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DARZALEX® (daratumumab)

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DARZALEX - MMY3006 (CASSIOPEIA) Study

Last Updated: 06/03/2025

Click on the following links to related sections within the document: CASSIOPEIA and Subgroup Analyses.
Abbreviations: AE, adverse event; ASCT, autologous stem cell transplantation; C, cycle; CI, confidence interval; CR, complete response; CT, computed tomography; 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; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NE, not evaluable; NR, not reached; Obs, observation; OR, odds ratio; OS, overall survival; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PR, partial response; PRO, patient-reported outcome; 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 iCorre (2025).5 jAvet-Loiseau (2021).6 kAvet-Loiseau (2019).7 lSonneveld (2019).8 mMoreau (2019b).9 nTouzeau (2020).10 oRoussel (2020).11

PRODUCT LABELING

CLINICAL DATA

CASSIOPEIA (MMY3006; NCT02541383) is an ongoing, open-label, 2-group, multicenter, randomized, phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib + thalidomide + dexamethasone (D-VTd) in patients with previously untreated MM who are eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).1,2 Moreau et al (2019)1 reported the results from Part 1 of this study. Moreau et al (2021)2 reported the results from Part 2 of the CASSIOPEIA study (maintenance treatment). 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. Corre et al (2025)5 reported the long-term minimal residual disease (MRD) status and progression-free survival (PFS) outcomes from the CASSIOPEIA study after a median follow-up of 80.1 months.

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.

Results - Part 1

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
  • Efficacy data from Part 1 of the study are presented in Table: Summary of Responses and MRD Status 100 Days after ASCT.
  • A total of 157/543 (29%) patients in the D-VTd group and 110/542 (20%) patients in the bortezomib + thalidomide + dexamethasone (VTd) group achieved the primary endpoint of sCR following consolidation (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.21-2.12; P=0.0010).
  • 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).
  • 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 (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).

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.
Safety
  • AEs are presented in Table: Most Common Adverse Events During Treatment in the Safety Population.
  • 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%).
  • 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%).
  • Infusion-related reactions (IRRs) related to DARZALEX were reported in 190 of 536 (35%) patients in the safety population.
  • Second primary malignancies occurred in 10 (2%) patients in the D-VTd group and 12 (2%) patients in the VTd group.

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.

Results - Part 2

Baseline Characteristics

Baseline Demographics and Disease Characteristics after Second Randomization2,12
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.

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).
    • 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.
  • ≥CR was achieved by 322 of 442 (73%) patients in the DARZALEX monotherapy group vs 270 of 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 of 304 (62%) patients in the DARZALEX monotherapy group vs 153 of 324 (47%) patients in the observation group (OR, 1.95; 1.40-2.72; P<0.0001).
  • MRD-negativity status (at 10-5 by next-generation sequencing [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).2,12
  • ORR was similar among groups (440 of 442 [>99%] patients in the DARZALEX monotherapy group vs 441 of 444 [99%] patients in the observation group).
  • The median 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).
    • 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).12
  • 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).
    • 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.12
    • ≥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.12
    • ≥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).
    • A total of 36 of 85 (42%) patients in the D-VTd group vs 57 of 114 (50%) patients 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.2,12
    • 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).

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 tx 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; tx, treatment; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.
Safety
  • AEs are presented in Table: Most Common AEs (≥10%) During Treatment or Observation in the Maintenance-Specific Safety Population.
  • 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) 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.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.

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.

Long-term Follow-up in CASSIOPEIA

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

  • This planned analysis represents 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 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.

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.

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 Population4
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.

MRD Status and PFS Outcome Analysis in CASSIOPEIA Study Part 1 and Part 2

Corre et al (2025)5 reported results on the long-term MRD status and PFS outcomes based on the MRD status from the CASSIOPEIA study after a median follow-up of 80.1 months.

Study Design/Methods

  • Patients were randomly assigned (1:1) to receive D-VTd or VTd for induction/consolidation. Patients were randomized to the maintenance phase to undergo DARZALEX maintenance or observation for 2 years. The MRD status was assessed at predefined timepoints during each study phase.
  • During maintenance, MRD analyses were conducted in patients who achieved a very good partial response (VGPR) or better (≥VGPR) at 6, 12, and 24 months of maintenance or observation.
  • During follow-up, MRD analyses were performed at 1, 2, and 3 years in patients who did not progress and were MRD-negative after 24 months of maintenance vs observation or at their last assessment since day 100 post-ASCT.
  • Sustained MRD-negativity rates were determined by consistent results of MRD-negativity (with no MRD-positive result between measurements) for a given length of time (minimum of 12 months, with measurements up to ≥36 months), as observed at any timepoint between postinduction and the end of follow-up, and were compared across treatment arms, stratified by depth of response .
  • The accumulative MRD-negativity rate was calculated as the proportion of patients achieving MRD-negativity before a set timepoint, compared within the maintenance ITT population, stratified by the study site, ISS disease stage, and cytogenetic risk status.

