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(daratumumab)

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DARZALEX® (daratumumab)
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DARZALEX - CASSIOPEIA Study

Last Updated: 06/02/2026

Click on the following links to related sections within the document: CASSIOPEIA Initial Results - Part 1, CASSIOPEIA Initial Results - Part 2, CASSIOPEIA Long-Term Follow-Up.

Abbreviations: AE, adverse event; ASCT, autologous stem cell transplantation; C, cycle; CI, confidence interval; CR, complete response; D, daratumumab; D-VTd, daratumumab + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HDT, high-dose chemotherapy; HR, hazard ratio; IQR, interquartile range; ITT, intention-to-treat; MM, multiple myeloma; MRD, minimal residual disease; NE, not evaluable; NR, not reached; Obs, observation; OR, odds ratio; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; TEAE, treatment-emergent adverse event; VTd, bortezomib + thalidomide + dexamethasone.
aMoreau (2019).1 bMoreau (2021).2 cPatients post-transplant underwent a second randomization. dFollowed by observation until PD. esCR after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days). fAfter second randomization. gMoreau et al (2024).3 hMoreau et al. Supplement. (2024).4

CLINICAL DATA

CASSIOPEIA (MMY3006; NCT02541383) was a phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) in patients with previously untreated multiple myeloma (MM) who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).1,2

Study Design/Methods

Phase 3 CASSIOPEIA Study Design1,2

Abbreviations: ASCT, autologous stem cell transplantation; C, cycle; CD, cluster of differentiation; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; D, daratumumab; d, dexamethasone; D-VTd, daratumumab + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HDT, high-dose chemotherapy; IV, intravenous; max, maximum; MM, multiple myeloma; MRD, minimal residual disease; NGS, Next-generation sequencing; ORR, overall response rate; OS, overall survival; PCD, plasma cell dyscrasia; PCL, plasma cell leukemia; PD, progressive disease; PFS, progression-free survival; PFS2, PFS after the next line of therapy; PO, per oral; PR, partial response; QW, once a week; Q2W, every 2 weeks; Q8W, every 8 weeks; SC, subcutaneous; sCR, stringent complete response; T, thalidomide; TTP, time to progression; V, bortezomib; VTd, bortezomib + thalidomide + dexamethasone.
aBegan after hematopoietic reconstitution but not earlier than 30 days after transplant. bDaratumumab or other anti-CD38 therapies. cIn patients with CR at a threshold of 10-5 by NGS.

Primary Analysis of Part 1 of the CASSIOPEIA Study

Moreau et al (2019)1 reported the results from Part 1 of the CASSIOPEIA study at a median follow-up of 18.8 months (range, 0.0-32.2).

Results

Baseline Characteristics

Demographics and Clinical Characteristics in the Intention-to-treat Population at Baseline1
Characteristic
D-VTd (n=543)
VTd (n=542)
Median (range) age, years
59 (22-65)
58 (26-65)
Male/Female, n (%)
316 (58.2)/227 (41.8)
319 (58.9)/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, Eastern Cooperative Oncology Group; FLCs, free light chains; ISS, International Staging System; MM, multiple myeloma; mos, months; PS, performance status; 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 International Staging System 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

Summary of Responses and MRD Status 100 Days after ASCT1
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, n (%)
   sCR
157 (29)
110 (20)
0.0010
   ≥CR
211 (39)
141 (26)
<0.0001
   CR
54 (10)
31 (6)
-
   ≥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: ASCT, autologous stem cell transplantation; 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.
  • A total of 157/543 patients (29%) in the D-VTd group and 110/542 patients (20%) in the bortezomib + thalidomide + dexamethasone (VTd) group achieved the primary endpoint of stringent complete response (sCR) following consolidation (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.21-2.12; P=0.0010).1
  • A significantly higher proportion of patients achieved complete response or better (≥CR) following consolidation in the D-VTd group vs the VTd group (211 [39%] vs 141 [26%]; P<0.0001).1
  • 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).1
  • PFS from first randomization was significantly improved in the D-VTd group vs the VTd group (hazard ratio [HR], 0.47; 95% CI, 0.33-0.67; P<0.0001). Median OS from first randomization regardless of second randomization was not reached in either treatment group (HR, 0.43; 95% CI, 0.23-0.80).1
Safety

Most Common Adverse Events During Treatment in the Safety Populationa, 1
Event, n (%)
D-VTd (n=536)
VTd (n=538)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   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-hematologic
   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 3/4 adverse events that were reported in at least 10% of patients in either treatment group are listed.
  • 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%).1
  • 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%).1
  • Serious adverse events (SAEs) occurred in 251 patients (47%) in the D-VTd group and 255 patients (47%) in the VTd group. The most common SAEs (occurring in ≥3% of patients in either group) were neutropenia (4% in D-VTd group and 1% in VTd group), pneumonia (4% and 2%), pyrexia (3% and 4%), and pulmonary embolism (1% and 4%).1
  • Infusion-related reactions (IRRs) related to DARZALEX were reported in 190 of 536 (35%) patients in the safety population.1
  • Second primary malignancies occurred in 10 (2%) patients in the D-VTd group and 12 (2%) patients in the VTd group.1

Primary Analysis of Part 2 of the CASSIOPEIA Study

Moreau et al (2021)2 reported the results from Part 2 of the CASSIOPEIA study (maintenance treatment) at a median follow-up of 35.4 months.

