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DARZALEX® (daratumumab)

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Use of DARZALEX + DARZALEX FASPRO in Newly Diagnosed Multiple Myeloma in Patients Eligible for Autologous Stem-Cell Transplantation

Last Updated: 01/02/2025

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 patients with multiple myeloma (MM). DARZALEX for IV use + DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies or use in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) for the treatment of patients with MM. Janssen does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • PERSEUS (MMY3014) is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with VRd (D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO + lenalidomide (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with newly diagnosed multiple myeloma (NDMM) eligible for autologous stem cell transplant (ASCT).1
    • Sonneveld et al (2023)1 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 group vs 29.1% (103/354) of patients in the VRd group experienced disease progression or death (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.30-0.59; P<0.0001), respectively. Overall complete response or better (≥CR) rate (87.9% vs 70.1%; P<0.0001) and overall minimal residual disease (MRD)-negativity rate (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 group were neutropenia (62.1% vs 51.0%), 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%).
    • Bertamini et al (2024)2 presented (at the 66th American Society of Hematology [ASH] Annual Meeting) results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTC) as a biomarker in transplant-eligible patients with NDMM. D-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).
  • CASSIOPEIA is a phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant eligible patients with previously untreated MM.3,4
    • Part 1: Moreau et al (2019)3 reported the results from Part 1 of CASSIOPEIA study. The first part of the study met the primary endpoint of stringent complete response (sCR) with 29% of patients treated with D-VTd achieving a sCR vs 20% treated with VTd (odds ratio [OR], 1.60; 95% CI, 1.21-2.12, P=0.0010). The most common AEs of any grade (occurring in ≥20% of patients in either group) were peripheral sensory neuropathy, constipation, asthenia, peripheral edema, nausea, neutropenia, pyrexia, paresthesia, and thrombocytopenia.
    • Part 2: Moreau et al (2021)4 reported results from Part 2 of the CASSIOPEIA study. The HR for PFS among patients after second randomization in the DARZALEX monotherapy group vs the observation group was 0.53 (95% CI, 0.42-0.68, P<0.0001). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 28% of patients in the DARZALEX monotherapy group vs 24% in the observation group.
    • Moreau et al (2024)5 reported long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization. In the D-VTd vs VTd cohort, the median PFS from first randomization after a median follow-up duration was 83.7 months (range, 70.2 months-not estimable [NE]) vs 52.8 months (range, 47.5-58.7 months). PFS on the next line of therapy from second randomization was longer in the DARZALEX maintenance group than in the observation group (HR, 0.59; 95% CI, 0.45-0.79; P=0.0002) in the maintenance-specific intent-to-treat (ITT) population. PFS on the next line of therapy from second randomization was longer in the VTd plus DARZALEX group than in the VTd plus observation group in the maintenance-specific ITT population (D-VTd plus DARZALEX vs D-VTd plus observation: HR, 1.01; 95% CI, 0.64-1.59; P=0.9; VTd plus DARZALEX vs VTd plus observation: HR, 0.43; 95% CI, 0.30-0.62; P<0.0001).
  • GRIFFIN is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) for patients with NDMM who are eligible for high-dose therapy (HDT) and ASCT.6-8
    • Part 1: Voorhees et al (2021)9 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 D-VRd consolidation, 56.3% patients achieved sCR, and 50.0% were 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 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)6 presented the primary analysis of the randomized portion of this study (N=207). Voorhees et al (2023)10 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 (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). 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%).
  • Costa et al (2019)11reported the results of an ongoing, phase 2 study (MASTER) evaluating the efficacy and safety of DARZALEX in combination with KRd (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)12 reported the results from the final analysis of the MASTER study (N=123) at a median follow-up of 42.2 months. The overall MRD-negative remission rate (next-generation sequencing [NGS]; <10-5 threshold) in MRD-evaluable patients at any point in treatment was 81% (95% CI, 73-88). The 3-year PFS rates were 88% (95% CI, 78-95) for patients with standard risk (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 overall survival (OS) rates were 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)13 reported the results of a post hoc analysis evaluating the clinical efficacy of DARZALEX-based quadruplet therapies, including D-KRd and D-VRd, in transplant-eligible patients with NDMM and 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% of patients; the estimated 24-month PFS rate was 92.4%, 95.7%, and 65.5%; and MRD-negativity (105) was reported in 80.0%, 86.4%, and 83.3% of patients. In the GRIFFIN study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.9%, 78.8%, and 61.5% of patients; the 24-month PFS rate was 96.7%, 93.8%, and 64.2%; and MRD-negativity (10-5) was reported in 76.1%, 55.9%, and 61.5% of patients. The total number of deaths reported in MASTER and GRIFFIN studies were 3 and 8, respectively.
  • EQUULEUS is a phase 1b study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of NDMM for transplant eligible and non-eligible patients.14
  • Several subgroup analyses have been identified which discuss the use of DARZALEX and DARZALEX FASPRO in NDMM patients who were eligible for ASCT. These subgroup analyses are included in the References section for your information.15-19

PRODUCT LABELING

CLINICAL DATA

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 R in VRd group in patients with NDMM eligible for ASCT. Sonneveld et al (2023)1 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 at cycles 1-2 and once every 2 weeks at 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 once 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 complete response (CR), they restarted on DARZALEX FASPRO.
        • Patients who did not achieved 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: Overall response rate (ORR), very good partial response or better (≥VGPR), sCR, and duration of MRD-negativity.

Results

Patient Characteristics

  • A total of 709 patients were randomized into the D-VRd (n=355) and VRd (n=354) groups.
  • 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 group who started the induction phase continued into the maintenance phase, respectively.
    • A total of 207/322 patients in the D-VRd group 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 (87.0%) patients in the D-VRd vs VRd group 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).

Demographics and Baseline Clinical Characteristics of the ITT Populationa,1
D-VRd (n=355)
VRd (n=354)
Median age (range), years
61.0 (32-70)
59.0 (31-70)
Male, n (%)
211 (59.4)
205 (57.9)
Race, n (%)
   Asian
4 (1.1)
6 (1.7)
   Black or African American
5 (1.4)
4 (1.1)
   White
330 (93.0)
323 (91.2)
   Other
4 (1.1)
3 (0.8)
   Missing data
12 (3.4)
18 (5.1)
ECOG PS, n (%)b
   0
221 (62.3)
230 (65.0)
   1
114 (32.1)
108 (30.5)
   2
19 (5.4)
16 (4.5)
   3
1 (0.3)
0
Type of measurable disease, n (%)
   IgG
204 (57.5)
185 (52.3)
   IgA
65 (18.3)
85 (24.0)
   Otherc
13 (3.7)
11 (3.1)
   Detected in urine only
43 (12.1)
46 (13.0)
   Detected in serum free light chains only
29 (8.2)
27 (7.6)
   NE
1 (0.3)
0
ISS disease stage,d n
355
353
   I, n (%)
186 (52.4)
178 (50.4)
   II, n (%)
114 (32.1)
125 (35.4)
   III, n (%)
55 (15.5)
50 (14.2)
Cytogenetic risk profile, n (%)e
   Standard risk
264 (74.4)
266 (75.1)
   High risk
76 (21.4)
78 (22.0)
   Indeterminate
15 (4.2)
10 (2.8)
Median time since diagnosis of multiple myeloma (range), months
1.2 (0.0-46.5)
1.1 (0.1-184.6)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; ISS, International Staging System; ITT, intent-to-treat; NE, not estimable; VRd, bortezomib + lenalidomide + dexamethasone.
aThe ITT population was defined as all patients who underwent randomization. Informal testing showed no significant differences between the 2 treatment groups in the characteristics evaluated at baseline.
bECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. One patient had an ECOG PS score of 0 at the time of randomization that worsened to an ECOG PS score of 3 at baseline.
cIncludes IgD, IgM, IgE, and biclonal.
dThe ISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
eCytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).

Duration of Treatment and Relative Dose Intensities During Induction/Consolidation/Maintenance Treatment in the Safety Populationa,b,20
D-VRd (n=351)
VRd (n=347)
Median duration
of treatment (range), months
45.7 (0.5-54.3)
42.2 (0.1-53.9)
Median relative dose intensity (range), %
Induction
Consolidation
Maintenance
Induction
Consolidation
Maintenance
   Bortezomib
(n=351)
98.0
(25.3-104.8)
(n=243)
97.8
(12.3-114.2)
NA
(n=347)
97.8
(40.2-110.4)
(n=236)
98.2
(9.5-106.0)
NA
   Lenalidomide
(n=351)
100
(28.6-122.2)
(n=271)
100
(29.5-116.7)
(n=316)
85.2
(8.5-152.8)
(n=347)
100
(36.7-105.6)
(n=260)
100
(23.3-100.0)
(n=300)
97.1
(39.7-150.4)
   Dexamethasone
(n=351)
100
(20.8-183.3)
(n=263)
100
(1.6-100.0)
NA
(n=347)
100
(35.9-121.9)
(n=250)
100
(10.0-125.0)
NA
Induction Cycles 1-2
(n=351)
Induction Cycles 3-4
(n=343)
Consolidation
(n=274)
Maintenance
(n=322)
      DARZALEX FASPRO
100
(50.0-100.4)
100
(25.0-100.0)
100
(50.0-100.0)
100
(67.6-100.0)
NA
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; NA, not available; VRd, bortezomib + lenalidomide + dexamethasone.
aDose intensity was defined as the ratio of the total administered dose to the total planned dose.
bThe safety population included all patients who received ≥1 dose of the study treatment.

Efficacy

  • A total of 50 (14.1%) vs 103 (29.1%) patients experienced disease progression or deaths in the D-VRd vs VRd group of the ITT population (HR, 0.42; 95% CI, 0.30-0.59; P<0.0001), respectively, crossing the prespecified stopping boundary for superiority at the first interim analysis (P=0.0126).
  • The estimated 48-month PFS rate for the D-VRd vs VRd group was 84.3% (95% CI, 79.5-88.1) vs 67.7% (95% CI, 62.2-72.6), respectively.
  • A summary of response rates and MRD status in the ITT population is presented in Table: Summary of Response Rates and MRD Status in the ITT Population.
  • Analyses of overall ≥CR rates and overall MRD-negativity rates (at 10-5) in prespecified subgroups appeared to favor D-VRd over VRd across clinically relevant subgroups.
  • Information on PFS in prespecified subgroup analysis is summarized in Table: PFS in Prespecified Subgroups.

Summary of Response Rates and MRD Status in the ITT Populationa,1
Parameter
D-VRd (n=355)
VRd (n=354)
P Valueb
Overall response
   n
343
332
-
   % (95% CI)
96.6 (94.2-98.2)
93.8 (90.7-96.1)
-
Response, n (%)
   ≥CR
312 (87.9)
248 (70.1)
<0.0001
      sCRc
246 (69.3)
158 (44.6)
-
      CR
66 (18.6)
90 (25.4)
-
   ≥VGPR
338 (95.2)
316 (89.3)
-
      VGPR
26 (7.3)
68 (19.2)
-
   PR
5 (1.4)
16 (4.5)
-
   SD
4 (1.1)
9 (2.5)
-
   PD
2 (0.6)
1 (0.3)
-
   Response could not be evaluated
6 (1.7)
12 (3.4)
-
MRD-negativity, n (%)d
   10-5 sensitivity
267 (75.2)
168 (47.5)
<0.0001
   10-6 sensitivity
231 (65.1)
114 (32.2)
-
Sustained MRD-negativity (10-5) for ≥12 months, n (%)
230 (64.8)
105 (29.7)
-
Abbreviations: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; FLC, free light chain; IMWG, International Myeloma Working Group; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aResponse rates and MRD-negativity rates at any time during the study. The responses were assessed based on the IMWG response criteria.
bP values were calculated with the use of the stratified Cochran-Mantel-Haenszel chi-squared test.
cCriteria for an sCR included the criteria for a CR plus a normal serum FLC ratio and the absence of clonal plasma cells in the bone marrow, as assessed by immunohistochemistry, immunofluorescence, or 2- to 4-color flow cytometry.
dThe MRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity and ≥CR. Sustained MRD-negativity for 12 months was defined as 2 consecutive MRD-negative results 12 months apart, without any MRD-positive results in between. The MRD status was assessed using bone marrow samples and evaluated using an NGS assay (clonoSEQ assay, version 2.0; Adaptive Biotechnologies) in accordance with the IMWG guidelines for assessing MRD.