Results

Efficacy

MRD-Negativity Rates at Any Time During Maintenance and Follow-up in the mITT Population5,13 
MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
Overall MRD-negativitya, %
   10-5
77.3
70.7
1.76
0.0417
70.9
51.2
3.16
<0.0001
   10-6
60.7
52
1.55
0.0365
48.4
30.7
2.41
<0.0001
At 6 monthsb, %
   10-5
59.4
53.3
1.27
0.2132
48.8
34.4
1.78
0.0043
   10-6
38.4
36.7
1.06
0.7662
27.2
19.5
1.58
0.0550
At 12 monthsb, %
   10-5
61.6
55.9
1.23
0.2667
48.8
33.0
1.92
0.0012
   10-6
39.3
34.9
1.17
0.4372
31.9
18.1
2.09
0.0013
At 24 months, %b
   10-5
62.9
50.7
1.62
0.0121
49.3
21.4
3.47
<0.0001
   10-6
46.3
31.4
1.81
0.0024
32.9
13.0
3.49
<0.0001
MRD-negativity conversion ratec, %
   10-5
36.7
25.0
1.74
0.1540
47.4
9.9
8.22
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.
aPost-consolidation after the second randomization.
bmITT population.
cPercentages were calculated with the number of patients with a post-consolidation MRD-positive status in each treatment group as the denominator (D-VTd/DARZALEX, n=60; D-VTd/Obs, n=68; VTd/DARZALEX, n=97; VTd/Obs, n=91).

MRD-Negativity With ≥CR Rates at Defined Time Points During Maintenance in the mITT Population5
MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At 6 months, %
   10-5
57.2
50.2
1.30
0.1750
44.1
29.8
1.85
0.0027
   10-6
37.6
35.8
1.06
0.7848
25.8
18.1
1.59
0.0541
At 12 months, %
   10-5
59.4
52.0
1.31
0.1541
47.4
30.2
2.08
0.0004
   10-6
38.9
34.5
1.18
0.4178
31.5
16.7
2.25
0.0005
At 24 months, %
   10-5
60.3
47.2
1.66
0.0081
47.4
20.5
3.41
<0.0001
   10-6
45.9
31.0
1.83
0.0021
31.9
12.6
3.47
<0.0001
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

Accumulative MRD-Negativity Rates in the mITT Population Over Time5
MRD-Negativity Sensitivity Threshold
D-VTd
VTd
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
MRD-negativity rate, %
   At day 28
      10-5
31.0
28.8
23.9
16.3
      10-6
8.7
9.2
8.5
4.7
   At day 100a
      10-5
68.1
64.2
47.4
51.2
      10-6
32.8
31.0
19.7
18.6
   At week 25
      10-5
74.2
68.6
61.5
55.3
      10-6
46.7
44.5
32.9
26.5
   At week 52
      10-5
75.1
71.6
66.7
57.7
      10-6
52.8
48.5
41.3
28.8
   At week 105
      10-5
77.7
73.8
71.4
58.1
      10-6
58.5
51.5
47.4
31.6
   At 12 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
59.4
53.3
47.4
28.8
   At 24 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
60.3
53.3
48.8
32.1
   At 36 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
60.7
53.3
48.8
32.1
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; VTd, bortezomib + thalidomide + dexamethasone.
aPost autologous stem cell transplantation.
bPre-progressive disease follow-up.

Accumulative MRD-Negativity With ≥CR Rates in the mITT Population Over Time5
MRD-Negativity Sensitivity Threshold
D-VTd
VTd
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
MRD-negativity with ≥CR, %
   At day 28
      10-5
28.4
27.9
22.1
12.6
      10-6
8.3
9.2
7.5
4.2
   At day 100a
      10-5
63.8
60.3
42.7
40.9
      10-6
31.9
30.6
17.8
17.2
   At week 25
      10-5
68.6
63.8
54.0
42.8
      10-6
45.9
43.2
31.0
23.7
   At week 52
      10-5
69.4
65.1
58.7
45.1
      10-6
52.0
46.7
39.0
25.1
   At week 105
      10-5
71.6
66.4
63.4
45.6
      10-6
57.6
49.8
44.6
26.0
   At 12 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
58.5
51.1
44.6
27.9
   At 24 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
59.4
51.1
46.0
28.4
   At 36 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
59.8
51.1
46.0
28.4
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; VTd, bortezomib + thalidomide + dexamethasone.
aPost autologous stem cell transplantation.
bPre-progressive disease follow-up.

