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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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Use of DARZALEX + DARZALEX FASPRO in Combination With Carfilzomib, Lenalidomide, and Dexamethasone in Multiple Myeloma

Last Updated: 05/09/2025

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.
  • Touzeau et al (2024)1 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 (2024)2 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 (2023)3 reported the results from the final analysis of the MASTER study 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)4 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.
  • Chhabra et al (2023)5 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
  • Other relevant literature regarding the use of DARZALEX and DARZALEX FASPRO in combination with KRd in patients with MM has been identified in addition to the data summarized above.6-12

PRODUCT LABELING

CLINICAL DATA

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

Touzeau et al (2024)1 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.

Baseline Patient and Disease Characteristics1
Characteristic
N=50
Median age (range), years
57 (38-65)
Male, n
28
Female, n
22
ECOG PS, n (%)
   0-1
47 (94)
   2
3 (6)
ISS stage, n (%)
   I
21 (42)
   II
17 (34)
   III
12 (24)
R-ISS stage, n (%)
   II
38 (76)
   III
12 (24)
EMDa
4 (9.3)
Primary plasma cell leukemia, n (%)
3 (6)
High-risk cytogenetic abnormalities, n (%)
50 (100)
   del17p
20 (40)
   t(4;14)
26 (52)
   t(14;16)
10 (20)
   gain1q
25 (50)
      1q duplication
20 (40)
      1q amplification
5 (10)
   del1p
6 (12)
   ≥2 HR cytogenetic abnormalities
30 (60)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EMD, extramedullary disease; HR, hazard ratio; ISS, International Staging System; R-ISS, Revised International Staging System.
aAssessed in patients with baseline PET-CT (n=43)
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.

Efficacy Outcomes1
Parameter
Patients
Response outcomes (n=48)
   ORR for patients completing second transplant, %
100
      CR for patients completing second transplant, %
81
   ORR by the end of induction, n (%)
46 (95)
   CR/sCR, n (%)
15 (31)
   CR/sCR before consolidation, n (%)
42 (48)
   CR/sCR by the end of yearly consolidation, n (%)
41 (70)
   CR/sCR before maintenance, n (%)
36 (81)
   VGPR, n (%)
29 (60)
MRD-negativity rate
   At 10-5 sensitivity threshold
      After induction , %
53
      Before maintenance, %
97
      Before maintenance in ITT population, %
64
   At 10-6 sensitivity threshold
      After induction , %
43
      Before maintenance, %
94
      Before maintenance in ITT population, %
62
Survival outcomes
   Median PFS
NR
      30-month PFS rate, % (95% CI)
80 (68-94),
   Median OS
NR
      30-month OS rate, % (95% CI)
91 (82-100)
Abbreviations: CI, confidence interval; CR, complete response; ITT, intent-to-treat; MRD, minimal residual disease; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; sCR, stringent complete response; VGPR, very good partial response.
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]).

AEs Reported Through Induction and Consolidation1
Event, n (%)
Induction (n=50)
Consolidation (n=42)
Any-Grade
Grade 3/4
Any-Grade
Grade 3/4
Hematologic
   Anemia
13 (26)
9 (18)
3 (7)
0 (0)
   Neutropenia
18 (36)
16 (32)
9 (21)
6 (14)
   Thrombocytopenia
13 (26)
7 (14)
8 (19)
4 (9)
Nonhematologic
   Infections
21 (42)
2 (4)
15 (35)
2 (5)
   Diarrhea
13 (26)
1 (2)
9 (21)
0 (0)
   Fatigue
13 (26)
0 (0)
8 (19)
0 (0)
   Nausea
13 (26)
2 (4)
2 (4)
1 (2)
   Constipation
10 (20)
0 (0)
2 (5)
0 (0)
   Psychiatric
10 (20)
2 (4)
2 (5)
0 (0)
   Skin rash
8 (16)
0 (0)
3 (7)
0 (0)
   Peripheral neuropathy
7 (14)
0 (0)
3 (7)
0 (0)

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

Derman et al (2024)2 (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.2
  • 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.2
  • Patients received 24 cycles (28-day cycle) of D-KRd which consisted of the following2:
    • 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.2
  • Primary endpoint: rate of sCR, and/or MRD-negative response (at a threshold of <10-5 by NGS) after treatment cycle 8.2
    • Considerations includes patients who cannot be evaluated for MRD by NGS due to2:
      • 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.