PFS in Prespecified Subgroups1
Subgroups
PFS
D-VRd
VRd
D-VRd
VRd
HR (95% CI)
No. of Progression Events or Deaths/Total No.
Median PFS, Months
Sex
   Male
36/211
61/205
NE
NE
0.51 (0.34-0.77)
   Female
14/144
42/149
NE
NE
0.29 (0.16-0.53)
Age
   <65 years
30/261
84/267
NE
NE
0.30 (0.20-0.46)
   ≥65 years
20/94
19/87
NE
NE
0.97 (0.52-1.81)
Race
   White
47/330
95/323
NE
NE
0.42 (0.30-0.60)
   Other
3/25
8/31
NE
NE
0.40 (0.11-1.50)
ISS staging
   I
18/186
35/178
NE
NE
0.46 (0.26-0.81)
   II
19/114
43/125
NE
NE
0.37 (0.22-0.64)
   III
13/55
25/50
NE
41.9
0.42 (0.22-0.83)
Type of MM
   IgG
28/204
58/185
NE
NE
0.36 (0.23-0.57)
   Non-IgG
13/78
31/96
NE
NE
0.46 (0.24-0.88)
Cytogenetic risk
   Standard risk
25/264
62/266
NE
NE
0.35 (0.22-0.56)
   High risk
24/76
38/78
NE
44.1
0.59 (0.36-0.99)
   Intermediate risk
1/15
3/10
NE
NE
0.16 (0.02-1.56)
ECOG PS
   0
28/221
60/230
NE
NE
0.42 (0.27-0.66)
   ≥1
22/134
43/124
NE
NE
0.41 (0.25-0.69)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.

Safety

  • The most common grade 3/4 AEs recorded in the D-VRd vs VRd group were neutropenia (62.1% vs 51.0%), 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%). See Table: Most Common AEs During Treatment in the Safety Population.
  • Grade 3/4 peripheral neuropathy occurred in 6.0% vs 4.9% of patients in the D-VRd vs VRd group, respectively.
  • Serious adverse events (SAEs) in the safety population are summarized in Table: SAEs in the Safety Population.
  • A second primary malignancy was observed in 37 patients (10.5%) in the D-VRd group and 25 patients (7.2%) in the VRd group.
  • The number of deaths recorded due to coronavirus disease 2019 (COVID-19) in the D-VRd vs VRd group was 4 (1.1%) vs 1 (0.3%) patients, respectively.
  • A total of 25.9% vs 54.2% of patients in the D-VRd vs VRd group discontinued treatment, respectively.
    • The most common reasons for treatment discontinuation over all phases of the study were AEs (D-VRd, 9.1%; VRd, 22.5%) and PD (D-VRd, 8.3%; VRd, 20.7%).
  • A total of 34 vs 44 patients died in the D-VRd vs VRd group, respectively.
    • A total of 7 patients died due to COVID-19 (D-VRd, n=4; VRd, n=3).

Most Common AEs During Treatment in the Safety Populationa,1
Event, n (%)
D-VRd (n=351)
VRd (n=347)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any AE
349 (99.4)
321 (91.5)
344 (99.1)
297 (85.6)
Hematologic AEs
   Neutropenia
243 (69.2)
218 (62.1)
204 (58.8)
177 (51.0)
   Thrombocytopenia
170 (48.4)
102 (29.1)
119 (34.3)
60 (17.3)
   Anemia
78 (22.2)
21 (6.0)
72 (20.7)
22 (6.3)
   Febrile neutropenia
34 (9.7)
33 (9.4)
38 (11.0)
35 (10.1)
Nonhematologic AEs
   Diarrhea
214 (61.0)
37 (10.5)
188 (54.2)
27 (7.8)
   Peripheral sensory neuropathy
188 (53.6)
15 (4.3)
179 (51.6)
14 (4.0)
   Constipation
119 (33.9)
8 (2.3)
118 (34.0)
6 (1.7)
   Pyrexia
111 (31.6)
8 (2.3)
109 (31.4)
9 (2.6)
   Insomnia
95 (27.1)
8 (2.3)
61 (17.6)
6 (1.7)
   Asthenia
94 (26.8)
12 (3.4)
89 (25.6)
9 (2.6)
   Cough
85 (24.2)
1 (0.3)
51 (14.7)
0
   Fatigue
84 (23.9)
10 (2.8)
92 (26.5)
18 (5.2)
   Rash
82 (23.4)
9 (2.6)
94 (27.1)
17 (4.9)
   Back pain
80 (22.8)
2 (0.6)
66 (19.0)
1 (0.3)
   Peripheral edema
72 (20.5)
4 (1.1)
74 (21.3)
1 (0.3)
   Nausea
71 (20.2)
2 (0.6)
58 (16.7)
2 (0.6)
   Infections
305 (86.9)
124 (35.3)
266 (76.7)
95 (27.4)
      COVID-19
123 (35.0)
12 (3.4)
83 (23.9)
4 (1.2)
      Upper respiratory tract
      infection
111 (31.6)
2 (0.6)
87 (25.1)
6 (1.7)
      Pneumonia
64 (18.2)
37 (10.5)
38 (11.0)
21 (6.1)
Second primary malignancy
37 (10.5)
NA
25 (7.2)
NA
Any IRR
21 (6.0)
3 (0.9)
NA
NA
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; NA, not applicable;
VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of the study treatment. AEs of any grade that were reported in ≥20% of patients in either treatment group and grade 3/4 AEs that were reported in ≥10% of patients in either treatment group are listed.

SAEs in the Safety Populationa,20
n (%)
D-VRd (n=351)
VRd (n=347)
Total no. of patients with SAEs
200 (57.0)
171 (49.3)
SAEs occurring in ≥2% of patients in either treatment group
   Infections
123 (35.0)
95 (27.4)
      Pneumonia
40 (11.4)
21 (6.1)
      COVID-19
13 (3.7)
6 (1.7)
      COVID-19 pneumonia
11 (3.1)
5 (1.4)
      Lower respiratory tract infection
9 (2.6)
3 (0.9)
      Sepsis
7 (2.0)
9 (2.6)
      Upper respiratory tract infection
7 (2.0)
8 (2.3)
   Febrile neutropenia
16 (4.6)
16 (4.6)
   Pyrexia
13 (3.7)
16 (4.6)
   Pulmonary embolism
9 (2.6)
5 (1.4)
   Atrial fibrillation
9 (2.6)
2 (0.6)
   Diarrhea
7 (2.0)
9 (2.6)
Abbreviations: COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; SAE, serious adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of the study treatment.
  • Median cluster of differentiation 34+ (CD34+) cell yield in the D-VRd vs VRd group was 5.5x106/kg vs 7.4x106/kg, respectively.
  • The proportion of patients proceeding to ASCT in the D-VRd vs VRd group was 89.7% vs 87.0%, respectively.
  • The median time to complete hematopoietic reconstitution in the D-VRd vs VRd group was 14 days each.

Significance of CTC as a Biomarker in Transplant-Eligible Patients With NDMM - Results From the PERSEUS Study

Bertamini et al (2024)2 presented (at the 66th ASH Annual Meeting) results from the PERSEUS study that highlighted the significance of CTC as a biomarker in transplant-eligible patients with NDMM.

Results

Patient Characteristics


Baseline Characteristics in Patients from the PERSEUS Study - CTC Subgroup2
Characteristic
D-VRd
(n=231)
VRd
(n=220)
P Value
CTC detected, n/N (%)
183/231 (79.2)
187/220 (85.0)
0.73
CTC, median (IQR), %
0.0104 (0.0009-0.0738)
0.0088 (0.0012-0.0746)
0.88
Median age (IQR), years
60 (53.5-65)
59 (52.8-65)
0.71
Female sex, n (%)
84 (36.4)
95 (43.2)
0.14
ISS disease stage, %
   I
53.2
50.9
0.76
   II
31.6
35.0
0.76
   III
15.2
14.1
0.76
High LDH, n (%)
63 (27.3)
42 (19.1)
0.04
Cytogenetic high-riska, n (%)
51 (22.1)
49 (22.3)
0.86
Abbreviations: CTC, circulating tumor cells; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IQR, interquartile range; ISS, International Staging System; LDH, lactate dehydrogenase; VRd, bortezomib, lenalidomide, and dexamethasone.aHigh-risk cytogenetics was defined by the presence of t(4;14), and/or t(14;16) and/or del17p by fluorescence in situ hybridization.

Efficacy

  • D-VRd vs VRd significantly improved patient outcomes across both high and low CTC levels (P<0.0001).2
    • D-VRd vs VRd improved MRD-negativity rates (with ≥CR; 10–5 and 10–6 sensitivities) and sustained MRD-negativity rates (with ≥CR; 10-5 and 10–6 sensitivities; ≥12 months) in patients with both high and low CTC levels and the results are presented in Table: Summary of Overall MRD-Negativity (with ≥CR) Rates.
  • Increasing levels of CTC were associated with inferior prognosis. The 4-year PFS estimates based on CTC log10 values are presented below.2
    • Log10 value of <0.001%: 93%.
    • Log10 value of 0.001-0.01%: 79%.
    • Log10 value of 0.01-0.1%: 71%.
    • Log10 value of 0.1-1%: 67%
    • Log10 value of ≥1%: 48%.
  • D-VRd vs VRd improved 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.2 The prognostic impact of CTC and other risk factors on PFS is presented in Table: Prognostic Impact of CTC and Other Risk Factors on PFS.
    • D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).2

Summary of Overall MRD-Negativity (with ≥CR) Rates2
Patients, %
CTC Low Levela
CTC High Levelb
D-VRd
(n=195)
VRd
(n=187)
P Value
D-VRd
(n=36)
VRd
(n=33)
P Value
Overall MRD-negativity (with ≥CR)c
   10-5 sensitivity
74
58
<0.001d
69
33
<0.01d
   10-6 sensitivity
66
39
<0.001d
47
21
<0.01d
Sustained MRD-negativity (with ≥CR; ≥12 months)e
   10-5 sensitivity
64
36
<0.0001f
50
15
<0.01f
   10-6 sensitivity
42
21
<0.0001f
39
6
<0.01f
Abbreviations: ≥CR, complete response or better; CTC, circulating tumor cells; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone.
aCTC-low is defined by CTC <0.175%.
bCTC-high is defined by CTC ≥0.175%.
cProportion of patients who achieved both MRD-negativity and ≥CR in the randomized ITT population.dP value from a Chi-square test.eTwo consecutive MRD-negative results ≥12 months apart with no MRD-positive results in between.fP value from a Fisher’s test.

Prognostic Impact of CTC and Other Risk Factors on PFS2
Risk Factor
HR (95% CI)
P Value
CTC (log10)
1.36 (1.15-1.60)
≤0.05
High-risk cytogeneticsa
2.71 (1.76-4.17)
≤0.05
   ISS stage II
1.31 (0.81-2.12)
>0.05b
   ISS stage III
2.5 (1.45-4.32)
≤0.05
Elevated LDH
1.04 (0.65-1.68)
>0.05b
Abbreviations: CI, confidence interval; CTC, circulating tumor cells; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase; PFS, progression-free survival.
aComparison with standard risk. High-risk cytogenetics is defined by the presence of t(4;14) and/or t(14;16) and/or del17p by fluorescence in situ hybridization. Absence of those is considered standard risk.
bNot significant.