Sustained MRD-Negativity Rates at Any Time During the Study - mITT Population5
Sustained MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At ≥12 months, %
   10-5
65.5
57.2
1.59
0.0369
50.7
32.1
2.53
<0.0001
   10-6
49.3
37.1
1.75
0.0053
32.4
15.3
2.89
<0.0001
At ≥24 months, %
   10-5
58.5
46.7
1.78
0.0056
43.7
20.9
3.50
<0.0001
   10-6
41.9
28.4
1.91
0.0017
25.4
10.2
3.20
<0.0001
At ≥36 months, %
   10-5
43.7
32.3
1.70
0.0088
31.9
12.1
3.79
<0.0001
   10-6
29.7
22.7
1.46
0.0821
19.7
6.5
3.74
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

Sustained MRD-Negativity With ≥CR Rates at Any Time During the Study - mITT Population5
Sustained MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At ≥12 months, %
   10-5
63.3
53.7
1.66
0.0191
48.8
29.3
2.64
<0.0001
   10-6
47.6
36.2
1.68
0.0096
31.9
14.9
2.92
<0.0001
At ≥24 months, %
   10-5
57.6
44.5
1.88
0.0022
42.7
20.0
3.54
<0.0001
   10-6
41.0
27.9
1.87
0.0023
24.9
10.2
3.11
<0.0001
At ≥36 months, %
   10-5
43.2
31.0
1.78
0.0047
31.5
11.6
3.87
<0.0001
   10-6
29.3
22.3
1.47
0.0807
19.7
6.5
3.74
<0.0001
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates Based on the Cytogenetic Risk Status - ITT Population13
MRD-Negativity Status
Standard Risk
P Value
High Risk
P Value
D-VTd
(n=460)
VTd
(n=454)
D-VTd
(n=82)a
VTd
(n=86)a
10-5, %
66.1
45.8
<0.0001
62.2
47.7
0.0595
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.
aAmong patients with high cytogenetic risk, 40 (49%) patients in the D-VTd group and 47 (55%) patients in the VTd group had a t(4;14) abnormality only, 31 (38%) patients in the D-VTd group and 33 (38%) patients in the VTd group had a del(17p) abnormality only, and 11 (13%) patients in the D-VTd group and 6 (7%) patients in the VTd group had both t(4;14) and del(17p) abnormalities. High cytogenetic risk was a stratification factor for the induction/consolidation phase (Part 1).

MRD-Negativity Rates Based on the Revised ISS Stage - ITT Population13
MRD-Negativity Status
ISS I
P Value
ISS II
P Value
ISS III
P Value
D-VTd
(n=103)
VTd
(n=146)
D-VTd
(n=383)
VTd
(n=344)
D-VTd
(n=49)
VTd
(n=50)
10-5, %
69.9
42.5
<0.0001
64.2
47.7
<0.0001
63.3
48.0
0.1284
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates Based on the Cytogenetic Risk Status - mITT Population13
MRD-Negativity Sensitivity Threshold
Standard Risk
P Value
High Risk
P Value
DARZALEX
(n=383)
Obs
(n=374)
DARZALEX
(n=57)a
Obs
(n=70)a
Overall MRD-negativityb, %
   10-5
73.4
61.8
0.0007
78.9
58.6
0.0150
   10-6
52.0
42.0
0.0060
73.7
40.0
0.0002
≥12 months of sustained MRD-negativityc, %
   10-5
56.4
46.0
0.0042
70.2
40.0
0.0007
   10-6
38.6
28.9
0.0045
57.9
14.3
<0.0001
Abbreviations: mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation.
aAmong patients with high cytogenetic risk, 34 (60%) patients in the DARZALEX group and 34 (49%) patients in the Obs group had a t(4;14) abnormality only, 21 (37%) patients in the DARZALEX group and 29 (41%) patients in the Obs group had a del(17p) abnormality only, and 2 (3%) patients in the DARZALEX group and 7 (10%) patients in the Obs group had both t(4;14) and del(17p) abnormalities. High cytogenetic risk was not a stratification factor for the maintenance phase (Part 2). When broken down by induction treatment arm, among patients with high cytogenetic risk, 19 (61%) patients in the D-VTd/DARZALEX group, 14 (42%) patients in the D-VTd/Obs group, 15 (58%) patients in the VTd/DARZALEX group, and 20 (54%) patients in the D-VTd/Obs group had a t(4;14) abnormality only; 11 (36%), 15 (46%), 10 (38%), and 14 (38%) patients, respectively, had a del(17p) abnormality only, and 1 (3%), 4 (12%), 1 (4%), and 3 (8%) patients, respectively, had both t(4;14) and del(17p) abnormalities.
bMRD-negativity in the maintenance ITT population during maintenance and follow-up.
cMRD-negativity in the maintenance ITT population from post-induction up to the end of follow-up.