Patient Demographics and Baseline Characteristics2
Characteristic
Total
(N=42)
Median age (range), years
58 (39-79)
   ≥65 years old, n (%)
12 (29)
Sex, n (%)
   Male
25 (60)
   Female
17 (40)
Race, n (%)
   White
23 (55)
   Black
13 (31)
   Asian
1 (2)
   More than 1 race
5 (12)
Ethnicity, n (%)
   Hispanic
5 (12)
   Non-Hispanic
37 (88)
ECOG PS, n (%)
   0
31 (74)
   1
11 (26)
ISS; R-ISS stage, n (%)
   I
21 (50); 14 (33)
   II
14 (33); 24 (57)
   III
7 (17); 4 (10)
IgG kappa monoclonal protein, n (%)
15 (36)
Extramedullary disease, n (%)
5 (12)
Cytogenetic risk by FISH, n (%)
   Unknown
1 (2)
   Standard
17 (41)
   High
24 (57)
      t(4;14)
10 (24)
      t(14;16)
3 (7)
      del(17p)
8 (19)
      1q copy number abnormalitiesa
14 (33)
      1q amplification
6 (14)
      2+ high-risk abnormalities
10 (24)
Number of cycles of therapy, median (range)
23 (1-24)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; Ig, immunoglobulin; ISS, International Staging System; R-ISS, Revised International Staging System.
aEight patients had a 1q gain (no amplification); of these, only 2 had no other high-risk abnormalities.

Patient Disposition13
Outcome, n (%)
Total
(N=42)
Reached end of therapy
21 (50)
Currently receiving treatment per protocol
11 (26)
Had disease progression during treatment
6 (14)
Discontinued protocol therapy earlya
4 (10)
Proceeded to ASCT off protocol
4 (10)
   In response
1 (2)
   After progression
3 (7)
Postprotocol therapies of responders
   Dual maintenance
15 (36)
   Single-agent maintenance
6 (14)
   All therapy discontinued at later point
6 (14)
Disease progression
7 (17)
Death
2 (5)
aOne due to geographic relocation, 1 due to psychological disturbance unrelated to treatment, 1 did not adhere to Risk Evaluation and Mitigation Strategy (REMS) program for lenalidomide, and 1 did not adhere to study protocol.

Characteristics of Patients With Disease Progression13
Patient
Cytogenetics at Diagnosis
EMD at Diagnosis
MS MRD Best Response
NGS MRD Best Response
Time to Progression
101-03
t(4;14)
No
Always positive
Always positive
41.2 months
101-13
t(4;14), 1q gain
Yes
Unknown (early progression)
Unknown (early progression)
0.8 months
101-25
t(4;14), 1q amplification, del(17p)
Yes
Always positive
Unknown (no clone)
18.7 months
101-26
t(4;14), 1q amplification
No
EXENT® negative,
LC-MS positive
Negative at 10-6
18.1 months
101-31
t(4;14)
Yes
Always positive
Negative at 10-5,
positive at 10-6
14.1 months
101-35
Unknown cytogenetics; 15% circulating plasma cells
No
Unknown (early progression)
Unknown (early progression)
1.2 months
101-40
t(4;14), 1q gain
Yes
Always positive
Unknown (no clone)
17.2 months
Abbreviations: EMD, extramedullary disease; LC-MS, liquid chromatography-mass spectrometry; MRD, minimal residual disease; MS, mass spectrometry; NGS, next-generation sequencing.
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.