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; clinicaltrials.gov identifier: NCT02541383) is an ongoing, open-label, 2-arm, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VTd in patients with previously untreated MM who are eligible for HDT and ASCT.3,4 Moreau et al (2019)3 reported the results from Part 1 of this study. Moreau et al (2021)4 reported the results from Part 2 of this study (maintenance treatment).

Study Design/Methods

  • Primary endpoint: Part 1: sCR after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days); Part 2: PFS after second randomization
  • Secondary endpoints: Part 1: PFS, time to progression (TTP), proportion of post-ASCT/consolidation MRD, proportion of post-induction sCR, PFS after next line of therapy (PFS2), OS; Part 2: TTP from second randomization, ≥CR, MRD-negativity rates (in patients with ≥CR at a threshold of 10-5 by NGS), PFS2, ORR, and OS from second randomization

Results - Part 1

Baseline Characteristics

Demographic and Clinical Characteristics in the Intent-to-treat Population at Baseline (CASSIOPEIA Part 1)3
Characteristic 
D-VTd (n=543)
VTd (n=542)
Median (range) age, years
59 (22-65)
58 (26-65)
Sex, n (%)
   Male
316 (58.2)
319 (58.9)
   Female
227 (41.8)
223 (41.1)
ECOG PS
   0
265 (49)
257 (47)
   1
225 (41)
230 (42)
   2
53 (10)
55 (10)
Type of measurable disease
   IgG
331 (61)
314 (58)
   IgA
80 (15)
99 (18)
Otherb
3 (2)
22 (4)
Detected in urine only
70 (13)
67 (12)
Detected in serum FLCs only
48 (9)
40 (7)
Unknown
1 (<1)a
0
ISS disease stagec
   I
204 (38)
228 (42)
   II
255 (47)
233 (43)
   III
84 (15)
81 (15)
Cytogenetic profile, n/total (%)d
   Standard risk
460/542 (85)
454/540 (84)
   High riske
82/542 (15)
86/540 (16)
Median time since MM dx (range), months
0.92 (0.2-9.4)
0.92 (0.2-22.9)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; dx, diagnosis; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; VTd, bortezomib + thalidomide + dexamethasone.
aOne patient was assessed as light-chain only, despite monoclonal peak in serum and urine.
bIncludes IgD, IgM, IgE, and biclonal.
cBaseline disease stage based on the revised ISS criteria.
dCytogenetic risk was assessed by fluorescence in-situ hybridization. Patients for whom cytogenetic testing failed were considered standard risk (D-VTd 7·6%; VTd 7·4%).
eThese patients had at least one high-risk abnormality: del17p (≥50% abnormal cells) or t(4;14) (≥30% abnormal cells).
Efficacy
  • Efficacy data from Part 1 of the study are presented in Table: Summary of Responses and MRD Status 100 Days after ASCT (CASSIOPEIA Part 1).
  • A total of 157/543 (29%) patients in the D-VTd group vs 110/542 (20%) patients in the VTd group achieved the primary endpoint of sCR following consolidation (OR, 1.60; 95% CI, 1.20-2.12; P=0.0010).
  • A significantly higher proportion of patients achieved ≥CR following consolidation in the D-VTd group vs the VTd group (211 [39%] vs 141 [26%]; P<0.0001).
  • The proportion of patients with MRD-negative status at a 10-5 sensitivity threshold following consolidation was larger in the D-VTd group than in the VTd group (346/543 [64%] vs 236/542 [44%]; P<0.0001) when assessed by multiparametric flow cytometry (MFC).
  • PFS from first randomization was significantly improved in the D-VTd group vs the VTd group (HR, 0.47; 95% CI, 0.33-0.67; P<0.0001). Median OS from first randomization regardless of second randomization was not reached (NR) in either treatment group (HR, 0.43; 95% CI, 0.23-0.80).

Summary of Responses and MRD Status 100 Days after ASCT (CASSIOPEIA Part 1)3
D-VTd (n=543)
VTd (n=542)
P valuea
Overall Response
   Number with response
503
487
-
   Percentage (95% CI)
92.6% (90.1-94.7)
89.9% (87.0-92.3)
0.11
Response
   sCR
157 (29%)
110 (20%)
0.0010
   CR
54 (10%)
31 (6%)
-
   ≥CR
211 (39%)
141 (26%)
<0.0001
   ≥VGPR
453 (83%)
423 (78%)
0.024
   VGPR
242 (45%)
282 (52%)
-
   PR
50 (9%)
64 (12%)
-
   SD
10 (2%)
15 (3%)
-
   PD
20 (4%)
25 (5%)
-
   Response could not be evaluated
10 (2%)
15 (3%)
-
MRD-negative Status (10-5)b
   MRD-negative regardless of response
346 (64%)
236 (44%)
<0.0001
   MRD-negative and ≥CRc
183 (34%)
108 (20%)
<0.0001
   MRD-negative and ≥VGPRc
338 (62%)
231 (43%)
<0.0001
Abbreviations: ≥CR, complete response or better; ≥VGPR, very good partial response or better; ASCT, autologous stem cell transplant; CI, confidence interval; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.aP values are given only for primary and secondary endpoints.bEuroFlow-based multiparametric flow cytometry.cPost-hoc analysis.
Safety
  • AEs are presented in Table: Most Common Adverse Events During Treatment in the Safety Population (CASSIOPEIA Part 1).
  • The most common any-grade AEs occurring in ≥20% of patients in either group (D-VTd [n=536] vs VTd [n=538]) were peripheral sensory neuropathy (59% vs 63%), constipation (51% vs 49%), asthenia (32% vs 29%), peripheral edema (30% vs 28%), nausea (30% vs 24%), neutropenia (29% vs 17%), pyrexia (26% vs 21%), paresthesia (22% vs 20%), and thrombocytopenia (20% vs 14%).
  • The most common grade 3/4 AEs occurring in ≥10% of patients (D-VTd vs VTd) were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), stomatitis (13% vs 16%), and thrombocytopenia (11% vs 7%).
  • SAEs occurred in 251 (47%) patients in the D-VTd group and 255 (47%) patients in the VTd group. The most common SAEs (occurring in ≥3% of patients in either group) in the D-VTd vs VTd group were neutropenia (4% vs 1%), pneumonia (4% vs 2%), pyrexia (3% vs 4%), and pulmonary embolism (1% vs 4%).
  • Infusion-related reactions (IRRs) related to DARZALEX were reported in 190/536 (35%) patients in the safety population.
  • Second primary malignancies occurred in 10 (2%) patients in the D-VTd group vs 12 (2%) patients in the VTd group.

Most Common Adverse Events During Treatment in the Safety Population (CASSIOPEIA Part 1)a, 3
Event, n (%) 
D-VTd (n=536)
VTd (n=538)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematological
   Neutropenia
157 (29)
148 (28)
89 (17)
79 (15)
   Thrombocytopenia
109 (20)
59 (11)
73 (14)
40 (7)
   Lymphopenia
99 (18)
91 (17)
67 (12)
52 (10)
Non-hematological
   Peripheral sensory neuropathy
314 (59)
47 (9)
340 (63)
46 (9)
   Constipation
272 (51)
7 (1)
262 (49)
7 (1)
   Asthenia
171 (32)
7 (1)
155 (29)
6 (1)
   Peripheral edema
162 (30)
3 (<1)
148 (28)
7 (1)
   Nausea
162 (30)
21 (4)
130 (24)
12 (2)
   Pyrexia
140 (26)
14 (3)
114 (21)
12 (2)
   Paresthesia
118 (22)
4 (<1)
108 (20)
6 (1)
   Stomatitis
86 (16)
68 (13)
104 (19)
88 (16)
Second primary malignancy
10 (2)
NA
12 (2)
NA
Any infusion-related reaction
190 (35)
19 (4)
NA
NA
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; NA, not applicable; VTd, bortezomib + thalidomide + dexamethasone.aAdverse events of any grade that were reported in at least 20% of patients in either treatment group and grade 3 or 4 adverse events that were reported in at least 10% of patients in either treatment group are listed.

Results - Part 2

Baseline Characteristics

Baseline Demographics and Disease Characteristics after Second Randomization (CASSIOPEIA Part 2)4
Characteristics, n (%)
DARZALEX Monotherapy
(n=442)
Observation
(n=444)
Median age (IQR), years
59 (53-63)
59 (53-63)
Male
261 (59)
254 (57)
ECOG PS
   0
252 (57)
260 (59)
   1
174 (39)
172 (39)
   ≥2
16 (4)
12 (3)
ISS disease stagea
   I
189 (43)
171 (39)
   II
181 (41)
214 (48)
   III
72 (16)
59 (13)
Cytogenetic profilea, n/total (%)
   Standard risk
383/440 (87)
374/444 (84)
   High risk
57/440 (13)
70/444 (16)
Type of induction/consolidation
   D-VTd
229 (52)
229 (52)
   VTd
213 (48)
215 (48)
Depth of responseb
   MRD-negative, ≥VGPR
337 (76)
337 (76)
   MRD-positive, ≥VGPR
68 (15)
69 (16)
   MRD-positive, PRc
37 (8)
38 (9)
Abbreviations: ≥VGPR, very good partial response or better; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; ISS, International Staging System; MRD, minimal residual disease; PR, partial response; VTd, bortezomib + thalidomide + dexamethasone. aPre-induction.bAs determined by MRD measured by multiparametric flow cytometry at 10-4 and post-consolidation response per investigator assessment used for stratification. cSix patients (3 who received previous D-VTd and 3 who received previous VTd) were MRD-negative with a response of PR at post-consolidation and were categorized as MRD-positive and PR due to the lack of specific stratum defined in the protocol for such patients.