MRD-Negativity Rates Based on the Revised ISS Stage - mITT Population13
MRD-Negativity Sensitivity
Threshold
ISS I
P Value
ISS II
P Value
ISS III
P Value
D-VTd
(n=105)
VTd
(n=102)
D-VTd
(n=287)
VTd
(n=310)
D-VTd
(n=44)
VTd
(n=29)
Overall MRD-negativitya, %
   10-5
74.3
65.7
0.1779
73.9
59.7
0.0002
75.0
65.5
0.3844
   10-6
48.6
42.2
0.3552
56.4
40.6
0.0001
61.4
51.7
0.4181
≥12 months of sustained MRD-negativityb, %
   10-5
59.0
45.1
0.0451
58.2
44.8
0.0011
56.8
48.3
0.4771
   10-6
41.9
30.4
0.0857
41.8
25.5
<0.0001
36.4
24.1
0.2745
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ISS, International Staging System; mITT, maintenance intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.
aMRD-negativity in the maintenance ITT population during maintenance and follow-up.
bMRD-negativity in the maintenance ITT population from post-induction up to the end of follow-up.
  • During post-induction, at 72 months, patients with MRD-negativity achieved a longer PFS as compared with patients with MRD-positivity, regardless of induction/consolidation treatment (67.2% vs 35%; HR, 0.40; 95% CI, 0.32-0.49; P<0.0001).5
    • The median PFS was not reached in patients with MRD-negativity in the D-VTd arm. PFS analysis results by the post-induction MRD status and the induction/consolidation arm in the ITT population are presented in Table: PFS Analysis by the Post-induction MRD Status and Induction/Consolidation Arm - ITT Population.5
    • A longer PFS was achieved by patients who were MRD-negative post-induction than  that achieved by patients who were not MRD-negative until post-consolidation, regardless of induction/consolidation or a second randomization (HR, 0.54; 95% CI, 0.42-0.70; P<0.0001).5,13
    • PFS improved with DARZALEX maintenance (HR, 0.63; 95% CI, 0.42-0.96; P=0.0294) vs observation (HR, 0.40; 95% CI, 0.28-0.59; P<0.0001) irrespective of whether MRD-negativity was achieved post-induction/consolidation.13
  • Maintenance with DARZALEX improved PFS irrespective of induction/consolidation treatment and the post-consolidation MRD status.5
  • DARZALEX induction/consolidation improved PFS regardless of the cytogenetic risk status and revised ISS disease stage in the ITT population.5,13
  • DARZALEX maintenance improved PFS regardless of the cytogenetic risk status and revised ISS disease stage.5,13

PFS Analysis by the Post-induction MRD Status and Induction/Consolidation Arm - ITT Population5
MRD Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd MRD-negative
76.9
Not reached
0.40 (0.27-0.59)
<0.0001
VTd MRD-negative
52.9
77
D-VTd MRD-positive
39.7
54.1
0.74 (0.61-0.89)
0.0018
VTd MRD-positive
30.8
45.3
D-VTd MRD-negative
76.9
Not reached
0.30 (0.22-0.41)
<0.0001
D-VTd MRD-positive
39.7
54.1
VTd MRD-negative
52.9
77
0.57 (0.43-0.75)
<0.0001
VTd MRD-positive
30.8
45.3
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; MRD, minimal residual disease; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

Analysis of PFS From Second Randomization by the Post-consolidation MRD Status Regardless of Induction/Consolidation - mITT Population5
MRD Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX MRD-negative
72.1
Not reached
0.54 (0.38-0.78)
0.0007
Obs MRD-negative
52.0
78.1
DARZALEX MRD-positive
47.3
66.2
0.48 (0.39-0.60)
<0.0001
Obs MRD-positive
26.2
36.6
DARZALEX MRD-negative
72.1
Not reached
0.48 (0.34-0.67)
<0.0001
DARZALEX MRD-positive
47.3
66.2
Obs MRD-negative
52.0
78.1
0.47 (0.36-0.60)
<0.0001
Obs MRD-positive
26.2
36.6
Abbreviations: CI, confidence interval; HR, hazard ratio; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; PFS, progression-free survival.

Analysis of PFS From Second Randomization by the Post-consolidation MRD Status in the D-VTd and VTd Treatment Arms - mITT Population5
MRD Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd/DARZALEX MRD-negative
73.8
Not reached
0.73 (0.45-1.17)
0.1909
D-VTd/Obs MRD-negative
63.5
Not reached
D-VTd/DARZALEX MRD-positive
47.5
60.8
0.82 (0.59-1.15)
0.2471
D-VTd/Obs MRD-positive
39.9
50.0
VTd/DARZALEX MRD-negative
69.4
Not reached
0.37 (0.21-0.63)
0.0002
VTd/Obs MRD-negative
35.0
49.6
VTd/DARZALEX MRD-positive
47.7
70.7
0.32 (0.24-0.43)
<0.0001
VTd/Obs MRD-positive
13.4
26.0
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis Based on the Cytogenetic Risk Status - ITT Population13
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd standard risk
57.0
87.3
0.60 (0.5-0.72)
<0.0001
VTd standard risk
39.7
57.8
D-VTd high risk
36.1
48.5
0.68 (0.47-0.99)
0.0410
VTd high risk
22.9
34.2
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis Based on the R-ISS Stage in the ITT Population13
R-ISS Stage
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd R-ISS I
65.0
Not reached
0.49 (0.33-0.72)
0.0002
VTd R-ISS I
36.9
60.8
D-VTd R-ISS II
52.1
75.4
0.64 (0.52-0.77)
<0.0001
VTd R-ISS II
37.2
51.1
D-VTd R-ISS III
41.4
56.8
0.63 (0.39-1.02)
0.0600
VTd R-ISS III
25.1
36.7
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; R-ISS, revised International Staging System;  VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis Based on the Cytogenetic Risk Status - mITT Population5
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX standard riska
57.3
Not reached
0.58 (0.48-0.71)
<0.0001
Obs standard risk
39.8
49
DARZALEX high riska
54.2
Not reached
0.39 (0.25-0.63)
<0.0001
Obs high risk
19.6
27.2
DARZALEX standard riska
57.3
Not reached
0.83 (0.55-1.25)
0.3696
DARZALEX high riska
54.2
Not reached
Abbreviations: CI, confidence interval; HR, hazard ratio; mITT, maintenance intent-to-treat; Obs, observation; PFS, progression-free survival.
aDARZALEX standard risk vs DARZALEX high risk: HR, 0.83; P=0.3696.