ORRs vs MRD-Negativity Rates2
Response
After 8 Cycles
Best Response
Evaluable for response, n
40
42
   ≥PR, n (%)
38 (95)
40 (95)
   ≥VGPR, n (%)
38 (95)
40 (95)
   ≥CR, n (%)
28 (70)
36 (86)
   sCR, n (%)
27 (68)
31 (74)
   PD, n (%)
2 (5)
2 (5)
   Early discontinuation, n (%)
2 (5)
-
   Early death, n (%)
2 (5)
-
MRD by NGS, n/n1 (%)
   MRD-negative (10-5)a
20/34 (59)
22/34 (65)
   MRD-negative (10-6)a
12/34 (35)
18/34 (53)
sCR and/or MRD-negative (10-5) by NGSa,n/n1 (%)
30/40 (75)
32/42 (76)
   95% CI, %
61-89
60-88
Mass spectrometry,n/n1 (%)
   EXENT® negativea
22/39 (56)
25/39 (64)
   LC-MS negativea
7/39 (18)
12/39 (31)
MRD kinetics,n/n1 (%)
   Sustained MRD-negative (10-5) by NGSb
NA
11/27 (40)
Converted after cycle 8c,n/n1 (%)
   MRD-positive at 10-5 to MRD-negative at 10-5
NA
1/10 (10)
   MRD-positive at 10-6 to MRD-negative at 10-6
NA
6/18 (30)
Abbreviations: CI, confidence interval; CR, complete response; LC-MS, liquid chromatography-mass spectrometry; MRD, minimal residual disease; NA, not available; NGS, next-generation sequencing; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
aPatients with no clone ID or baseline mass spectrum are excluded from the denominator. Missing MRD or mass spectra results at a timepoint for those with a baseline are MRD-positive.
bMRD <10-5 on 2 or more instances at least 1 year apart. The denominator includes patients with trackable MRD and at least 1 year of MRD follow-up if they had at least 1 MRD-negative result.
cDenominator includes patients still on protocol with trackable MRD who were MRD-positive at the end of cycle 8.
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-KRd2
End of Cycle 8
Disagreement, %
Agreement, %
LC-MS Positive/
NGS Negative
LC-MS Positive/
NGS Negative
Both Positive
Both Negative
EXENT® vs NGS at 10-5
15.6
9.4
28.1
46.9
LC-MS vs NGS at 10-5
46.9
3.1
34.4
15.6
EXENT® vs NGS at 10-6
6.3
13
37.5
31.3
LC-MS vs NGS at 10-6
28.1
9.4
53.1
9.4
Abbreviations: LC-MS, liquid chromatography-mass spectrometry; NGS, next-generation sequencing.
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.

TEAEs During D-KRd2
TEAE, n (%)
All-Grade
(N=42)
Grade ≥3
(N=42)
Hematologic
   Lymphopenia
29 (69)
15 (36)
   Thrombocytopenia
27 (64)
11 (26)
   Anemia
25 (59)
1 (2)
   Neutropenia
11 (26)
9 (21)
Nonhematologic
   Fatigue
37 (88)
1 (2)
Infection
   Upper respiratorya
28 (67)
3 (7)
   Skin/soft tissue
5 (12)
1 (2)
   Urinary tract
2 (5)
0 (0)
   Otherb
9 (21)
0 (0)
   Hyperglycemia
32 (76)
3 (7)
   Diarrhea
30 (71)
2 (5)
   Lower extremity edema
28 (67)
0 (0)
   Dyspnea
26 (62)
0 (0)
   Hypertension
24 (57)
7 (17)
   Liver enzyme elevations
17 (40)
4 (10)
   Peripheral sensory neuropathy
17 (40)
0 (0)
   Nausea
15 (35)
1 (2)
Cardiac events, any
   Chest pain
3 (7)
0 (0)
   Atrial fibrillation
2 (5)
1 (2)
   Sinus bradycardia
4 (10)
0 (0)
   Sinus tachycardia
3 (7)
0 (0)
   Reduced ejection fraction
4 (10)
1 (2)
Electrolyte imbalances, any
   Hyperkalemia
5 (12)
1 (2)
   Hypocalcemia
13 (31)
2 (5)
   Hypokalemia
23 (55)
4 (10)
   Hypomagnesemia
5 (12)
0 (0)
   Hypophosphatemia
9 (21)
1 (2)
   Hyponatremia
4 (10)
0 (0)
   Rash
13 (31)
2 (5)
   Blurred vision
11 (26)
0 (0)
   Acute kidney injuryc
8 (19)
2 (5)
   Infusion reactions
4 (10)
0 (0)
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019.
aIncludes 16 patients with COVID-19 infection (1 grade 3 event).
bThree gastrointestinal infections, 2 fungal rashes, 2 mucositis, 1 bacterial pneumonia, and 1 ear infection.
cIncludes 1 case of thrombotic microangiopathy.

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

Costa et al (2023)3 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.