Patient Disposition (CASSIOPEIA Part 2)4
Patients, n
DARZALEX Monotherapy
Observation
Second randomization (1:1)
442
444
   D-VTd
229
229
   VTd
213
215
Patients who completed treatment
340a
316
   Patients who discontinued
100
128
   Progressive disease
61
119
   Adverse event
15
2
Other
24
7
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; VTd, bortezomib + thalidomide + dexamethasone.aPatients who did not receive assigned DARZALEX monotherapy (n=2).
Efficacy
  • After a median follow-up of 35.4 months (interquartile range [IQR], 30.2-39.9), median PFS from second randomization was NR (95% CI, not estimable [NE]-NE) in the DARZALEX monotherapy group vs 46.7 months (95% CI, 40.0-NE) in the observation group (HR, 0.53; 95% CI, 0.42-0.68; P<0.0001).
    • The DARZALEX monotherapy group experienced 108 PFS events, while the observation group experienced 173 events.
    • The PFS benefit of the DARZALEX monotherapy group vs the observation group was consistent across most prespecified subgroups, except for patients with ISS stage III disease, patients with creatinine clearance (CrCl) ≤90 mL/min, and those who received VTd as a part of induction, ASCT, and consolidation treatment group as presented in Table: PFS in Prespecified Subgroups (CASSIOPEIA Part 2).
  • ≥CR was achieved by 322/442 (73%) patients in the DARZALEX monotherapy group vs 270/444 (61%) in the observation group (OR, 2.17; 95% CI, 1.54-3.07; P<0.0001).
  • The improved response was achieved by 188/304 (62%) patients in the DARZALEX monotherapy group vs 153/324 (47%) in the observation group (OR, 1.95; 1.40-2.72; P<0.0001).
  • MRD-negativity status (at 10-5 by NGS) was achieved by 259 (58.6%) patients in the DARZALEX monotherapy group vs 209 (47.1%) in the observation group (OR, 1.80; 95% CI, 1.33-2.43; P=0.0001).4,21
  • ORR was similar among groups (440/442 [>99%] patients in the DARZALEX monotherapy group vs 441/444 [99%] patients in the observation group).
  • The median TTP was NR (95% CI, NE-NE) in the DARZALEX monotherapy group vs 46.7 months (95% CI, 40.0-NE) in the observation group (HR, 0.49; 95% CI, 0.38-0.62; P<0.0001).
    • The DARZALEX monotherapy group experienced 98 events vs 172 events in the observation group.
  • The median PFS2 was immature for both the groups (HR, 0.62; 95% CI, 0.40-0.96).22
  • The median OS was NR in the DARZALEX monotherapy group vs the observation group (29 deaths in DARZALEX monotherapy group vs 29 deaths in observation group; 95% CI, NE-NE).
    • The most common cause of death was PD (DARZALEX monotherapy, 45% [n=13]; observation group, 81% [n=22]).
  • In the ITT population, there was no difference in the PFS for patients who received D-VTd + DARZALEX monotherapy vs D-VTd + observation (HR, 1.02; 95% CI, 0.71-1.47; P=0.9133) as a part of induction/consolidation and maintenance treatment therapies.21
    • ≥CR was achieved by 76.4% patients in the D-VTd + DARZALEX monotherapy group vs 71.6% in the D-VTd + observation group (OR, 1.43; 95% CI, 0.87-2.37; P=0.1624) as a part of induction/consolidation and maintenance treatment therapies.
    • MRD-negativity status (at 10-5 by NGS in patients with ≥CR) was achieved by 64.2% of patients in the D-VTd + DARZALEX monotherapy group vs 57.6% in the D-VTd + observation group (OR, 1.43; 95% CI, 0.93-2.19; P=0.1037) as a part of induction/consolidation and maintenance treatment therapies.
  • In the ITT population, a PFS benefit was observed in patients who received VTd + DARZALEX monotherapy vs VTd + observation (HR, 0.32; 95% CI, 0.23-0.46; P<0.0001) as a part of induction/consolidation and maintenance treatment therapies.21
    • ≥CR was achieved by 69% patients in the VTd + DARZALEX monotherapy group vs 49.3% in the VTd + observation group (OR, 3.14; 95% CI, 1.93-5.10; P<0.0001) as a part of induction/consolidation and maintenance treatment therapies.
    • MRD-negativity status (at 10-5 by NGS in patients with ≥CR) was achieved by 52.6% of patients in the VTd + DARZALEX monotherapy group vs 35.8% in the VTd + observation group (OR, 2.26; 95% CI, 1.47-3.48; P=0.0002) as a part of induction/consolidation and maintenance treatment therapies.
  • After a median follow-up of 44.5 months (IQR, 38.9-49.1), an updated analysis was performed from first randomization (Part 1 CASSIOPEIA study) of patients in the D-VTd group vs VTd group.4,21
    • The median PFS was NR (95% CI, NE-NE) in the D-VTd group vs 51.5 months (95% CI, 46.3-NE) in the VTd group (HR, 0.58; 95% CI, 0.47-0.72; P<0.0001).
    • The median OS was NR for patients in the D-VTd group and VTd group (41 [8%] deaths of patients in D-VTd group vs 73 [13%] deaths in VTd group; HR, 0.54; 95% CI, 0.37-0.79).

PFS in Prespecified Subgroups (CASSIOPEIA Part 2)4
Hazard Ratio, (95% CI)
Sex
   Male
0.57 (0.42-0.76)
   Female
0.53 (0.35-0.81)
Age, years
   <50
0.38 (0.20-0.74)
   50-60
0.56 (0.39-0.79)
   >60
0.67 (0.46-0.98)
ISS disease staging
   I
0.50 (0.32-0.78)
   II
0.56 (0.40-0.79)
   III
0.75 (0.44-1.29)
Cytogenetic risk
   High risk
0.43 (0.25-0.73)
   Standard risk
0.62 (0.48-0.82)
Baseline renal function (CrCl)
   >90 mL/min
0.51 (0.38-0.68)
   ≤90 mL/min
0.72 (0.47-1.12)
Type of MM
   IgG
0.64 (0.48-0.87)
   Non-IgG
0.44 (0.26-0.75)
Baseline ECOG PS
   0
0.55 (0.40-0.76)
   ≥1
0.57 (0.40-0.82)
Induction/consolidation tx group
   D-VTd
1.05 (0.73-1.51)
   VTd
0.34 (0.24-0.47)
MRD status
   MRD-positive
0.46 (0.31-0.67)
   MRD-negative
0.61 (0.44-0.83)
Response
   ≥VGPR
0.58 (0.45-0.75)
   PR
0.39 (0.21-0.73)
Abbreviations: ≥VGPR, very good partial response or better; CI, confidence interval; CrCl, creatinine clearance; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; PFS, progression-free survival; PR, partial response; tx, treatment; VTd, bortezomib + thalidomide + dexamethasone.
Safety
  • AEs are presented in Table: Most Common AEs (≥10%) During Treatment or Observation in the Maintenance-Specific Safety Population (CASSIOPEIA Part 2).
  • Any TEAEs occurred in 95% (n=420) of patients in the DARZALEX monotherapy group vs 89% (n=394) in the observation group.
  • SAEs occurred in 23% (n=100) of patients in the DARZALEX monotherapy group vs 19% (n=84) in the observation group.
  • SAEs that occurred in >1% of patients in the DARZALEX monotherapy vs observation groups were pneumonia (n=11 [3%] vs n=7 [2%]) and lung infection (n=6 [1%] vs n=7 [2%]), respectively.
  • DARZALEX infusions were interrupted in 21% (n=93) of patients due to an AE.
  • DARZALEX treatment was discontinued in 3% (n=13) of patients due to an AE.
  • Grade ≥3 TEAEs were reported in 28% (n=122) of patients in the DARZALEX monotherapy group (who received at least 1 dose) vs 24% (n=108) in the observation group.
  • IRRs occurred in 54.5% (n=115) of patients in the DARZALEX monotherapy group.22
  • Two AEs led to death in the DARZALEX monotherapy group (septic shock and natural killer-cell lymphoblastic lymphoma, n=1 each); both were treatment-related.

Most Common AEs (≥10%) During Treatment or Observation in the Maintenance-Specific Safety Population (CASSIOPEIA Part 2)4
AE, n (%)
DARZALEX Monotherapy
(n=440)
Observation
(n=444)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Hematologica
   Lymphopenia
15 (3)
14 (3)
2 (<1)
9 (2)
3 (1)
5 (1)
   Neutropenia
3 (1)
9 (2)
0
0
10 (2)
0
Non-hematologica
   Bronchitis
166 (38)
2 (<1)
1 (<1)
130 (29%)
4 (1)
0
   Nasopharyngitis
76 (17)
0
0
49 (11)
0
0
   Upper respiratory tract
   infection
64 (15)
0
0
35 (8)
1 (<1)
0
   Herpes Zoster
30 (7)
1 (<1)
0
63 (14)
2 (<1)
0
   Pneumonia
18 (4)
10 (2)
1 (<1)
13 (3)
6 (1)
0
   Diarrhea
56 (13)
1 (<1)
0
0
10 (2)
   Asthenia
60 (14)
0
0
51 (11)
2 (<1)
   Influenza-like illness
54 (12)
0
0
49 (11)
0
0
   Hypogammaglobulinemia
53 (12)
3 (1)
0
13 (3)
3 (1)
0
   Arthralgia
50 (11)
1 (<1)
0
50 (11)
2 (<1)
0
   Back Pain
45 (10)
2 (<1)
0
59 (13)
2 (<1)
0
   Peripheral Sensory Neuropathy
65 (15)
4 (1)
0
46 (10)
5 (1)
0
   Cough
78 (18)
1 (<1)
0
40 (9)
0
0
   Hypertension
15 (3)
13 (3)
0
10 (2)
7 (2)
0
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.
aThe most common grade 3 or 4 TEAEs were lymphopenia, hypertension, and neutropenia.

Long-term Follow-up in CASSIOPEIA Study

Moreau et al (2024)5 reported long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization.

Study Design

  • This planned analysis presented the study's conclusion with the final data cutoff of September 1, 2023. During the induction and consolidation phases, efficacy assessments were conducted on the ITT population cohort, encompassing all patients from the first randomization. In the maintenance phase, efficacy analyses were performed on the maintenance-specific ITT population, including patients randomized during the second randomization.

Results

Patient Disposition
  • Between September 22, 2015, and August 1, 2017, a total of 1085 patients were enrolled and randomized to receive D-VTd (n=543) and VTd (n=542).
  • Overall, 458 patients (84%) in the D-VTd group and 428 patients (79%) in the VTd group, who completed consolidation and achieved a ≥PR, were re-randomized to either DARZALEX maintenance (n=442) or observation (n=444).
    • At a clinical data cutoff of September 1, 2023, 339 patients (77%) had completed DARZALEX maintenance, and 317 patients (71%) had completed observation during the maintenance phase.
    • A total of 61 patients (14%) in the DARZALEX maintenance group and 118 patients (27%) in the observation group had discontinued treatment due to disease progression during the maintenance phase.
Efficacy

Summary of Long-term PFS and OS From First Randomization After a Median Follow-up Duration of 80.1 Months5
Efficacy
D-VTd (n=543)
VTd (n=542)
Median PFS, months (95% CI)
83.7 (70.2-NE)
52.8 (47.5-58.7)
   HR (95% CI)
0.61 (0.52-0.72)
P value
<0.0001
PFS events
255
335
Median OS (95% CI)
NR (NE-NE)
NR (NE-NE)
   Estimated 72-month OS rate, % (95% CI)
86.7 (83.5-89.3)
77.7 (73.9-81.0)
OS, HR (95% CI)
0.55 (0.42-0.73)
P value
<0.0001
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

Summary of Long-term PFS From Second Randomization After a Median Follow-up Duration of 70.6 Months5
Efficacy
DARZALEX Maintenance
Observation
D-VTd + DARZALEX Maintenance  
D-VTd + Observation
VTd + DARZALEX Maintenance  
D-VTd + Observation
PFS events
186
279
91
114
95
165
   PFS, HR
   (95% CI)
0.49 (0.40-0.59)
0.76 (0.58-1.00)
0.34 (0.26-0.44)
   P value
<0.0001
0.048
<0.0001
Median PFS, months (95% CI)
NR
(79.9-NE)
45.8
(41.8-49.6)
NR
(74.6-NE)
72.1
(52.8-NE)
NR
(66.9-NE)
32.7
(27.2-38.7)
Estimated
72-month PFS, % (95% CI)
57.1
(52.1-61.7)
36.5
(31.9-41.2)
60.3
(53.5-66.4)
50.5
(43.8-56.9)
53.7
(46.3-60.6)
20.8
(15.2-27.0)
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; NE, not estimable; NR, not reached; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