PFS Analysis Based on the R-ISS Stage - mITT Population13
R-ISS Stage
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX R-ISS I
58.4
Not reached
0.55 (0.37-0.82)
0.0032
Obs R-ISS I
41.9
49.1
DARZALEX R-ISS II
57.9
Not reached
0.52 (0.41-0.65)
<0.0001
Obs R-ISS II
35.5
45.2
DARZALEX R-ISS III
50.0
Not reached
0.54 (0.30-0.97)
0.0359
Obs R-ISS III
24.1
33.1
Abbreviations: CI, confidence interval; HR, hazard ratio; mITT, maintenance intent-to-treat; Obs, observation; PFS, progression-free survival; R-ISS, revised International Staging System.

Avet-Loiseau et al (2021)6 presented MRD results from Part 1 and Part 2 of the CASSIOPEIA study to demonstrate the impact of DARZALEX maintenance therapy on MRD-negativity.

Study Design

  • Sustained MRD-negativity rates were calculated using MRD responses observed at any timepoint during the study.

Results

Efficacy
  • In Part 1, the ITT population (N=1,085) was analyzed, which included all
    first-randomization patients.
  • Following induction and consolidation, improvement in rates of ≥CR + MRD-negativity (MFC; 10-5) was observed with D-VTd vs VTd.
  • ≥CR + MRD-negativity rates (regardless of second randomization):
    • Post-induction: D-VTd, 9.2%; VTd, 5.4% (OR, 1.79; P=0.0150).
    • Post-consolidation: D-VTd, 33.7%; VTd, 19.9% (OR, 2.06; P<0.0001).
    • ≥1 years sustained: D-VTd, 50.1%; VTd, 30.1% (OR, 2.37; P<0.0001).
    • ≥2 years sustained: D-VTd, 35.5%; VTd, 18.8% (OR, 2.41; P<0.0001).
  • In Part 2, the maintenance ITT population (N=886) was analyzed, which included all
    re-randomized patients (DARZALEX, n=442; observation, n=444).
  • During maintenance, ≥CR + MRD-negativity rates (NGS; 10-5) with DARZALEX vs observation were as follows:
    • MRD-negative: DARZALEX, 58.6%; observation, 47.1% (OR, 1.80; P=0.0001).
    • ≥1 years sustained: DARZALEX, 42.3%; observation, 31.5% (OR, 1.71; P=0.0004).
    • ≥2 years sustained: DARZALEX, 20.4%; observation, 17.6% (OR, 1.21; P=0.2855).
  • Rates of ≥CR + MRD negativity at 10-5 and 10-6 (NGS) during maintenance are presented in Table: Rates of ≥CR + MRD-Negativity at 10-5 and 10-6 (NGS) at Any Timepoint During Maintenance.

Rates of ≥CR + MRD-Negativity at 10-5 and 10-6 (NGS) at Any Timepoint During Maintenancea, 6
MRD-negativity rate, %
10-5
10-6
OR, P value
MRD-negativity at any timepoint during maintenance
   D-VTd -> DARZALEX
64
57
1.43b,
P=0.1037c
   D-VTd -> Observation
58
49
   VTd -> DARZALEX
53
42
2.26b,
P=0.0002c
   VTd -> Observation
36
24
1-year sustained MRD-negativity during maintenance
   D-VTd -> DARZALEX
48
37
1.41b,
P=0.0885c
   D-VTd -> Observation
41
31
   VTd -> DARZALEX
36
26
 2.22b,
P=0.0006c
   VTd -> Observation
21
14
2-year sustained MRD-negativity during maintenance
   D-VTd -> DARZALEX
29
19
1.47b,
P=0.0789c
   D-VTd -> Observation
22
16
   VTd -> DARZALEX
11
10
 0.83b,
P=0.5481c
   VTd -> Observation
13
8
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; NGS, next-generation sequencing; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.
aPost-consolidation after the second randomization.
bOR for 10-5 MRD-negativity rates.
cP value was calculated based on a stratified Cochran-Mantel-Haenszel chi-squared test.