Patient Demographics and Baseline Characteristics (MASTER)3
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
Total
(N=123)
Sex, n (%)
   Male
33 (62)
24 (52)
13 (54)
70 (57)
   Female
20 (38)
22 (48)
11 (46)
53 (43)
Age, years
   Median (IQR)
60 (50-69)
61 (57-68)
60 (56-66)
61 (55-68)
   ≥70, n (%)
12 (23)
10 (22)
2 (8)
24 (20)
Race/ethnicity, n (%)
   Non-Hispanic White
42 (79)
33 (72)
19 (79)
94 (76)
   Non-Hispanic Black
10 (19)
11 (24)
4 (17)
25 (20)
   Other
1 (2)
2 (4)
1 (4)
4 (3)
ECOG PS, n (%)
   0-1
42 (79)
40 (87)
17 (71)
99 (80)
   2
11 (21)
6 (13)
7 (29)
24 (20)
LDH concentration, U/L, n (%)
   <240 U/L
45 (85)
34 (74)
18 (75)
97 (79)
   ≥240 U/L
8 (15)
12 (26)
6 (25)
26 (21)
β₂ microglobulin concentration, n (%)
   <3.5 g/L
36 (67)
22 (48)
7 (29)
65 (53)
   ≥3.5 to <5.5 g/L
12 (23)
12 (26)
6 (25)
29 (24)
   ≥5.5 g/L
5 (9)
12 (26)
11 (46)
29 (24)
Albumin concentration, n (%)
   <3.5 g/dL
15 (28)
20 (44)
12 (50)
47 (38)
   ≥3.5 g/dL
38 (72)
26 (57)
12 (50)
66 (54)
Cytogenetic abnormality, n (%)
   Hyperdiploidy
27 (51)
20 (44)
4 (17)
51 (41)
   del(13q)
19 (36)
20 (44)
18 (75)
57 (46)
   Gain/amp 1q
0
24 (52)
20 (83)
44 (36)
   del(1p)
3 (6)
4 (9)
5 (21)
12 (10)
   t(11;14)
14 (26)
7 (15)
0
21 (17)
   t(4;14)
0
8 (17)
13 (54)
21 (17)
   t(14;16)
0
2 (4)
4 (17)
6 (5)
   del(17p)
0
12 (26)
14 (58)
26 (21)
ISS disease stage, n (%)
   I
28 (53)
15 (33)
5 (21)
48 (39)
   II
20 (38)
19 (41)
8 (33)
46 (37)
   III
5 (9.4)
12 (26)
11 (46)
29 (24)
R-ISS, n (%)
   I
25 (47)
11 (24)
0
35 (28)
   II
27 (51)
23 (50)
13 (54)
63 (51)
   III
1 (2)
12 (26)
11 (46)
25 (20)
Multiple myeloma clinical manifestation, n (%)
   Bone disease
43 (81)
29 (63)
18 (75)
90 (73)
   Renal failure
2 (4)
8 (17)
6 (25)
16 (13)
   Anemia
22 (42)
30 (65)
20 (83)
72 (59)
   Hypercalcemia
8 (15)
7 (15)
7 (29)
22 (18)
Ig isotype, n (%)
   IgG
27 (51)
26 (57)
14 (58)
67 (54)
   IgA
12 (23)
15 (33)
8 (33)
35 (28)
   Light chain
14 (26)
5 (11)
2 (8)
21 (17)
Therapy before enrollment,a n (%)
   Yes
26 (49)
25 (54)
10 (42)
61 (50)
   No
27 (51)
21 (46)
14 (58)
62 (50)
MRD trackable by NGS (clonoSEQ®), n (%)
   Yes
50 (94)
44 (96)
24 (100)
118 (96)
   No
3 (6)
2 (4)
0
5 (4)
Abbreviations: 0/1/≥2 HRCAs, standard-/high-/ultra high-risk cytogenetic abnormalities; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; IQR, interquartile range; ISS, International Staging System; LDH, lactate dehydrogenase; MRD, minimal residual disease; NGS, next-generation sequencing; R-ISS, Revised International Staging System. aOne cycle of bortezomib with or without cyclophosphamide and with or without dexamethasone was allowed according to the protocol.
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).

MRD-Negative Response Rates (MASTER)a,3
0 HRCA
(n=50)
1 HRCA
(n=44)
≥2 HRCAs
(n=24)
Total
(N=118)
Rate of NGS MRD <10-5 (primary endpoint)
   At any point in treatment, n (%)
39 (78)
38 (86)
19 (79)
96 (81)
      95% CI
64-88
73-95
58-93
73-88
Rate of NGS MRD <10-6 (post hoc exploratory endpoint)
   At any point in treatment, n (%)
34 (68)
35 (80)
15 (63)
84 (71)
      95% CI
53-80
65-90
41-81
62-79
CR + MRD <10-5, n (%)
38 (76)
33 (75)
14 (58)
85 (72)
   95% CI
62-87
60-87
37-78
63-80
MRD <10-5 at 2 consecutive assessments and transitioned to MRD-SURE, n (%)
33 (66)
36 (82)
15 (63)
84 (71)
   95% CI
51-66
67-92
41-81
62-79
Sustained MRD <105, n (%)
32 (64)
32 (73)
11 (46)
-
   95% CI
49-77
57-85
26-67
-
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CR, complete response; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; NGS, next-generation sequencing.
aHRCA included gain/amp 1q, t(4;14), t(14;16), t(14;20), or del(17p).
  • 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.