PFS in Prespecified Subgroups23
Subgroup
DARZALEX
Observation
HR (95% CI)
n/N
Median PFS, Months
n/N
Median PFS, Months
All patients in the maintenance-specific ITT population
186/442
NE
279/444
45.8
0.54 (0.45-0.65)
Sex
   Female
122/261
79.9
164/254
42.6
0.58 (0.46-0.73)
   Male
64/181
NE
115/190
48.3
0.47 (0.35-0.64)
Age
   <50 years
26/63
79.9
47/68
45.7
0.41 (0.25-0.66)
   50-60 years
79/198
NE
120/200
45.8
0.55 (0.41-0.73)
   >60 years
81/181
NE
112/176
46.2
0.59 (0.44-0.78)
Site
   IFM
157/373
NE
248/391
45.7
0.53 (0.44-0.65)
   HOVON
29/69
NE
31/53
46.0
0.60 (0.36-0.99)
ISS staging
   I
70/189
NE
97/171
49.6
0.51 (0.38-0.70)
   II
81/181
NE
141/214
41.7
0.56 (0.42-0.73)
   III
35/72
NE
41/59
42.3
0.58 (0.37-0.92)
Cytogenetic risk
   High risk
26/57
NE
56/70
27.2
0.39 (0.25-0.63)
   Standard risk
160/383
NE
223/374
49.0
0.58 (0.48-0.71)
Pre-maintenance baseline renal function (CrCl)
   >90 mL/min
131/303
NE
199/305
43.0
0.52 (0.42-0.65)
   ≤90 mL/min
55/139
NE
80/139
49.6
0.60 (0.42-0.84)
Type of MM
   IgG
124/253
71.1
182/270
42.6
0.59 (0.47-0.74)
   Non-IgG
36/93
NE
57/92
44.6
0.50 (0.33-0.77)
Pre-maintenance baseline ECOG performance status
   0
108/252
NE
160/260
47.4
0.57 (0.45-0.73)
   ≥1
78/190
NE
119/184
42.3
0.50 (0.37-0.66)
Induction/consolidation treatment group
   VTd
95/213
32.7
165/215
32.7
0.37 (0.28-0.47)
   D-VTd
91/229
NE
114/229
72.1
0.77 (0.59-1.02)
MRD
   MRD-positive
66/105
46.5
95/107
24.2
0.44 (0.32-0.60)
   MRD-negative
120/337
NE
184/337
61.1
0.55 (0.40-0.70)
Response
   VGPR or better
163/405
NE
242/406
48.3
0.56 (0.46-0.68)
   PR
23/37
46.5
37/38
20.1
0.32 (0.19-0.56)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; HOVON, Dutch-Belgian Cooperative Trial Group for Hematology Oncology; HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; Ig, immunoglobulin; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; MRD, minimal residual disease; NE, not estimable; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.

Best Response From Second Randomization by Induction/Consolidation and Maintenance Therapies in the Maintenance-Specific ITT Population23
Response Rates, %
DARZALEX
Observation
D-VTd
(n=229)
VTd
(n=213)
D-VTd
(n=229)
VTd
(n=215)
sCR
71.6
64.8
65.9
47.9
≥CR
76.9
70.0
72.1
49.8
CR
5.2
5.2
6.1
1.9
VGPR
16.6
28.2
21.8
40.0
PR
6.1
1.4
6.1
8.8
Abbreviations: ≥CR, complete response or better; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.

Proportion of Patients With a ≥CR and Sustained MRD Negativity at Any Timepoint From Post-induction Onwards in the Maintenance-Specific ITT Population5
MRD Negativity Sensitivity Threshold
D-VTd
OR
(95% CI)
P Value
VTd
OR
(95% CI)
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At any time point
   10-5, %
65.1
58.1
1.47
(0.95-2.26)
0.080
53.5
36.3
2.33
(1.51-3.60)
0.0001
   10-6, %
58.1
48.9
1.56
(1.04-2.34)
0.031
43.7
26.5
2.44
(1.56-3.81)
<0.0001
≥12 Months
   10-5, %
56.3
46.3
1.61
(1.08-2.41)
0.020
44.1
24.7
2.71
(1.73-4.23)
<0.0001
   10-6, %
47.6
36.2
1.68
(1.13-2.50)
0.0096
31.9
14.9
2.92
(1.77-4.82)
<0.0001
≥24 Months
   10-5, %
49.8
36.7
1.82
(1.23-2.71)
0.0028
36.2
16.7
3.15
(1.94-5.12)
<0.0001
   10-6, %
41.0
27.9
1.87
(1.25-2.81)
0.0023
24.9
10.2
3.11
(1.78-5.44)
<0.0001
Abbreviations: ≥CR, complete response or better; CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates at 10-5 Sensitivity Threshold Following Induction and Consolidation in the ITT Population23
Post-induction
Post-consolidation
D-VTd
(n=543)
VTd
(n=542)
D-VTd
(n=543)
VTd
(n=542)
MRD-negativity rate, %
9.2
5.4
33.7
20.3
   P value
0.015
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.

Summary of First-Line Subsequent Combination Therapies by Induction/Consolidation Treatment in the Maintenance-Specific ITT Population23
Efficacy
D-VTd/DARA
(n=229)
D-VTd/Obs
(n=229)
VTd/DARA
(n=213)
VTd/Obs
(n=215)
Total no. of patients with first-line subsequent combination therapies
85
100
75
159
   Total no. of patients with first-line subsequent anti-CD38 therapies
32 (37.6)
61 (61.0)
30 (40.0)
108 (67.9)
      DARA, lenalidomide, and dexamethasone
22 (25.9)
42 (42.0)
21 (28.0)
80 (50.3)
      DARA and lenalidomide
0
1 (1.0)
1 (1.3)
1 (0.6)
      Other DARA-containing regimens
7 (8.2)
17 (17.0)
7 (9.3)
23 (14.5)
      Isatuximab-containing regimens
3 (3.5)
1 (1.0)
1 (1.3)
4 (2.5)
   Patients with first-line subsequent non-anti-CD38 therapies
      Carfilzomib, lenalidomide, and dexamethasone
28 (32.9)
19 (19.0)
22 (29.3)
15 (9.4)
      Ixazomib, lenalidomide, and dexamethasone
6 (7.1)
4 (4.0)
8 (10.7)
15 (9.4)
      Lenalidomide and dexamethasone
2 (2.4)
3 (3.0)
1 (1.3)
6 (3.8)
      Bortezomib, lenalidomide, and dexamethasone
0
1 (1.0)
3 (4.0)
2 (1.3)
      All other carfilzomib-containing regimens without DARA
11 (12.9)
7 (7.0)
5 (6.7)
8 (5.0)
      All other bortezomib-containing regimens without DARA
0
4 (4.0)
1 (1.3)
3 (1.9)
      All other pomalidomide-containing regimens
4 (4.7)
1 (1.0)
2 (2.7)
2 (1.3)
      Other
5 (5.9)
1 (1.0)
4 (5.3)
4 (2.5)
Abbreviations: CD, cluster of differentiation; DARA, DARZALEX; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; Obs, observation; VTd, bortezomib + thalidomide + dexamethasone.
Safety

Causes of Death During and After the Maintenance Phase by Induction/Consolidation Treatment in the Maintenance-Specific Safety Population23
Cause of Death, n (%)
DARZALEX
Observation
D-VTd
(n=229)
VTd
(n=211)
D-VTd
(n=229)
VTd
(n=215)
Total patients who died after 2nd randomization
25 (10.9)
41 (19.4)
21 (9.2)
48 (22.3)
Primary cause of death
   Adverse event
2 (0.9)
2 (0.9)
1 (0.4)
0
      Related to DARZALEX
0
1 (0.5)
0
0
      Unrelated
2 (0.9)
1 (0.5)
1 (0.4)
0
   Progressive disease
14 (6.1)
27 (12.8)
18 (7.9)
31 (14.4)
   Other
9 (3.9)
12 (5.7)
2 (0.9)
17 (7.9)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; VTd, bortezomib + thalidomide + dexamethasone.

SPMs by Induction/Consolidation Treatment in the Maintenance-Specific Safety Population23
SPMs, n (%)
DARZALEX
Observation
D-VTd
(n=229)
VTd
(n=211)
D-VTd
(n=229)
VTd
(n=215)
Total patients with SPMs
26 (11.4)
26 (12.3)
14 (6.1)
22 (10.2)
   Non-cutaneous
19 (8.3)
11 (5.2)
8 (3.5)
9 (4.2)
      Prostate cancer
3 (1.3)
4 (1.9)
2 (0.9)
1 (0.5)
      Breast cancer
2 (0.9)
0
1 (0.4)
2 (0.9)
      Invasive ductal breast carcinoma
0
1 (0.5)
1 (0.4)
2 (0.9)
      Leiomyosarcoma
0
0
1 (0.4)
0
      Lung adenocarcinoma
1 (0.4)
1 (0.5)
1 (0.4)
0
      Squamous cell carcinoma of lung
0
0
1 (0.4)
0
      Testicular germ cell cancer
0
0
1 (0.4)
0
      Adenocarcinoma of colon
2 (0.9)
0
0
0
      Adenocarcinoma of the cervix
0
1 (0.5)
0
0
      Anaplastic thyroid cancer
1 (0.4)
0
0
0
      Bladder cancer
1 (0.4)
0
0
0
      Bladder cancer recurrent
1 (0.4)
0
0
0
      Follicular thyroid cancer
1 (0.4)
0
0
0
      Hepatocellular carcinoma
0
1 (0.5)
0
0
      Intraductal proliferative breast lesion
1 (0.4)
0
0
0
      Lung cancer metastatic
1 (0.4)
1 (0.5)
0
0
      Lung neoplasm malignant
1 (0.4)
0
0
0
      Neoplasm of appendix
0
0
0
1 (0.5)
      Non-small cell lung cancer stage IV
0
1 (0.5)
0
0
      Pancreatic carcinoma
0
0
0
1 (0.5)
      Papillary renal cell carcinoma
0
1 (0.5)
0
0
      Papillary thyroid cancer
1 (0.4)
0
0
1 (0.5)
      Squamous cell carcinoma of oral cavity
1 (0.4)
0
0
0
      Squamous cell carcinoma of tongue
1 (0.4)
0
0
0
      Testicular seminoma (pure)
1 (0.4)
0
0
0
      Thyroid cancer
1 (0.4)
0
0
1 (0.5)
      Transitional cell carcinoma
2 (0.9)
0
0
0
   Cutaneous
5 (2.2)
9 (4.3)
4 (1.7)
9 (4.2)
      Basal cell carcinoma
3 (1.3)
5 (2.4)
3 (1.3)
4 (1.9)
      Bowen’s disease
0
0
1 (0.4)
0
      Lip squamous cell carcinoma
0
0
0
1 (0.5)
      Malignant melanoma
0
0
0
2 (0.9)
      Squamous cell carcinoma
0
2 (0.9)
0
1 (0.5)
      Squamous cell carcinoma of skin
2 (0.9)
3 (1.4)
0
1 (0.5)
   Hematologic
2 (0.9)
6 (2.8)
2 (0.9)
6 (2.8)
      Myelodysplastic syndrome
1 (0.4)
2 (0.9)
1 (0.4)
1 (0.5)
      Non-Hodgkin’s lymphoma
0
0
1 (0.4)
0
      Non-Hodgkin’s lymphoma recurrent
0
0
1 (0.4)
0
      Acute lymphocytic leukemia
0
0
0
1 (0.5)
      Acute myeloid leukemia
0
0
0
3 (1.4)
      Blastic plasmacytoid dendritic cell neoplasia
0
1 (0.5)
0
0
      Diffuse large B-cell lymphoma
0
1 (0.5)
0
0
      Epstein-Barr Virus associated lymphoma
0
0
0
1 (0.5)
      Natural killer-cell lymphoblastic lymphoma
0
1 (0.5)
0
0
      T-cell lymphoma
1 (0.4)
1 (0.5)
0
0
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; SPM, second primary malignancy; VTd, bortezomib + thalidomide + dexamethasone.

DARZALEX in Combination with Bortezomib, Lenalidomide, and Dexamethasone

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742) is an open-label, multicenter, 2-Part, randomized, active-controlled, phase 2 United States study evaluating the safety and efficacy of D-VRd in patients with NDMM eligible for HDT and ASCT.6-8

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 endpoints: sCR (by end of post-ASCT consolidation)
  • Secondary endpoints: MRD (10-5 via NGS), CR, ORR, ≥VGPR

Part 1: Safety Run-in Phase Final Analysis

Voorhees et al (2021)9 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 (GRIFFIN Part 1).
  • Median follow-up was 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.
  • All patients in the safety run-in phase (N=16) completed induction therapy, stem cell mobilization, ASCT, consolidation, and entered maintenance therapy.
  • A total of 87.5% (n=14) of patients completed study therapy, and 2 (12.5%) discontinued the therapy because of PD (n=1) or AE (n=1; neuralgia or thrombocytopenia) during maintenance therapy.
  • Stem cell collection and neutrophil and platelet engraftment are present in table: Stem Cell Collection and Transplantation (GRIFFIN Part 1).