Subgroup Analysis of Maintenance ≥CR + MRD-Negativity (NGS; 10-5) Rates6
Subgroup
DARZALEX
n/N (%)
Observation
n/N (%)
OR (95% CI)
Age
   <50 years
41/63 (65.1)
26/68 (38.2)
3.01 (1.48-6.14)
   50-60 years
110/198 (55.6)
100/200 (50.0)
1.25 (0.84-1.85)
   >60 years
108/181 (59.7)
83/176 (47.2)
1.66 (1.09-2.52)
Sex
   Male
114/261 (55.2)
107/254 (42.1)
1.69 (1.19-2.40)
   Female
115/181 (63.5)
102/190 (53.7)
1.50 (0.99-2.28)
Site
   IFM
227/373 (60.9)
191/391 (48.8)
1.63 (1.22-2.17)
   HOVON
32/69 (46.4)
18/53 (34.0)
1.68 (0.80-3.52)
ISS stage
   I
111/189 (58.7)
86/171 (50.3)
1.41 (0.93-2.13)
   II
102/181 (56.4)
93/214 (43.5)
1.68 (1.13-2.50)
   III
46/72 (63.9)
30/59 (50.8)
1.71 (0.85-3.45)
Cytogenetic risk
   High risk
41/57 (71.9)
33/70 (47.1)
2.87 (1.36-6.05)
   Standard risk
217/383 (56.7)
176/374 (47.1)
1.47 (1.10-1.96)
Pre-maintenance baseline renal function (CrCl)
   >90 mL/min
174/303 (57.4)
140/305 (45.9)
1.59 (1.15-2.19)
   ≤90 mL/min
85/139 (61.2)
69/139 (49.6)
1.60 (0.99-2.57)
Type of MM
   IgG
130/253 (51.4)
113/270 (41.9)
1.47 (1.04-2.07)
   Non-IgG
65/93 (69.9)
52/92 (56.5)
1.79 (0.97-3.27)
Pre-maintenance baseline ECOG PS score
   0
145/252 (57.5)
130/260 (50.0)
1.36 (0.96-1.92)
   ≥1
114/190 (60.0)
79/184 (42.9)
1.99 (1.32-3.01)
Induction/ASCT/consolidation
   VTd
112/213 (52.6)
77/215 (35.8)
1.99 (1.35-2.93)
   D-VTd
147/229 (64.2)
132/229 (57.6)
1.32 (0.90-1.92)
Response
   VGPR or better
255/405 (63.0)
209/406 (51.5)
1.60 (1.21-2.12)
   PR
4/37 (10.8)
0/38
NE (NE-NE)
Abbreviations: ASCT, autologous stem cell transplantation; CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HOVON, the Dutch-Belgian Cooperative Group for Hematology-Oncology; IFM, Intergroupe Francophone du Myelome; IgG, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; NE, not estimable; NGS, next-generation sequencing; OR, odds ratio; PR, partial response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.

Evaluation of MRD Status and Association with PFS in CASSIOPEIA Study Part 1

Avet-Loiseau et al (2019)7 evaluated MRD status and its association with PFS in Part 1 of the CASSIOPEIA study.

Study Design

  • MRD was assessed via MFC at the 10-5 threshold.

Results

  • Post-induction MRD-negativity rates: 34.6% D-VTd vs 23.1% VTd (P<0.0001).
  • Post-consolidation MRD-negativity rates: 63.7% D-VTd vs 43.5% VTd (P<0.0001).
    • Post-consolidation MRD-negativity rates were also significantly higher for D-VTd versus VTd by NGS; 56.6% vs 36.8%; P<0.0001.
  • Accounting for treatment group and MRD-negativity, multivariate analyses showed a PFS benefit in patients achieving MRD-negativity (HR, 0.31; 95% CI, 0.20-0.50; P<0.0001).
    • D-VTd showed additional PFS benefits vs VTd based on these analyses (HR, 0.48; 95% CI, 0.30-0.78; P=0.0028).
  • A supplementary analysis performed in patients achieving ≥CR post consolidation showed a higher proportion of patients achieved MRD-negativity and ≥CR with D-VTd vs VTd (33.7% vs 19.9%; P<0.0001).
    • A PFS benefit was observed in patients who achieved MRD-negativity and ≥CR (HR, 0.22; 95% CI, 0.10-0.48; P= 0.0001).
      • Based on these analyses, D-VTd showed an additional PFS benefit versus VTd (HR, 0.46; 95% CI, 0.28-0.73; P= 0.0011).

Subgroup Analysis of High-Risk Patients from Part 1 of CASSIOPEIA Study

Sonneveld et al (2019)8 presented a subgroup analysis of high-risk patients (based on cytogenetic risk status and ISS stage) in Part 1 of the CASSIOPEIA study.

Study Design/Methods

  • Patients were stratified by ISS stage (I, II, or III), and cytogenetic risk status.
  • Cytogenetic risk was assessed by fluorescence in-situ hybridization (FISH) or karyotyping.
  • Patients with high-risk cytogenetics had at least one high-risk abnormality centrally confirmed during screening: del17p (≥50% abnormal cells) or t(4;14) (≥30% abnormal cells).
  • MRD was assessed via MFC at the 10-5 threshold.

