cycles of D-KRd (n=40), the rate of sCR and/or MRD-negativity (<10^-5) was 30/40 (75%; 95% CI, 61-89), and ORR at the end of 8 cycles was 38/40 (95%). See Table: ORRs vs MRD-Negativity Rates.
  • Two (5%) patients had primary refractory disease: one had 2 HRCAs; the other had a sample insufficient for cytogenetic analysis but had 15% circulating plasma cells at diagnosis, which had not met the previously established criteria (≥20% plasma cells) for plasma cell leukemia.
• The rate of sCR and ≥CR as the best response in the intent-to-treat (ITT) population (N=42) was achieved by 31 (74%) and 36 (86%) patients, respectively.
  • The best response of sCR and/or MRD-negativity (10^-5) was achieved in 32 (76%) patients.
• At a median follow-up duration of 27 months (range, 1.5-52 months), there were 7 progression events and 2 deaths (both due to progression).
• The estimated 3-year PFS was 85% (0 HRCA, 100%; 1 HRCA, 92%; 2+ HRCAs, 60%).
  • Of the 7 patients with progression, 6 had at least one of the following: extramedullary disease (n = 4), 2+ HRCAs (n = 4), or circulating plasma cells (n=1).
• The estimated 3-year OS was 95%.
• Clonotypic tracking for MRD using NGS was performed for 34 (81%) patients.
  • Clonotypic tracking failure occurred in 4 (9.5%) patients, leading to a calibration rate of 90%.
  • Calibration material was not suitable for 4 (9.5%) patients.
• Among 33 patients evaluable for MRD from cycle 8 onward:
  • Six patients had 1 MRD result below 10^-5 with less than 1 year of follow-up.
  • Eleven (41%) of the remaining 27 patients maintained MRD-negativity at the 10^-5 threshold, defined as 2 consecutive MRD-negative results separated by at least 1 year.

Agreement Between Liquid Chromatography-Mass Spectrometry and NGS

• Agreement between liquid chromatography-mass spectrometry (LC-MS) and NGS following cycle 8 of D-KRd has been presented in Table: Agreement Between LC-MS and NGS Following Cycle 8 of D-KRd.
  • Agreement between EXENT^® and NGS at cycle 8:
    • For the 10^-5 threshold:
      • Agreement was 75% between 32 paired EXENT^® and NGS (10^-5) samples (Cohen’s kappa, 0.48; 95% CI, 0.18-0.79).
      • Disagreement included 3 cases of NGS positive/EXENT^® negative and 5 cases of NGS negative/EXENT^® positive.
    • For the 10^-6 threshold:
      • Agreement was 69% between paired EXENT^® and NGS (10⁻⁶) samples (Cohen’s kappa, 0.39; 95% CI, 0.10-0.69).
      • Disagreement included 8 cases of NGS positive/EXENT^® negative and 2 cases of NGS negative/EXENT^® positive.
    • By the end of cycle 24, concordance with EXENT^®/NGS improved to 84% for both 10⁵ and 10^-6 thresholds.
  • Agreement between LC-MS and NGS at cycle 8:
    • For the 10^-5 threshold:
      • Agreement was 50% between 32 paired LC-MS and NGS (10^-5) samples (Cohen’s kappa, 0.14; 95% CI, -0.08 to 0.36).
      • Most discordant cases were NGS negative/LC-MS positive (15/16 cases; 94%).
    • For the 10^-6 threshold:
      • Agreement was 63% between paired LC-MS and NGS (10⁻⁶) samples (Cohen’s kappa, 0.11; 95% CI, -0.21 to 0.43).
      • Disagreement was seen in 9 cases of NGS negative/LC-MS positive and 3 cases of NGS positive/LC-MS negative.
    • By the end of cycle 24:
      • For the 10^-5 threshold, 7 of 8 discordant cases (88%) were LC-MS positive/ NGS negative.
      • For the 10^-6 threshold, 5 of 6 discordant cases (83%) were LC-MS positive/ NGS negative.