Baseline Characteristics (GRIFFIN Part 1)9
D-VRd
(n=16)
Age, years
   Median (range)
62.5 (46-65)
      <65 years, n (%)
14 (87.5)
      ≥65 years, n (%)
2 (12.5)
Sex, n (%)
   Male
8 (50.0)
   Female
8 (50.0)
Race, n (%)
   White
11 (68.8)
   Black or African American
4 (25.0)
   Asian
1 (6.3)
ECOG PS, n (%)a
   0
3 (18.8)
   1
10 (62.5)
   2
3 (18.8)
ISS disease stage, n (%)b
   I
12 (75.0)
   II
2 (12.5)
   III
2 (12.5)
Cytogenetic risk profile, n (%)c
   Standard
12 (75.0)
   High risk
4 (25.0)
Median (range) time since diagnosis of multiple myeloma, months
1.6 (0-5)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System.
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization (locally tested); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) in those patients with cytogenetic risk data available.

Stem Cell Collection and Transplantation (GRIFFIN Part 1)9
D-VRd
(n=16)
CD34+ yield, median (range) (x 106 cells/kg)
8.05 (3.5-17.6)
CD34+ cells transplanted, median (range) (x 106 cells/kg)
4.72 (2.2-6.0)
Patients receiving plerixafor for mobilization, n (%)
9 (56.3)
Patients receiving cyclophosphamide, n (%)
0
Days to neutrophil (0.5 x 109/L) engraftmenta median (maximum)
14
Days to platelet (20 x 109/L) engraftmentb median (maximum)
13.5
Abbreviation: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone.
aFor neutrophil engraftment, there were 15 evaluable patients.bFor platelet engraftment, there were 16 evaluable patients.
Safety
  • During cycle 1, 3/16 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 patient (6.3%) experienced a grade 3/4 infection (pneumonia and bronchitis).
  • Grade 1/2 IRRs occurred in 31.3% (n=5) of patients.
    • IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.
  • A SAE occurred in 11 (68.6%) patients.
  • Eleven patients (68%) experienced a SAE. For the incidences of Grade 3/4 TEAEs, please see Table: Most Common Grade 3/4 TEAEs (GRIFFIN Part 1).

Most Common Grade 3/4 TEAEs (GRIFFIN Part 1)9
Patients, n (%)
D-VRd (n=16)
Grade 3/4a
Total
15 (93.8)
Most commonly occurring
   Neutropenia
7 (43.8)
   Pneumonia
5 (31.3)
   Lymphopenia
5 (31.3)
   Thrombocytopenia
4 (25.0)
   Hypertension
3 (18.8)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
aNo Grade 5 TEAEs were reported.
Efficacy
  • At a median follow-up of 40.8 months (range, 20.6-43.0), disease progression occurred in 3 patients.
  • Median time to first response was 0.77 months (range, 0.1-2.1), and median duration of response was NE.
  • Median time to ≥CR was 7.36 months (range, 2.8-18.5), and median duration of ≥CR was NE.
  • Estimated 24-months PFS and OS rates was 93.8%.
  • Estimated 36-month PFS and OS rates were 78.1% and 93.8%, respectively.
  • MRD-negativity rates at 10-5 vs 10-6 sensitivity threshold:
    • 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 (50.0%) patients.
  • Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort (GRIFFIN Part 1).

Updated Response Rates Over Time for the Safety Run-in Cohort (GRIFFIN Part 1)a, 9
Patients, %
By End of
D-VRd Induction
By End of
D-VRd Consolidation
By Last Follow-up
D-R Maintenance
sCR
-
56.3
93.8
CR
12.5
12.5
-
≥CR
12.5
68.8
93.8
VGPR
56.3
31.3
6.3
PR
31.3
-
-
Abbreviations: ≥CR, complete response or better; CR, complete response; D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
Response data are shown for the response-evaluable population (N=16).
aPercentages do not add up to 100% due to rounding.

Part 2: Randomized Phase

Voorhees et al (2020)6,7,24 presented the primary analysis and updated analysis of the randomized portion of this study. Kaufman et al (2020)25 presented a 1-year update of safety and efficacy results at the 62nd ASH Annual Meeting & Exposition in December 2020. Laubach et al (2021)26 presented updated efficacy and safety results after 2 years of maintenance therapy in the GRIFFIN Study. Voorhees et al (2023)10 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).

Patient Demographics in the Randomized Phase (ITT; GRIFFIN Part 2)6
Characteristic
D-VRd
(n=104)
VRd
(n=103)
Age
   Median (range), years
59 (29-70)
61 (40-70)
   ≥65 years
28 (26.9)
28 (27.2)
Male, n (%)
58 (55.8)
60 (58.3)
ECOG PS,a n (%)
n=101
n=102
   0
39 (38.6)
40 (39.2)
   1
51 (50.5)
52 (51)
   2
11 (10.9)
10 (9.8)
ISS stage,b n (%)
   I
49 (47.1)
50 (48.5)
   II
40 (38.5)
37 (35.9)
   III
14 (13.5)
14 (13.6)
Baseline creatinine clearance, n (%)
   30-50 mL/minute
9 (8.7)
9 (8.7)
   >50 mL/minute
95 (91.3)
94 (91.3)
Cytogenetic profile,c n (%)
n=98
n=97
   Standard risk
82 (83.7)
83 (85.6)
   High risk
16 (16.3)
14 (14.4)
Time since diagnosis of MM
n=103
n=102
   Median (range), months
0.7 (0-12)
0.9 (0-61)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, international staging system; ITT, intent-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone.
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum-β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization, high risk was defined as the presence of del17p, t((4:14), or t(14:16) among patients with available cytogenetic risk data.
Efficacy (22.1-Month Follow-Up)
  • Primary endpoint met with D-VRd improving the sCR rate by end of consolidation (D-VRd vs VRd, 42.4% vs 32.0%; OR, 1.57; 95% CI, 0.87-2.82; 1-sided P=0.068).
    • The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1.
  • A significantly higher proportion of patients achieved an ORR following consolidation in D-VRd vs VRd group (99.0% vs 91.8%; 2-sided P=0.0160)
  • The rate of ≥VGPR was 90.9% with D-VRd vs 73.2% with VRd.
  • The rate of ≥CR was 51.5% with D-VRd vs 42.3% with VRd.
  • The percentage of patients achieving ≥CR at the end of induction, ASCT, consolidation, and clinical cutoff in the D-VRd arm was 19.2%, 27.3%, 51.5%, and 79.8%, respectively, vs 13.4%, 19.6%, 42.3%, and 60.8% in the VRd arm.
  • In the 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, 4.07; 95% CI, 2.18-7.59; P<0.0001). Additional MRD results are in Table: Post-Consolidation MRD Negativity (GRIFFIN Part 2).
  • Median stem cell yield (D-VRd vs VRd): 8.2 vs 9.4 x 106 cells.

Post-Consolidation MRD-Negativity (GRIFFIN Part 2)6
MRD-Negative Status (10-5),a n(%); ITT
D-VRd (n=104)
VRd (n=103)
Odds Ratio (95% CI)b
P-valuec
MRD-negative regardless of response
53/104
(51.0)
21/103
(20.4)
4.07
(2.18-7.59)
<0.0001
MRD-negative with CR or better
49/104
(47.1)
19/103
(18.4)
3.89
(2.07-7.33)
<0.0001
In patients achieving CR or better
49/69
(62.0)
19/59
(32.2)
3.57
(1.72-7.44)
0.0006
MRD Evaluable Population
53/77
(68.8)
21/65
(32.3)
4.47
(2.19-9.11)
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone.
aThe threshold of MRD-negativity was defined as 1 tumor cell per 105 white cells. MRD status is based on assessment of bone marrow aspirates by next-generation sequencing in accordance with International Myeloma Working Group criteria. MRD assessments occurred in patients who had both baseline (with clone identified/calibrated) and post-baseline MRD (with negative, positive, or indeterminate result) samples taken (D-VRd, n = 71; VRd, n = 55). Patients with a missing or inconclusive assessment were considered MRD-positive.
bMantel-Haenszel estimate of the common odds ratio for stratified tables is used. The stratification factors are ISS stage (I, II, III) and CrCl [30-50 mL/min or 50 mL/min]) at randomization. An odds ratio >1 indicates an advantage for the DARZALEX group.
cP values were calculated from the Fisher’s exact test.
  • At the median follow up of 22.1 months, D-VRd achieved higher sCR (62.6% vs 45.4%; OR, 1.98; 95% CI, 1.12-3.49; 2-sided P=0.0177), CR (17.2% vs 15.5%), and ≥CR (79.8% vs 60.8%; OR, 2.53; 95% CI, 1.33-4.81; 2-sided P=0.0045) vs VRd.
  • In the ITT population, median PFS and OS were NR in the D-VRd and VRd arms. In the D-VRd vs VRd arms (Kaplan-Meier estimates):
    • 12-month PFS rates were 96.9% vs 95.3%.
    • 24-month PFS rates were 95.8% vs 89.8%.
    • 12-month OS rates were 99.0% vs 97.9%.
    • 24-month OS rates were 95.8% vs 93.4%.
  • DARZALEX did not impact time to engraftment and hematopoietic reconstitution. See Table: Stem Cell Collection and Transplantation (GRIFFIN Part 2).

Stem Cell Collection and Transplantation (GRIFFIN Part 2)24
D-VRd
VRd
Median (range) stem cell yield, x 106 CD34+ cells/kga, b
8.2 (3-33)
9.4 (4-29)
Median stem cells transplanted, x 106 CD34+ cells/kgc
4.2
4.8
Patients receiving plerixafor for mobilization, n(%)d
66 (70)
45 (56)
Patients receiving cyclophosphamide, n (%)d
5 (5)
4 (5)
Median (max) days to neutrophil engraftment (0.5 x 109/L)
12 (31)
12 (23)
Median (max) days to platelet engraftment (20 x 109/L)
13 (31)
12 (23)
Abbreviations: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; max, maximum; VRd, bortezomib + lenalidomide + dexamethasone.aAmong patients who underwent peripheral blood stem cell apheresis (D-VRd, n=93; VRd, n=80).
bOne patient in the D-VRd group had a stem cell yield <3 x 106 cells/kg; no patients in either group had a stem cell yield <2 x 106 cells/kg.
cAmong patients receiving transplant (D-VRd, n=94; VRd, n=78).
dAmong patients who underwent mobilization (D-VRd, n=95; VRd, n=80). Patients underwent stem cell mobilization with G-CSF with or without plerixafor, according to institutional standards; if unsuccessful, cyclophosphamide-based mobilization was permitted.
Safety
  • In the updated safety and efficacy analysis, any grade infections occurred in 91% of patients in the D-VRd arm vs 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.6,24 See Table: Most Common TEAEs (GRIFFIN Part 2).
    • Pneumonia was reported in 13% of patients in the D-VRd arm vs 15% of patients in the VRd arm.