Final Analysis Survival Outcomes (MASTER)3
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
3-year PFS rate (N=123), %
88
79
50
   95% CI
78-95
67-88
30-70
3-year OS rate (N=123), %
94
92
75
   95% CI
88-98
86-96
63-85
3-year PFS rate for MRD-evaluable patients (n=118), %
88
80
50
   95% CI
78-94
68-90
30-70
3-year OS rate for MRD-evaluable patients (n=118), %
94
94
75
   95% CI
88-98
87-99
63-85
3-year PFS rate for patients reaching MRD-SURE (n=84), %
88
85
60
   95% CI
77-96
73-96
35-82
3-year OS rate for patients reaching MRD-SURE (n=84), %
97
93
100
   95% CI
91-100
84-100
NC-100
Cumulative incidence of progression rate for patients reaching MRD-SURE (n=84), %
9
9
47
   95% CI
1-19
1-18
23-72
2-year cumulative incidence of disease progression or MRD resurgence rate for patients reaching MRD-SURE (n=84), %
9
14
60
   95% CI
1-19
4-26
35-81
2-year PFS rate after cessation of therapy, %
88
85
53
   95% CI
77-95
73-94
28-78
2-year OS rate after cessation of therapy, %
97
93
100
   95% CI
91-100
85-99
NC-100
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CI, confidence interval; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; NC, not calculated; OS, overall survival; PFS, progression free survival.

PFS and OS for Different Study Populations (MASTER)3,14
Characteristic
1 HRCA vs 0 HRCA
≥2 HRCAs vs 0 HRCA
PFS for entire population
   HR (95% CI)
2.27 (0.91-5.68)
6.29 (2.49-15.89)
P value
0.81
<0.0001
OS for entire population
   HR (95% CI)
1.22 (0.30-4.88)
5.36 (1.53-18.75)
P value
0.78
0.0085
PFS for MRD-evaluable patients
   HR (95% CI)
2.03 (0.80-5.16)
5.98 (2.37-15.09)
P value
0.14
<0.0001
OS for MRD-evaluable patients
   HR (95% CI)
0.91 (0.20-4.08)
5.12 (1.46-17.97)
P value
0.90
0.011
PFS for patients reaching MRD-SURE
   HR (95% CI)
1.84 (0.62-5.51)
4.37 (1.38-13.82)
P value
0.27
0.012
OS for patients reaching MRD-SURE
   HR (95% CI)
1.24 (0.17-8.87)
1.74 (0.15-20.16)
P value
0.83
0.66
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; OS, overall survival; PFS, progression free survival.

Landmark PFS and OS According to MRD Status at Different Timepoints (MASTER)14
Characteristic
Landmark PFS according to MRD status (<10-5) at end of induction
   HR (95% CI)
1.06 (0.50-2.12)
   Log-rank P value
0.94
Landmark OS according to MRD status (<10-5) at end of induction
   HR (95% CI)
0.33 (0.07-1.49)
   Log-rank P value
0.11
Landmark PFS according to MRD status (<10-5) after AHCT
   HR (95% CI)
0.95 (0.43-2.08)
   Log-rank P value
0.90
Landmark OS according to MRD status (<10-5) after AHCT
   HR (95% CI)
0.63 (0.28-2.27)
   Log-rank P value
0.48
Exploratory landmark PFS according to MRD status (<10-6) at end of induction
   HR (95% CI)
0.85 (0.37-2.00)
   Log-rank P value
0.72
Exploratory landmark OS according to MRD status (<10-6) at end of induction
   HR (95% CI)
0.28 (0.04-2.17)
   Log-rank P value
0.15
Exploratory landmark PFS according to MRD status (<10-6) after AHCT
   HR (95% CI)
1.00 (0.48-2.10)
   Log-rank P value
0.99
Exploratory landmark OS according to MRD status (<10-6) after AHCT
   HR (95% CI)
0.26 (0.05-1.22)
   Log-rank P value
0.065
Abbreviations: AHCT, autologous hematopoietic cell transplantation; CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.
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.