Agreement Between LC-MS and NGS Following Cycle 8 of D-KRd⁵

Safety

• Notable all-grade/grade ≥3 AEs are presented in Table: TEAEs During D-KRd.
• DARZALEX dose reductions were done in 2 patients (5%), primarily as temporary omissions to minimize exposure during the onset of the COVID-19 pandemic.
• Carfilzomib dose reductions occurred in 11 patients (26%; 1 instance of thrombotic microangiopathy).
• Lenalidomide dose reductions were done in 23 patients (55%).
• Dexamethasone dose reductions were done in 22 patients (52%).
• Grade 3 atrial fibrillation and heart failure each occurred in 1 patient; both conditions resolved.
• No patients discontinued treatment or experienced death attributable to toxicity.

Phase 2 Study of D-KRd Followed by ASCT in Patients With NDMM

Costa et al (2019)⁶ presented the results of an ongoing phase 2 study (MASTER; clinicaltrials.gov identifier: NCT03224507) evaluating the efficacy and safety of D-KRd induction followed by AHCT and MRD-adapted consolidation therapy for patients with NDMM at a median follow-up of 7.4 months. Costa et al (2023)⁷ reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months. Results from the final analysis are reported below.

Study Design/Methods

• Key eligibility criteria: Patients of any age group with NDMM with measurable disease and ECOG PS of ≤2 who had measurable renal function (CrCl ≥40 mL/min) and were either untreated or had received up to 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCd) were included. Patients with a concomitant or recent malignancy, or significant cardiopulmonary disease were excluded.
• Primary endpoint: Rate of MRD-negative responses (<10^-5) by NGS (clonoSEQ^®).
• Secondary endpoints: Toxicity of D-KRd, rates and kinetics of MRD resurgence upon treatment discontinuation, PFS, and OS.
• Exploratory endpoints: PFS and OS for patients who transitioned to MRD-SURE and were monitored off therapy.
• Enrichment for patients with HRCA was planned during recruitment.

Results

Patient Characteristics

• A total of 123 patients were enrolled, of whom 118 (96%) patients with MRD were evaluable. See Table: Patient Demographics and Baseline Characteristics (MASTER).
• The median duration of follow-up was 42.2 months (interquartile range [IQR], 34.5-46.0) overall (0 HRCA, 43.7 months [IQR, 36.3-47.4]; 1 HRCA, 42.1 months [IQR, 32.9-45.8]; ≥2 HRCAs, 35.4 months [IQR, 26.1-43.4]).
• The median duration of therapy was 11.6 months (IQR, 8.0-14.8) overall and 11.2 months (IQR, 8.412.4) for those who entered MRD-SURE.

Efficacy

• A total of 96 patients (81%; 95% CI, 73-88) reached MRD <10^-⁵ at any point during treatment. See Table: MRD-Negative Response Rates (MASTER).
• Of the 118 MRD-evaluable patients, 84 (71%) entered protocol-directed observation and MRD-SURE, 24 (20%) proceeded to lenalidomide maintenance, and 10 (8%) discontinued treatment (died, n=3; disease progression, n=5; patient’s choice, n=2).

• A total of 33 PFS events were recorded among the 123 enrolled patients; 32 PFS events were recorded among 118 MRD-evaluable patients. See Table: Final Analysis Survival Outcomes (MASTER).
• A total of 6 patients had disease progression while receiving protocol-directed therapy (induction, n=1; after AHCT and before consolidation, n=1; consolidation, n=4).
  • All 6 patients had gain/amp 1q, 5 had del(17p), and 5 had ≥2 HRCAs; all patients died of disease progression/complications of subsequent therapy within 1.3-10.8 months after initial progression.
• Of the 118 MRD-evaluable patients, the 3-year PFS for those who reached sustained MRD-negativity (n=75 [64%]) vs those who did not reach sustained MRD-negativity (n=43 [36%]) was 89% (95% CI, 82-94) vs 55% (95% CI, 39-69). See Table: PFS and OS for Different Study Populations (MASTER).
• Of the 106 patients without disease progression at 18 months from enrollment, the 3year PFS for those who reached sustained MRD-negativity vs those who did not reach sustained MRD-negativity was 89% (n=75; 95% CI, 82-94) vs 70% (n=31; 95% CI, 5483), respectively.
• At the last MRD-SURE observation timepoint, 61 patients (MRD-evaluable, 52%; transitioned to MRDSURE, 73%) remained free of therapy with sustained MRDnegativity, including 3 patients who died of unrelated causes without previous disease progression. See Table: Landmark PFS and OS According to MRD Status at Different Timepoints (MASTER).
• Of the 84 patients who transitioned to MRD-SURE, 23 patients (27%) resumed therapy, of whom 16 patients resumed due to disease progression without MRD resurgence and 7 patients resumed due to MRD resurgence without progression.