Most Common TEAEs (GRIFFIN Part 2)a, 6,24
Event, n (%)
D-VRd
(n=99)
VRd
(n=102)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
57 (57.6)
41 (41.4)
36 (35.3)
22 (21.6)
   Thrombocytopenia
43 (43.4)
16 (16.2)
36 (35.3)
9 (8.8)
   Leukopenia
36 (36.4)
16 (16.2)
29 (28.4)
7 (6.9)
   Anemia
35 (35.4)
9 (9.1)
33 (32.4)
6 (5.9)
   Lymphopenia
30 (30.3)
23 (23.2)
28 (27.5)
22 (21.6)
Non-hematologic
   Fatigue
68 (68.7)
6 (6.1)
62 (60.8)
6 (5.9)
   Upper respiratory tract infection
62 (62.6)
1 (1.0)
45 (44.1)
2 (2.0)
   Peripheral neuropathyb
59 (59.6)
7 (7.1)
74 (72.5)
8 (7.8)
   Diarrhea
59 (59.6)
7 (7.1)
51 (50.0)
4 (3.9)
   Constipation
51 (51.5)
2 (2.0)
40 (39.2)
1 (1.0)
   Cough
50 (50.5)
0
27 (26.5)
0
   Nausea
49 (49.5)
2 (2.0)
50 (49.0)
1 (1.0)
   Pyrexia
45 (45.5)
2 (2.0)
28 (27.5)
3 (2.9)
   Insomnia
42 (42.4)
2 (2.0)
31 (30.4)
1 (1.0)
   Back pain
36 (36.4)
1 (1.0)
34 (33.3)
4 (3.9)
   Edema peripheral
34 (34.3)
2 (2.0)
35 (34.3)
3 (2.9)
   Arthralgia
33 (33.3)
0
33 (32.4)
2 (2.0)
Infusion-related reactions
42 (42.4)
6 (6)c
-
-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aAny grade TEAEs are listed that occurred in ≥30% of patients in either group. The safety analysis population included all randomized patients who received ≥1 dose of study treatment; analysis was according to treatment received.
bIncludes patients with neuropathy peripheral and peripheral sensory neuropathy.
cNo grade 4 infusion-related reactions were reported.

Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)10 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 (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, 3.0 [IQR, 3.0-5.0]).

Patient Disposition10
Patients, n
D-VRd (n=104)
VRd (n=103)
Treated with maintenance therapy
90
70
Completed maintenance therapy
74
48
Discontinued treatment during maintenance therapy
16
22
   AE
6
7
   PD
3
8
   Patient withdrawal
2
4
   Lost to follow-up
2
0
   Death
1
1
   Other
2
2
Discontinued treatment by final analysis
26
53
Abbreviations: AE, adverse event; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone.
Efficacy
  • At the final analysis, among response-evaluable patients in the D-VRd (n=100) vs VRd (n=98) arm, respectively, sCR was achieved in 67% vs 48% of patients (OR, 2.18; 95% CI, 1.22-3.89; 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.10,27

Summary of Response Over Time10
Timepoint, %
D-VRd
VRd
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
End of inductiona
12
7
19
53
26
2
7
6
13
43
35
8
End of post-ASCT consolidationa
42
9
52
39
8
1
32
10
42
31
19
8
Final analysisb
67
16
83
13
3
1
48
12
60
17
14
8
Abbreviations: ≥CR, complete response or better; ASCT, autologous stem cell transplant; CR, complete response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IQR, interquartile range; NE, not estimable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
Rates shown are the number of patients with each type of response divided by the response-evaluable population.aResponse rates were from the primary analysis cutoff (median follow-up, 13.5 months) and the response-evaluable population comprised 196 patients (D-VRd, n=99; VRd, n=97). bResponse rates were also evaluated at the time of the final analysis (median follow-up 49·6 months; IQR 47·4-52·1), and the response-evaluable population comprised 198 patients (D-VRd, n=100; VRd, n=98).

Response Duration Among Patients in the D-VRd vs VRd Arm10
Parameter
D-VRd
VRd
Median duration to first response (ORR), months (95% CI)
0.8 (0.8-0.8)
0.8 (0.8-1.0)
Median duration to sCR, months (95% CI)
10.2 (8.8-13.0)
14.3 (9.2-21.7)
   HR (95% CI)
1.26 (0.86-1.83)
   P value
0.2339
Median duration to ≥VGPR, months (95% CI)
2.2 (2.1-2.7)
3.0 (2.2-6.3)
Median duration to ≥CR, months (95% CI)
8.9 (7.9-9.4)
9.6 (8.4-12.2)
Median DOR
NR
NR
   Estimated 48-month DOR, % (95% CI)
89 (79.9-94.3)
71 (55.8-81.4)
Abbreviations: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; DOR, duration of response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; NR, not reached; ORR, overall response rate; sCR, stringent complete response; VRd, bortezomib + lenalidomide + dexamethasone.

Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance10,27
Parameter
D-VRd
VRd
P value
Response,a n
100
98
-
   ORR, n (%)
99 (99)
90 (92)
0.016b
      ≥CR
83 (83)
59 (60)
0.0005b
      CR
16 (16)
12 (12)
-
      sCR
67 (67)
47 (48)
0.0079b
      ≥VGPR
96 (96)
76 (78)
0.0002b
      VGPR
13 (13)
17 (17)
-
      PR
3 (3)
14 (14)
-
   SD, n (%)
1 (1)
8 (8)
-
   PD, n (%)
0
0
-
MRD negative
   ITT population, n
104
103
-
      10-5 sensitivity, n (%)
67 (64)
31 (30)
<0.0001c
         OR (95% CI)
4.23 (2.35-7.62)
      10-6 sensitivity, n (%)
37 (36)
16 (16)
0.0013c
         OR (95% CI)
2.95 (1.52-5.75)
   In patients achieving ≥CR, n
83
59
-
      10-5 sensitivity, n (%)
64 (77)
28 (47)
0.0004c
      10-6 sensitivity, n (%)
35 (42)
14 (24)
0.031c
Durable MRD negativity
   Lasting ≥12 months, n
104
103
-
      10-5 sensitivity, n (%)
46 (44)
14 (14)
<0.0001c
         OR (95% CI)
5.00 (2.50-9.99)
      10-6 sensitivity, n (%)
10 (10)
4 (4)
0.16c
         OR (95% CI)
2.48 (0.76-8.07)
Abbreviations: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; MRD, minimal residual disease; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.The predefined per protocol final analysis occurred after all patients completed ≥1 year of long-term follow-up after the end-of-study treatment, died, or withdrew from study participation, whichever occurred first.aResponse rate is based on the response-evaluable population, which included randomized patients who had a confirmed diagnosis of MM, had measurable disease at baseline, received ≥1 dose of study treatment, and had ≥1 postbaseline disease assessment. The response-evaluable population for the primary analysis included 99 patients in the D-VRd group and 97 patients in the VRd group.bP value was calculated using the Cochran-Mantel-Haenszel Chi-square test stratified by ISS disease stage (I, II, or III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.cP value was calculated using Fisher’s exact test.
  • By the end of the 2-year maintenance therapy, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and VRd arms, respectively, who were previously MRD-positive at the end of the consolidation phase, converted to MRD negative (10-5). MRD-negativity rates continuously improved over time and were consistently higher in the D-VRd vs VRd arm. See Table: Summary of MRD-Negativity Rates Over Time (ITT Population).

Summary of MRD-Negativity Rates Over Time (ITT Population)a,10,27
Timepoint, %
D-VRd
VRd
MRD-Negativity (10-5)
MRD-Negativity (10-6)
MRD-Negativity (10-5)
MRD-Negativity (10-6)
End of induction
22
1
8
0
Post-ASCT consolidation
50
11
20
3
End of study
64
36
30
16
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; sCR, stringent complete response; VRd, bortezomib + lenalidomide + dexamethasone. aMRD was evaluated by NGS using the clonoSEQ assay. MRD assessments occurred at the first evidence of suspected CR or sCR, after induction (but before stem cell collection), after consolidation, and after 12 and 24 months of maintenance, regardless of response.
  • No patient in either treatment arm with sustained MRD-negativity 10-5 lasting ≥12 months became MRD-positive later.
  • The median time to MRD-negativity in the D-VRd vs VRd arm at sensitivity thresholds of 10-5 and 10-6, respectively, was 8.5 vs 34.6 months (HR, 2.70; 95% CI, 1.72-4.23; P<0.0001) and 33.9 months vs NR (HR, 1.93; 95% CI, 1.05-3.54; P=0.031).
  • Efficacy and survival outcomes are summarized in Table: Efficacy and Survival Outcomes (ITT Population).

Efficacy and Survival Outcomes (ITT Population)10,27
Parameter
D-VRd
VRd
Median PFS, months
NR
NR
   3-year PFS rate, %
89
80.7
   4-year PFS rate, %
87.2
70
   PFS HR (95% CI); P value
0.45 (0.21-0.95); 0.032
Median PFS in patients who received lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who received SoC lenalidomide therapy after study completion, %
96
80
Median PFS in patients who did not receive lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who did not receive SoC lenalidomide therapy after study completion, %
100
86
Median OS, months
NR
NR
   3-year OS rate, %
92.7
92.2
   4-year OS rate, %
92.7
92.2
   OS HR (95% CI); P value
0.90 (0.31-2.56); 0.84a
Disease progression or death, n/N (%)
11/104 (11)
18/103 (17)
   HR (95% CI)
0.45 (0.21-0.95)
   P value
0.032
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; ITT, intent-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival; SoC, standard of care; VRd, bortezomib + lenalidomide + dexamethasone.
aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, and III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.An HR <1 indicates an advantage for D-VRd. P value is based on the log-rank test stratified with ISS staging and baseline CrCl at randomization.
Safety
  • Among safety-evaluable patients in the D-VRd (n=99) vs VRd (n=102) arms, grade 3/4 TEAEs occurred in 86% (n=85) vs 79% (n=81), respectively.
  • In the D-VRd vs VRd arm, serious TEAEs occurred in 46% (n=46) vs 52% (n=53) of patients, respectively.
    • The most common serious TEAEs included pneumonia (15% vs 14%) and pyrexia (11% vs 10%).
  • TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33% [n=33]; VRd, 31% [n=32]). One patient in each arm died due to TEAEs unrelated to study treatment.
  • Any-grade infections were more common in the D-VRd vs VRd arm (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment arms for grade 3/4 infections (D-VRd, 29%; VRd, 26%) and infections leading to treatment discontinuation (D-VRd, 2%; VRd, 3%).
    • During maintenance therapy (cycle 7 and onwards) in the 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, 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.27

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

DARZALEX in Combination with KRd

Costa et al (2019)11 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 in patients with NDMM at a median follow-up of 7.4 months. Costa et al (2023)12 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, with Eastern Cooperative Oncology Group performance status 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 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-surveillance (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 (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, 8.4-12.4) for those who entered MRD-SURE.

Patient Demographics and Baseline Characteristics (MASTER)12
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
Total
(N=123)
Sex, n (%)
   Men
33 (62)
24 (52)
13 (54)
70 (57)
   Women
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 years, n (%)
12 (23)
10 (22)
2 (8)
24 (20)
Racial/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, 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, 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: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, 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; discontinued due to disease progression, n=5; patients choice, n=2).

MRD-Negative Response Rates (MASTER)a,12
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 <10-5, n (%)
32 (64)
32 (73)
11 (46)
-
   95% CI
49-77
57-85
26-67
-
Abbreviations: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; CI, confidence interval; 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 123 included patients and 32 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 phase, 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 from 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), respectively. See Table: PFS and OS for Different Study Populations (MASTERS).
  • Of the 106 patients without disease progression at 18 months from enrollment, the 3-year 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, 54-83), respectively.
  • At the last MRD-SURE observation timepoint, 61 patients (MRD-evaluable patients, 52%; transitioned to MRD-SURE, 73%) remained free of therapy with sustained MRD-negativity, 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 resumed due to disease progression without MRD resurgence and 7 due to MRD resurgence without progression.