Most Common TEAEs (MASTER)3
Event, n (%)
Grade 1/2
Grade 3
Grade 4
Grade 5
All events
123 (100)
69 (56)
22 (18)
3 (2)
Hematologic
   Neutropenia
8 (7)
36 (29)
7 (6)
0
   Lymphopenia
6 (5)
18 (15)
10 (8)
0
   Anemia
13 (11)
11 (9)
2 (2)
0
   Thrombocytopenia
11 (9)
9 (7)
3 (2)
0
   Leukopenia
10 (8)
6 (5)
6 (5)
0
Nonhematologic
   Fatigue
58 (47)
11 (9)
0
0
   Bone pain
61 (50)
7 (6)
0
0
   Maculopapular rash
45 (37)
5 (4)
0
0
   Nausea
49 (40)
0
0
0
   Constipation
48 (39)
0
0
0
   Upper respiratory tract infection
44 (36)
1 (1)
0
0
   Diarrhea
38 (31)
5 (4)
0
0
   Insomnia
32 (26)
3 (2)
0
0
   Dyspnea
32 (26)
2 (2)
0
0
   Cough
33 (27)
0
0
0
   Hypertension
19 (15)
13 (11)
0
0
   Dizziness
29 (24)
1 (1)
0
0
   Peripheral sensory neuropathy
24 (20)
2 (2)
0
0
   Dysgeusia
25 (20)
0
0
0
   Hyperglycemia
18 (15)
5 (4)
1 (1)
0
   Headache
22 (18)
2 (2)
0
0
   Fever
23 (19)
0
0
0
   Edema in limbs
21 (17)
1 (1)
0
0
   Increased ALT concentration
19 (15)
2 (2)
0
0
   Weight loss
17 (14)
1 (1)
0
0
   Hypophosphatemia
7 (6)
9 (7)
0
0
   Weight gain
13 (11)
1 (1)
0
0
   Increased ASP concentration
12 (10)
1 (1)
0
0
   Hypocalcemia
11 (9)
1 (1)
1 (1)
0
   Thromboembolic event
8 (7)
3 (2)
2 (2)
0
   Lung infection
4 (3)
3 (2)
2 (2)
1 (1)
   Acute kidney injury
8 (7)
1 (1)
0
0
   Sudden death
0
0
0
2 (2)
   Hemolytic uremic syndrome
0
0
1 (1)
0
   Heart failure
1 (1)
0
0
0
IRR
32 (26)
2 (2)
0
0
Abbreviations: ALT, alanine transaminase; ASP, aspartate aminotransferase; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.

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

Callander et al (2024)4 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

Baseline Patient and Disease Characteristics in Patients Who Received D-KRd in MASTER4
Characteristic
Standard-Risk
0 HRCA
(n=53)
High-Risk
1 HRCA
(n=46)
Ultra-High-Risk
≥2 HRCAs
(n=24)
Total
(n=123)
Median age (range), years
60 (36-79)
61 (35-77)
60 (41-72)
60 (35-79)
Sex, n (%)
   Male
33 (62.3)
24 (52.2)
13 (54.2)
70 (56.9)
   Female
20 (37.7)
22 (47.8)
11 (45.8)
53 (43.1)
ISS disease stage,a n (%)
   I
28 (52.8)
15 (32.6)
5 (20.8)
48 (39.0)
   II
20 (37.7)
19 (41.3)
8 (33.3)
46 (37.4)
   III
5 (9.4)
12 (26.1)
11 (45.8)
29 (23.6)
Cytogenetic abnormality,b n (%)
   del(17p)
0
12 (26.1)
14 (58.3)
26 (21.1)
   t(4;14)
0
8 (17.4)
13 (54.2)
21 (17.1)
   t(14;16)
0
2 (4.3)
4 (16.7)
6 (4.9)
   Gain/amp(1q21)
0
24 (52.2)
20 (83.3)
44 (35.8)
   t(14;20)
0
0
0
0
Median duration of study treatment, months
   Induction/consolidationc
11.5
11.5
11.7
11.5
Abbreviations: ASCT, autologous stem cell transplantation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System.
aISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
bCytogenetic risk was assessed by fluorescence in situ hybridization (local testing).
cDuration of study treatment is from onset of therapy to completion of consolidation therapy, including ASCT.
Efficacy