Results

Baseline Characteristics

Baseline Demographics and Disease Characteristics after Second Randomization2,5
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
   0/1/≥2
252 (57) / 174 (39) / 16 (4)
260 (59) / 172 (39) / 12 (3)
ISS disease stagea
   I/II/III
189 (43) / 181 (41) / 72 (16)
171 (39) / 214 (48) / 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: 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; ≥VGPR, very good partial response or better; 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.
  • Reasons for discontinuation during DARZALEX monotherapy vs observation are presented in Table: Patient Disposition.2

Patient Disposition2
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 not reached (95% CI, not evaluable [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).2
    • 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 International Staging System (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.

PFS in Prespecified Subgroups2
Hazard Ratio, (95% CI)
Male/Female
0.57 (0.42-0.76) / 0.53 (0.35-0.81)
Age <50 / 50-60 / >60 years
0.38 (0.20-0.74) / 0.56 (0.39-0.79) / 0.67 (0.46-0.98)
ISS disease staging I/II/III
0.50 (0.32-0.78) / 0.56 (0.40-0.79) / 0.75 (0.44-1.29)
Cytogenetic risk: High risk/Standard risk
0.43 (0.25-0.73) / 0.62 (0.48-0.82)
Baseline renal function (CrCl): >90 / ≤90 mL/min
0.51 (0.38-0.68) / 0.72 (0.47-1.12)
Type of MM: IgG/Non-IgG
0.64 (0.48-0.87) / 0.44 (0.26-0.75)
Baseline ECOG PS: 0/≥1
0.55 (0.40-0.76) / 0.57 (0.40-0.82)
Induction/consolidation treatment group
   D-VTd
1.05 (0.73-1.51)
   VTd
0.34 (0.24-0.47)
MRD: positive/negative
0.46 (0.31-0.67) / 0.61 (0.44-0.83)
Response: ≥VGPR/PR
0.58 (0.45-0.75) / 0.39 (0.21-0.73)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.
  • ≥CR was achieved by 322 of 442 patients (73%) in the DARZALEX monotherapy group vs 270 of 444 patients (61%) in the observation group (OR, 2.17; 95% CI, 1.54-3.07; P<0.0001).2
  • The improved response was achieved by 188 of 304 patients (62%) in the DARZALEX monotherapy group vs 153 of 324 patients (47%) in the observation group (OR, 1.95; 1.40-2.72; P<0.0001).2
  • MRD-negativity status (at 10-5 by next-generation sequencing [NGS]) was achieved by 259 patients (58.6%) in the DARZALEX monotherapy group vs 209 patients (47.1%) in the observation group (OR, 1.80; 95% CI, 1.33-2.43; P=0.0001).2,5
  • ORR was similar among groups (440 of 442 patients [>99%] in the DARZALEX monotherapy group vs 441 of 444 patients [99%] in the observation group).2
  • The median time to progression (TTP) was not reached (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).2
    • The DARZALEX monotherapy group experienced 98 events vs 172 events in the observation group.
  • The median PFS was immature for both the groups (HR, 0.62; 95% CI, 0.40-0.96).5
  • The median OS was not reached in the DARZALEX monotherapy group vs observation group (29 deaths in the DARZALEX monotherapy group vs 29 deaths in the observation group; 95% CI, NE-NE).2
    • The most common cause of death was progressive disease (DARZALEX monotherapy, 45% [n=13]; observation group, 81% [n=22]).
  • In the intent-to-treat (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.5
    • ≥CR was achieved by 76.4% of 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 treatment therapies.5
    • ≥CR was achieved by 69% of 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 treatment therapies.
  • For patients who were not randomized to Part 2, median PFS was 30.7 months (95% CI, 14.3-NE) in the D-VTd group (n=85) vs 25.4 months (95% CI, 20.4-33.2) in the VTd group (n=114).2
    • A total of 36 of 85 patients (42%) in the D-VTd group vs 57 of 114 patients (50%) in the VTd group had a PFS event.
  • 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.2,5
    • The median PFS was not reached (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 not reached for patients in the D-VTd group vs 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).
Safety