Results

  • High-risk (del17p or t[4:14]): 15% (n=82) D-VTd vs 16% (n=86) VTd.
  • ISS Stage III: 15.5% (n=84) D-VTd vs 14.9% (n=81) VTd.
Efficacy
  • Efficacy data from the subgroup analyses of the study are presented in Table: Post-consolidation Response and MRD status for High-risk Patients.
  • Median follow-up was 18.8 (range, 0.0-32.2) months.
  • Treatment effect of D-VTd over VTd with respect to rates of sCR was not demonstrated in patients with high-risk cytogenetics (OR, 0.83; 95% CI, 0.42-1.66) or patients with ISS stage III disease (OR, 1.07; 95% CI, 0.54-2.12).
  • The rate of ≥CR was 36.6% with D-VTd vs 32.6% with VTd (OR, 1.11; 95% CI,
    0.58-2.10) in the high-risk cytogenetic subgroup and 44.0% with D-VTd vs 33.3% with VTd (OR, 1.54; 95% CI, 0.83-2.88) in the ISS stage III subgroup.
  • MRD-negative rate was 59.8% with D-VTd vs 44.2% with VTd (OR, 1.88; 95% CI,
    1.02-3.46) and 64.3% with D-VTd vs 45.7% with VTd (OR, 2.14; 95% CI, 1.15-4.00) in the high-risk cytogenetics and ISS stage III subgroups, respectively.
  • PFS: D-VTd reduced the risk of disease progression or death vs VTd in cytogenetic
    high-risk (HR, 0.67; 95% CI, 0.35-1.30) and ISS stage III (HR, 0.66; 95% CI, 0.32-1.39) subgroups.

Post-consolidation Response and MRD status for High-risk Patients8
ISS Disease Stage III
High-risk Cytogenetics
D-VTd (n=84)
VTd (n=81)
P value
D-VTd (n=82)
VTd (n=86)
P value
Response, %a
   ORR
86
89
-
84
85
-
   sCR
29
27
0.8506
24
28
0.4839
   ≥CR
44
33
-
37
33
-
   CR
16
6
-
12
5
-
   VGPR
35
51
-
42
48
-
   PR
7
5
-
6
5
-
MRD-negative Status (10-5)b
   MRD-negative, %
64
46
0.0190
60
44
0.0679
   MRD-negative and ≥CR, %
39
25
0.0516
29
23
0.5103
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VTd, bortezomib + thalidomide +dexamethasone.
aP values are given only for sCR.
bEuroFlow-based multiparametric flow cytometry.

CASSIOPET Companion Study

Moreau et al (2019)9 presented the results of the CASSIOPET companion study of CASSIOPEIA1, which evaluated the prognostic value of PET/CT at diagnosis,
post-consolidation PET-CR rates of D-VTd vs VTd, and concordance between PET/CT and MRD-negativity.

Study Design/Methods

  • A subset of patients randomized in Part 1 of the CASSIOPEIA study underwent PET/CT scans at baseline prior to the first dose and post-consolidation 100 days after ASCT.
    • The imaging data acquired from the PET/CT scans were centrally assessed and analyzed using IMAGYS platform.
    • Images were interpreted by an independent team of nuclear medicine physicians blinded to patient treatment.
  • Baseline assessments included bone marrow diffuse uptake, bone focal lesions, extramedullary disease, paramedullary disease, most intense fluoro-deoxyglucose (FDG) uptake, and maximum standardized uptake value (SUVmax).
  • Post-consolidation assessment included evaluating the Deauville score of the most intense lesion on day 100 to define CR and unconfirmed CR (uCR).
  • MRD was assessed via MFC at the 10-5 threshold.

Results

Patient Characteristics
  • A total of 268 patients had assessable baseline PET data (D-VTd, n=137; VTd, n=131) and 184 patients had assessable post-consolidation PET data (D-VTd, n=101; VTd, n=83). See Table: Select Baseline Disease Characteristics.
  • The median follow-up for exploratory objectives was 29.2 months.