Efficacy Outcomes by Cytogenetic Risk Statusin the MASTER Studya,4
Parameter
Standard-Risk
0 HRCA (n=53)
High-Risk
1 HRCA (n=46)
Ultra-High-Risk
≥2 HRCAs (n=24)
≥CR,b %
90.6
89.1
70.8
24-month PFS rate, %
92.4
95.7
65.5
36-month PFS rate, %
89.9
86.2
52.4
MRDnegative
   Evaluable population, n
50c
44c
24c
      10-5 sensitivity, %
80.0
86.4
83.3
      10-6 sensitivity, %
68.0
79.5
66.7
   Patients achieving ≥CR, n
45
39
17
      10-5 sensitivity, %
84.4
89.7
94.1
Durable MRD-negativity lasting ≥12 months
   Evaluable population, n
50c
44c
24c
      10-5 sensitivity, %
64.0
72.7
50.0
MRD (10-5) conversion rate
   Evaluable population, n
-
-
-
      MRD-positive by the end of
      induction and then became
      MRD-negative, %
NA
NA
NA
      MRD-positive by the end of
      consolidation and then became
      MRD-negative, %
NA
NA
NA
   Median time to MRD-negativity
   (10-5),c months
7.5
7.1
7.6
Abbreviations: ≥CR, complete response or better; D-R, DARZALEX + lenalidomide; MRD, minimal residual disease; NA, not available; 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). Six patients were not evaluable for cytogenetic abnormalities.
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.

Stem Cell Collection in the MASTER Study

Chhabra et al (2023)5 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.

Baseline Characteristics in the D-KRd Arm of the MASTER Study5
Characteristic
All Patients
(N=123)
Received Upfront Plerixafor
Received Rescue Plerixafor
Received G-CSF Onlya
Patients who underwent mobilization, n
116
81
35
4
Age, years
   Median (range)
61 (31-79)
61 (31-79)
62 (43-70)
66 (64-69)
   ≥65, n (%)
44 (38)
31 (38)
13 (37)
4 (100)
   ≥75, n (%)
22 (19)
21 (26)
1 (3)
0 (0)
Male, n (%)
65 (56)
47 (58)
18 (51)
1 (25)
R-ISS disease stage, n (%)
   I
35 (30)
27 (33)
8 (23)
0 (0)
   II
58 (50)
41 (51)
17 (49)
1 (25)
   II
22 (19)
13 (16)
9 (26)
3 (75)
Cytogenetic risk, n (%)b
   Standard risk
74 (64)
52 (64)
22 (63)
2 (50)
   High risk
42 (36)
29 (36)
13 (37)
2 (50)
Abbreviations: D-KRd, DARZALEX + carfilzomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; R-ISS, Revised International Staging System.
aD-KRd patients who received only G-CSF are a subset of those in the rescue plerixafor strategy group for this summary of patient characteristics.
bCytogenetic 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
  • 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).
  • A total of 5 patients in the in the D-KRd arm of the MASTER study failed to collect a minimum of 2×106/kg CD34+.
    • These 5 patients were remobilized with upfront plerixafor, and 2 of them received granulocyte-macrophage colony-stimulating factor (GM-CSF) in addition to G-CSF.
  • No patient received chemomobilization.
  • The median number of days for stem cell collection was 2 in patients in the D-KRd arm of the MASTER study.
  • A total of 2 of 116 mobilized patients the in the D-KRd arm of the MASTER study did not undergo ASCT, whereas 114 of them received a median CD34+ cell dose of 3.2×106/kg.
  • A total of 97 patients in the D-KRd arm of the MASTER study received melphalan 200 mg/m2 for conditioning.
  • The median number of days for neutrophil recovery in the D-KRd arm of the MASTER study was 12 days (range, 9-17) in patients who engrafted after ASCT.
  • The median number of days for platelet recovery in the D-KRd arm of the MASTER study was 17 (range not reported).
  • Additional data stratified by upfront plerixafor use, rescue plerixafor use, and G-CSF-only use are summarized in Table: Summary of ASCT in the D-KRd Arm of the GRIFFIN Study.