Final Analysis Survival outcomes (MASTER)12
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
3-year PFS rates (N=123), %
88
79
50
   95% CI
78-95
67-88
30-70
3-year OS rates (N=123), %
94
92
75
   95% CI
88-98
86-96
63-85
3-year PFS rates for MRD-evaluable patients (n=118), %
88
80
50
   95% CI
78-94
68-90
30-70
3-year OS rates for MRD-evaluable patients (n=118), %
94
94
75
   95% CI
88-98
87-99
63-85
3-year PFS rates for patients reaching MRD-SURE (n=84), %
88
85
60
   95% CI
77-96
73-96
35-82
3-year OS rates for patients reaching MRD-SURE (n=84), %
97
93
100
   95% CI
91-100
84-100
NC-100
Cumulative incidence of progression rates for patients reaching MRD-SURE (n=84), %
9
9
47
   95% CI
1-19
1-18
23-72
2-year cumulative incidences of disease progression or MRD resurgence rates for patients reaching MRD-SURE (n=84), %
9
14
60
   95% CI
1-19
4-26
35-81
2-year PFS after cessation of therapy, %
88
85
53
   95% CI
77-95
73-94
28-78
2-year OS after cessation of therapy, %
97
93
100
   95% CI
91-100
85-99
NC-100
Abbreviations: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, 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)12,28
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 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 MRD-SURE
   HR (95% CI)
1.24 (0.17-8.87)
1.74 (0.15-20.16)
P value
0.83
0.66
Abbreviations: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, 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)28
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) post-AHCT
   HR (95% CI)
0.95 (0.43-2.08)
   Log-rank P value
0.90
Landmark OS according to MRD status (<10-5) post-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) post-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) post-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 was discontinued in 2 patients each 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 123 included patients.
    • Three patients died during protocol-directed therapy (not judged to be treatment related), of whom 2 had sudden death and 1 died from metapneumovirus pneumonia.
    • Three patients died after therapy and while on MRD-SURE without disease progression due to sudden death, COVID-19 pneumonia, and an accidental fall (n=1 each).
    • Nine patients died from progression of MM while receiving protocol-directed therapy (n=6) and after the completion of therapy (n=3).
  • A total of 4 patients died among 118 MRD-evaluable patients.

Most Common TEAEs (MASTER)12
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
Non-hematologic
   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.

Analysis of Transplant-Eligible Patients with HRCA from MASTER and GRIFFIN Studies

Callander et al (2024)13 reported the results of a post hoc analysis evaluating the clinical efficacy of the DARZALEX-based quadruplet therapies D-KRd and D-VRd in transplant-eligible patients with NDMM and HRCAs from the MASTER (median follow-up, 31.1 months) and GRIFFIN (median follow-up, 49.6 months) studies, respectively.

Study Design/Methods

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

Results

Patient Characteristics
  • Among patients receiving DARZALEX-based treatment in the MASTER (n=123) study, a total of 53 (43.1%), 46 (37.4%) and 24 (19.5%) patients, respectively, had 0 HRCA, 1 HRCA and 2+ HRCA cytogenetic risk.
  • Among patients receiving DARZALEX-based treatment in the GRIFFIN (N=120 [randomized phase, n=104; safety run-in, n=16]) study, a total of 67 (55.8%), 34 (28.3%) and 13 (10.8%) patients, respectively, had 0 HRCA, 1 HRCA and 2+ HRCA cytogenetic risk.
  • Baseline patient and disease characteristics from the GRIFFIN and MASTER studies are summarized in Table: Baseline Patient and Disease Characteristics (MASTER and GRIFFIN).

Baseline Patient and Disease Characteristics (MASTER and GRIFFIN)13
Characteristic
MASTER
GRIFFINa
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
Total
(n=123)
0 HRCA
(n=67)
1 HRCA
(n=34)
≥2 HRCAs
(n=13)
Total
(n=123)
Median age (range), years
60
(36-79)
61
(35-77)
60
(41-72)
60
(35-79)
59.0
(34-70)
59.5
(29-70)
62.0
(49-70)
60.0
(29-70)
Sex, n (%)
   Male
33 (62.3)
24 (52.2)
13 (54.2)
70 (56.9)
37 (55.2)
18 (52.9)
9 (69.2)
64 (56.1)
   Female
20 (37.7)
22 (47.8)
11 (45.8)
53 (43.1)
30 (44.8)
16 (47.1)
4 (30.8)
50 (43.9)
ISS stageb, n (%)
   I
28 (52.8)
15 (32.6)
5 (20.8)
48 (39.0)
42 (62.7)
13 (38.2)
5 (38.5)
60 (52.6)
   II
20 (37.7)
19 (41.3)
8 (33.3)
46 (37.4)
20 (29.9)
17 (50.0)
4 (30.8)
41 (36.0)
   III
5 (9.4)
12 (26.1)
11 (45.8)
29 (23.6)
5 (7.5)
4 (11.8)
4 (30.8)
13 (11.4)
Cytogenetic abnormalityc, n (%)
   del(17p)
0
12 (26.1)
14 (58.3)
26 (21.1)
0
4 (11.8)
8 (61.5)
12 (10.5)
   t(4;14)
0
8 (17.4)
13 (54.2)
21 (17.1)
0
3 (8.8)
5 (38.5)
8 (7.0)
   t(14;16)
0
2 (4.3)
4 (16.7)
6 (4.9)
0
0
1 (7.7)
1 (0.9)
   Gain/amp(1q21)
0
24 (52.2)
20 (83.3)
44 (35.8)
0
26 (76.5)
12 (92.3)
38 (33.3)
   t(14;20)
0
0
0
0
0
1 (2.9)
0
1 (0.9)
Median duration of study treatmentd, months
   Induction/consolidatione
11.5
11.5
11.7
11.5
8.1
8.1
7.4
8.1
   Maintenance
-
-
-
-
24.4
24.2
23.9
24.2
Abbreviation: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ASCT, allogeneic stem cell transplant; ISS, International Staging System.
aFor GRIFFIN, the D-VRd group included patients from the randomized phase (n=104) and the safety run-in phase (n=16). Patients were grouped by HRCA: 0 HRCA (n=67), 1 HRCA (n=34), or ≥2 HRCAs (n=13). Six patients were not estimable for cytogenetic abnormalities.
bISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization (local testing).
d Study duration is reported for evaluable patients for induction/consolidation (0 HRCA, n=66; 1 HRCA, n=32; ≥2 HRCAs, n=13; total, n=111) and maintenance (0 HRCA, n=62; 1 HRCA, n=29; ≥2 HRCAs, n=10; total, n=101).
eDuration of study treatment is from initiation of therapy to completion of consolidation therapy, including ASCT.
Efficacy

Efficacy Outcomes by Cytogenetic Risk Status (MASTER)a,13
Parameter
Standard-Risk
0 HRCA
(n=53)
High-Risk
1 HRCA
(n=46)
Ultra-High-Risk
≥2 HRCAs
(n=24)
≥CRb, %
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
MRD negativity
   Evaluable population, n
50c
44c
24c
      10-5 sensitivity, %
80.0
86.4
83.3
      10-6 sensitivity, %
68.0
79.5
66.7
   In 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: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; ≥CR, complete response or better; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; HRCA, high-risk cytogenetic abnormalities; 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: 0 HRCA, 1 HRCA, or ≥2 HRCAs.
bEvaluable patients in MASTER included all enrolled patients (0 HRCA, n=53; 1 HRCA, n=46; ≥2 HRCAs, n=24).
cFor MASTER, data are for all enrolled patients with available MRD data.

Efficacy Outcomes by Cytogenetic Risk Status(GRIFFIN)a,13
Parameter
Standard-Risk
0 HRCA
(n=67)
High-Risk
1 HRCA
(n=34)
Ultra-High-Risk
≥2 HRCAs
(n=13)
≥CRb, %
90.9
78.8
61.5
24-month PFS rate, %
96.7
93.8
64.2
36-month PFS rate, %
96.7
90.5
53.5
48-month PFS rate, %
93.7
90.5
53.5
MRD negativity
   Evaluable population, n
67c
34c
13c
      10-5 sensitivity, %
76.1
55.9
61.5
      10-6 sensitivity, %
44.8
26.5
15.4
   In patients achieving ≥CR, n
60
26
8
      10-5 sensitivity, %
83.3
69.2
87.5
Durable MRD-negativity lasting ≥12 months
   Evaluable population, n
67c
34c
13c
      10-5 sensitivity, %
53.7
38.2
30.8
MRD (10-5) conversion rate
   Evaluable population, n
67c
34c
13c
      MRD-positive by the end of induction and
      then became MRD-negative, %
49.3
41.2
38.5
      MRD-positive by the end of consolidation
      and then became MRD-negative, %
19.4
11.8
23.1
   Median time to MRD-negativity (10-5)c,months
8.5
8.6
19.6
Abbreviations: ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; ≥CR, complete response or better; 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; HRCA, high-risk cytogenetic abnormalities; MRD, minimal residual disease; PFS, progression-free survival.
aHRCAs include any of the following genetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21) (≥3 copies of chromosome 1q21). Patients were grouped into categories: 0 HRCA, 1 HRCA, or ≥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-VRd group included patients from the randomized phase (n=104) and 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 estimable for cytogenetic abnormalities.
Safety
  • In MASTER, 3 patients died while on D-KRd therapy (0 HRCA, n=2 [both sudden death]; ≥2 HRCAs, n=1 [metapneumovirus infection during transplant]).
    • Two patients died after discontinuation of therapy and during follow-up, respectively (1 HRCA, n=2 [fall and COVID-19 pneumonia]). Neither of the deaths were preceded by PD.
  • In GRIFFIN, 8 patients died while on D-VRd therapy (0 HRCA, n=2 [due to an AE (bronchopneumonia) and PD]; 1 HRCA, n=1 [due to PD]; ≥2 HRCAs, n=4 [all due to PD]; NE for cytogenetics, n=1 [due to respiratory failure]).

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 02 January 2025.

References

Show
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7 Voorhees PM, Kaufman J, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Oral Presentation presented at: The 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
8 Voorhees PM, Costa L, Reeves B, et al. Interim safety analysis of a phase 2 randomized study of daratumumab (Dara), lenalidomide (R), bortezomib (V), and dexamethasone (d; Dara-RVd) vs RVd in patients (pts) with newly diagnosed multiple myeloma (MM) eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) (GRIFFIN). Poster presented at: The 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA.  
9 Voorhees PM, Rodriguez C, Reeves B, et al. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021;5(4):1092-1096.  
10 Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
11 Costa LJ, Chhabra S, Medvedova E, 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 Annual Meeting of the American Society of Hematology (ASH); Dec 7-10, 2019; Orlando, FL.  
12 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.  
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17 Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA)/ bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Poster presented at: The European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain.  
18 Rodriguez-Otero P, Voorhees PM, Boccadoro M, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone in transplant-eligible patients with multiple myeloma: a pooled analysis of patients aged ≥65 years from both PERSEUS and GRIFFIN studies. Poster presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
19 Rodriguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) with DARA-R (D-R) maintenance in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) in the PERSEUS trial. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL, USA.  
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21 Moreau P, Hulin C, Perrot A, et al. Supplementary Appendix to Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.  
22 Sonneveld P, Broijl A, Gay F, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): a multicenter, randomized, phase 3 study (PERSEUS). Poster presented at: 55th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2019; Chicago, IL.  
23 Moreau P, Hulin C, Perrot A, et al. Supplement to: Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. [published online ahead of print June 14, 2024]. Lancet Oncol. 2024. doi:10.1016/s1470-2045(24)00282-1.  
24 Voorhees P, Kaufman J, Laubach J, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): GRIFFIN study update. Oral Presentation presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.  
25 Kaufman J, Laubach J, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 12 months of maintenance therapy. Oral Presentation presented at: 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; San Diego, CA.  
26 Laubach J, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual Meeting.  
27 Voorhees PM, Sborov DW, Laubach J, et al. Supplement to: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
28 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.