Most Common AEs (≥10%) During Treatment or Observation in the Maintenance-Specific Safety Population2
AE, n (%)
DARZALEX Monotherapy
(n=440)
Observation
(n=444)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Hematologic
   Lymphopenia
15 (3)
14 (3)
2 (<1)
9 (2)
3 (1)
5 (1)
   Neutropenia
3 (1)
9 (2)
0
0
10 (2)
0
Non-hematologic
   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
Abbreviation: AE, adverse event.
aThe most common grade 3/4 TEAEs were lymphopenia, hypertension, and neutropenia.
  • Any TEAEs occurred in 95% of patients (n=420) in the DARZALEX monotherapy group vs 89% (n=394) in the observation group.2
  • SAEs occurred in 23% of patients (n=100) in the DARZALEX monotherapy group vs 19% (n=84) in the observation group.2
  • 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.2
  • DARZALEX infusions were interrupted in 21% of patients (n=93) due to an AE.2
  • DARZALEX treatment was discontinued in 3% of patients (n=13) due to an AE.2
  • Grade ≥3 TEAEs were reported in 28% of patients (n=122) in the DARZALEX monotherapy group (who received at least 1 dose) vs 24% (n=108) in the observation group.2
  • IRRs occurred in 54.5% of patients (n=115) in the DARZALEX monotherapy group.2
  • 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.2

Final Analysis of the CASSIOPEIA Study

Moreau et al (2024)3 reported long-term outcomes of the CASSIOPEIA study after a median follow-up of 80.1 months from the first randomization and at a median follow-up of 70.6 months from the second randomization.

Study Design

  • During the induction and consolidation phases, efficacy assessments were conducted on the ITT population cohort, encompassing all patients from the first randomization.3
  • In the maintenance phase, efficacy analyses were performed on the maintenance-specific ITT population, including patients randomized during the second randomization.3

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).3
  • 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).3
    • 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 of 80.1 Months3
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.
  • A summary of efficacy data at a median follow-up of 70.6 months
    (IQR, 66.4-76.1) is presented in Table: Summary of Long-term PFS From Second Randomization After a Median Follow-up of 70.6 Months.3
    • 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 ITT population.4
    • 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 population4:
      • D-VTd plus DARZALEX vs D-VTd plus observation: HR, 1.01; 95% CI, 0.64-1.59; P=0.97.
      • VTd plus DARZALEX vs VTd plus observation: HR, 0.43; 95% CI, 0.30-0.62; P<0.0001.
      • No significant difference was observed in PFS on next line of therapy between the D-VTd plus daratumumab group and the D-VTd plus observation group.
    • PFS on DARZALEX vs observation in all prespecified subgroups is presented in Table: PFS in Prespecified Subgroups.4

Summary of Long-term PFS From Second Randomization After a Median Follow-up of 70.6 Months3
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 Subgroups4
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; IgG, immunoglobulin G; 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 Population4
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; 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 Population3
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 timepoint
   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; 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 Population4
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.
  • A total of 85 (37%) of 229 patients in the D-VTd plus DARZALEX group and 75 (35%) of 213 patients in the VTd plus DARZALEX group, who were assigned to received DARZALEX-maintenance, also received subsequent antimyeloma therapy.3
  • Similarly, a total of 100 (44%) of 229 patients in the D-VTd plus observation group and 159 (74%) of 215 in the VTd plus observation group received subsequent antimyeloma therapy.3
  • Among those who received subsequent therapy, 61 (61%) of 100 patients in the D-VTd plus observation group and 108 (68%) of 159 patients in the VTd plus observation group received an anti-CD38-based first subsequent therapy, compared to 32 (38%) of 85 patients in the D-VTd plus DARZALEX group and 30 (40%) of 75 patients in the VTd plus DARZALEX group.3
  • The most frequently administered anti-CD38-based treatment regimen was DARZALEX, lenalidomide, and dexamethasone.3
  • A summary of first-line subsequent combination therapies by induction/consolidation treatment in the maintenance-specific ITT population is presented in Table: Summary of First-Line Subsequent Combination Therapies by Induction/Consolidation Treatment in the Maintenance-Specific ITT Population.4

Summary of First-Line Subsequent Combination Therapies by Induction/Consolidation Treatment in the Maintenance-Specific ITT Population4
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)
      DARZALEX, lenalidomide, and  
      dexamethasone
22 (25.9)
42 (42.0)
21 (28.0)
80 (50.3)
      DARZALEX and lenalidomide
0
1 (1.0)
1 (1.3)
1 (0.6)
      Other DARZALEX-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 DARZALEX
11 (12.9)
7 (7.0)
5 (6.7)
8 (5.0)
      All other bortezomib-containing regimens
      without DARZALEX
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: 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 Population4
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 Population
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.

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 20 May 2026. The search was limited to publications from 2021 to present.

 

References

Show
1 Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38.  
2 Moreau P, Hulin C, Perrot A, et al. 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. J Clin Oncol. 2021;22(10):1378-1390.  
3 Moreau P, Hulin C, Perrot A, et al. 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. Lancet Oncol. 2024;25(8):1003-1014.  
4 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. Lancet Oncol. 2024;25(8):1003-1014.  
5 Moreau P, Hulin C, Perrot A, et al. Supplement 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.