Summary of ASCT in the D-KRd Arm of the MASTER Studya,5
Parameter
All Patients
(N=123)
Received Upfront Plerixafor
Rescue Plerixafor Strategyb
Received Rescue Plerixafor
Received G-CSF Only
Pts who underwent
mobilization, n
116
81
31
4
Pts who received plerixafor, n
112
81
31
0
Mobilization attempts, n (%)
   1
108 (93)
76 (94)
26 (90)
4 (100)
   2
8 (7)
5 (6)
3 (10)
0
   3
0
0
0
0
   4
0
0
0
0
   Missing
0
0
0
0
Median stem cell collection target per ASCT (range), ×106 CD34+ cells/kg
3 (2-3)
3 (2-3)
3 (2-3)
2 (2-3)
Median duration of stem cell collection (range), days
2 (1-4)
2 (1-4)
2 (1-3)
1.5 (1-2)
Median stem cell yield (range), ×106 CD34+ cells/kg
6.0 (2.2-13.9)
6.2 (2.3-13.9)
5.2 (2.2-11.5)
3.9 (2.2-5.5)
Pts who collected the minimum threshold for ASCT, n (%)
116 (100)
81 (100)
31 (100)
4 (100)
Pts who collected 2x the minimum threshold for
ASCT, n (%)
93 (80)
65 (80)
26 (84)
2 (50)
Number of CD34+ cells transplanted (106 cells/kg),
median (range)
3.2 (2.0-8.3)
3.2 (2.0-8.3)
3.2 (2.1-5.7)
2.7 (2.2-2.8)
Median duration from end of induction to
apheresis (range), days
24 (2-104)
26 (2-104)
22 (8-103)
12.5 (8-29)
Pts who completed ASCT, n (%)
114 (98)
81 (100)
29 (93)
4 (100)
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.
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.

LITERATURE SEARCH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 17 September 2024.

 

References

Show
1 Touzeau C, Perrot A, Hulin C, et al. Daratumumab carfilzomib lenalidomide and dexamethasone with tandem transplant in high-risk newly diagnosed myeloma. Blood. 2024;143(20):2029-2036.  
2 Derman BA, Cooperrider J, Rosenblatt J, et al. Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant. Blood Cancer J. 2024;14(1):87.  
3 Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901.  
4 Callander NS, Silbermann R, Kaufman JL, et al. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer J. 2024;14(1):69.  
5 Chhabra S, Callander N, Watts N, et al. Stem cell mobilization yields with daratumumab- and lenalidomide-containing quadruplet induction therapy in newly diagnosed multiple myeloma: findings from the MASTER and GRIFFIN trials. Transplant Cell Ther. 2023;29(3):174.e1-174.e10.  
6 Bhutani M, Robinson M, Paul B, et al. Interim results of a risk-adaptive phase II study: carfilzomib, lenalidomide, dexamethasone and daratumumab (KRD-Dara) in newly diagnosed multiple myeloma (NDMM) at the Levine Cancer Institute (LCI). Abstract presented at: 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
7 Derman B, Major A, Rosenblatt J, et al. A phase 2 study of extended daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.  
8 Costa L, Chhabra S, Godby K, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, measurable residual disease (MRD)-based, response-adapted Dara-KRd consolidation in patients with newly diagnosed multiple myeloma (NDMM). Oral Presentation presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.  
9 Giri S, Chhabra S, Medvedova E, et al. Quadruplet induction, autologous transplantation and minimal residual disease adapted consolidation and treatment cessation in older adults ≥70y with newly diagnosed multiple myeloma: a subgroup analysis of the MASTER trial. Poster presented at: 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
10 Landgren O, Hultcrantz M, Lesokhin AM, et al. Weekly carfilzomib, lenalidomide, dexamethasone and daratumumab (wKRd-D) combination therapy in newly diagnosed multiple myeloma: final results from a clinical and correlative phase 2 study. Oral Presentation presented at: 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020; Virtual Meeting.  
11 Chari A, Usmani S, Krishnan A, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma (MMY1001): updated results from an open-label, phase 1b study. Poster presented at: 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA.  
12 Janssen Research & Development, LLC. A study of JNJ-54767414 (HuMax CD38) (anti-CD38 monoclonal antibody) in combination with backbone treatments for the treatment of patients with multiple myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 August 14]. Available from: https://clinicaltrials.gov/ct2/show/NCT01998971 NLM Identifier: NCT01998971.  
13 Derman BA, Cooperrider J, Rosenblatt J, et al. Supplement to: Final analysis of a phase II trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma without transplant. Blood Cancer J. 2024;14(1):87.  
14 Costa LJ, Chhabra S, Medvedova E, et al. Supplement to: Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. [published online ahead of print september 27, 2023]. Lancet Haematol. doi:10.1016/s2352-3026(23)00236-3.  
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