Safety

• All patients had ≥1 TEAE.
• DARZALEX doses were neither reduced nor discontinued in any patient due to toxicity.
  • Carfilzomib and lenalidomide each was discontinued in 2 patients due to toxicity.
• The most common TEAEs reported in the MASTER study are presented in Table: Most Common TEAEs (MASTER).
• The most common serious TEAEs were pneumonia (n=8) and thromboembolic events (n=3).
• No patient developed a secondary malignancy due to protocol-directed therapy.
• A total of 15 patients died among the 123 enrolled patients.
  • Three patients died during protocol-directed therapy (not judged to be treatment-related), of whom 2 had a sudden death and 1 died from metapneumovirus pneumonia.
  • Three patients died after therapy while on MRD-SURE without disease progression due to sudden death, COVID-19 pneumonia, and accidental fall (n=1 each).
  • Nine patients died of MM progression, of whom 6 died while receiving protocoldirected therapy and 3 died after completion of therapy.
• A total of 4 patients died among 118 MRD-evaluable patients.

Phase 2 Study of D-KRd in Patients With NDMM and HRCAs

Callander et al (2024)⁸ reported post hoc analysis results evaluating the clinical efficacy of the 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 MASTER are summarized below.

Study Design/Methods

• Patients with HRCA were included who had ≥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 MASTER (n=123) study, a total of 53 (431.%), 46 (37.4%) and 24 (19.5%) 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-KRd in MASTER.

Efficacy

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

Safety

• In MASTER, 3 patients died while on D-KRd therapy (0 HRCA, n=2 [sudden death]; ≥2 HRCAs, n=1 [metapneumovirus infection during transplant]).
  • Two patients died after discontinuation of therapy and during follow-up (1 HRCA, n=2 [fall and COVID-19 pneumonia]). Neither of the deaths were preceded by PD.

Phase 2 Study of DARZALEX Comparing the Efficacy and Safety Outcomes of Patients With NDMM Aged ≥70 Years vs <70 Years in the MASTER Study

Giri et al (2022)⁹ presented post hoc subgroup analysis of patients aged ≥70 years vs <70 years in the MASTER study.

Study Design/Methods

• All patients received induction therapy with D-KRd, followed by ASCT and responseadapted DKRd consolidation.
• Patients who achieved 2 consecutive MRD-negative assessments entered treatment-free observation and MRD-SURE (10^-5).
• Primary endpoint: achievement of MRD-negativity (10^-5) by NGS
• Secondary endpoints: achievement of MRD-negativity (10^-6) at any point, postinduction rate of MRD-negativity, and rates of CR, PFS, and OS

Results

Baseline Characteristics

• Of the 123 enrolled patients, 24 (19.5%) patients were aged ≥70 years at the time of diagnosis and 5 patients were aged ≥75 years.^9,16 See Table: Baseline Characteristics According to Age Group (MASTER).
• Overall, 24 patients received planned ASCT.
• In patients aged ≥70 years vs <70 years, median time on protocol treatment was 11.7 months vs 11.6 months, respectively (P=0.85).

Efficacy

• At a median follow-up of 36 months, efficacy results according to age group are summarized in Table: Efficacy Results According to Age Group (MASTER).

Safety

• In patients aged ≥70 years vs <70 years, grade ≥3 AEs were reported in 79% vs 69%, respectively (P=0.31).
• In patients aged ≥70 years, there were no treatment discontinuations due to toxicity.
• During the treatment period, 3 deaths were reported, of whom, 1 patient was aged ≥70 years (unwitnessed sudden death 2 months after ASCT and before consolidation).

Stem Cell Collection in the MASTER Study

Chhabra et al (2023)¹⁰ 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 123 patients randomized in the MASTER study, 116/123 (94%) patients in the D-KRd arm completed induction therapy and underwent stem cell mobilization.
• Among the mobilized patients, 99% (114 of 116) in the D-KRd arm underwent ASCT.
• The median duration of follow-up was 32 months.
• The baseline patient demographics and clinical characteristics are summarized in Table: Baseline Characteristics in the D-KRd Arm of the GRIFFIN Study.