Select Baseline Disease Characteristics9
Characteristic
D-VTd (n=137)
VTd (n=131)
Total (N=268)
Baseline PET-negative response, n (%)
22 (16.1)
32 (24.4)
54 (20.1)
Baseline PET-positive response, n (%)
115 (83.9)
99 (75.6)
214 (79.9)
Focal lesion, n (%)
96 (70.1)
84 (64.1)
180 (67.2)
Focal lesion SUVmax, median (range)
6.89 (2.34-48.50)
5.35 (1.90-23.23)
6.12 (1.90-48.50)
Extramedullary disease, n (%)
15 (10.9)
6 (4.6)
21 (7.8)
Paramedullary disease, n (%)
26 (19.0)
21 (16.0)
47 (17.5)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; PET, positron emission tomography; SUVmax, maximum standardized uptake value; VTd, bortezomib + thalidomide + dexamethasone.
Efficacy
  • PFS was improved among patients who were PET-negative (CR and uCR) vs PET-positive (PR and stable disease) at baseline (HR, 0.42; 95% CI, 0.18-0.97; P=0.0365).
    • PFS was improved in the D-VTd vs VTd group among patients with baseline
      PET-negative response (HR, 0.00; 95% CI; P=0.0239) and baseline PET-positive response (HR, 0.57; 95% CI; P=0.0531).
    • The HR for paramedullary vs non-paramedullary disease among patients with baseline PET-negative response was 2.39 (95% CI, 1.29-4.45; P=0.0058).
  • The post-consolidation PET CR rates were high and similar across treatment groups. See Table: Post-consolidation PET Response.
    • The PET-negative vs PET-positive response rate was 89.6% vs 10.3%.
  • The HR for PFS among patients with post-consolidation PET-negative vs PET‍-positive response was 0.51 (95% CI, 0.19-1.35; P=0.1673).
    • The HR for the PFS among patients with post-consolidation double negative
      (PET/CT- and MRD-negative) vs no double negative response was 0.49 (95% CI, 0.23-1.05; P=0.0605).
    • The HR for the PFS among patients with post-consolidation double negative
      (PET/CT- and MRD-negative) and ≥CR vs no double negative response or ≤very good partial response (VGPR) was 0.49 (95% CI, 0.20-1.22; P=0.1161).
  • The kappa coefficient for post-consolidation concordance between MRD (10-5) and PET/CT negativity was 0.0091. See Table: Post-consolidation Concordance Between PET/CT and MRD.
  • A significantly higher proportion of patients reached double negativity of PET/CT and MRD (10-5) following consolidation in the D-VTd vs VTd group (66.7% vs 47.5%; OR, 2.21; 95% CI, 1.20-4.07; P=0.0105). See Table: Post-consolidation Double Negativity Rate.

Post-consolidation PET Response9
Response, n (%)
D-VTd (n=101)
VTd (n=83)
Total (N=184)a
PET CR
65 (64.4)
53 (63.9)
118 (64.1)
PET uCR
26 (25.7)
21 (25.3)
47 (25.5)
PET PR+SD
10 (9.9)
9 (10.8)
19 (10.3)
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; PET, positron emission tomography; PR, partial response; SD, stable disease; uCR, unconfirmed complete response; VTd, bortezomib + thalidomide + dexamethasone.
aMain reason for reduction in patients from baseline to post-consolidation was due to the exclusion of baseline PET-negative patients.

Post-consolidation Concordance Between PET/CT and MRD9
Parameter
PET/CT Positivea
PET/CT Negativeb
Kappa coefficient (SE)c
MRDd,e
   Positive, n
7
55
0.0091 (0.0587)
   Negative, n
12
102
MRDe+≥CR
   Positive/≤VGPR, n
13
97
0.0214 (0.0368)
   Negative+≥CR, n
6
60
Abbreviations: CR, complete response; CT, computed tomography; MRD, minimal residual disease; PET, positron emission tomography; SE, standard error.
aPET partial response and stable disease.
bPET CR and PET unconfirmed CR.
cMeasures agreement between two categories; kappa coefficient of 1 indicates complete agreement, while a kappa coefficient of 0 indicates no agreement.
dRegardless of response.
ePer multiparametric flow cytometry at the 10-5 threshold.

Post-consolidation Double Negativity Ratea,9
Double negativity rate, n (%)
D-VTd (n=96)
VTd (n=80)
Odds ratio (95% CIb)
P valuec
PET/CT and MRDd
64 (66.7)
38 (47.5)
2.21 (1.20-4.07)
0.0105
PET/CT and MRDd+≥CR
40 (41.7)
20 (25.0)
2.14 (1.12-4.10)
0.0206
Abbreviations: CI, confidence interval; CR, complete response; CT, computed tomography; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; PET, positron emission tomography; VTd, bortezomib + thalidomide + dexamethasone.
aExcludes patients with a Day 100 PET/CT performed > ±30 days apart from the Day 100 MRD assessment. bBased on Mantel-Haenszel estimate of the common odds ratio.
cP value calculated using the Cochran Mantel-Haenszel Chi-Squared test.
dPer multiparametric flow cytometry at the 10-5 threshold.

Evaluation of Baseline slimCRAB Subgroup and Association to Efficacy Outcomes in CASSIOPEIA Study

Touzeau et al (2020)10 performed a subgroup analysis from Part 1 of the CASSIOPEIA study based on baseline slimCRAB criteria.

Study Design

  • Patients in the CRAB subgroup had ≥1 feature of CRAB criteria.
    • CRAB criteria:
      • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (> 11mg/dL).
      • Renal insufficiency: CrCl <40 mL/min or serum creatinine >177 µmol/L (>2 mg/dL).
      • Anemia: hemoglobin levels of >20 g/L below the lowest limit of normal, or a hemoglobin level of <100 g/L.
      • Bone lesions: ≥1 osteolytic lesion on skeletal radiography, CT, or PET/CT; if bone marrow has <10% clonal plasma cells, >1 lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement).
  • Patients in the slim-only subgroup had >1 of the slim criteria and excluded patients with ≥1 conventional CRAB criterion based on baseline data collection.
    • Slim criteria:
      • ≥60% clonal bone marrow plasma cells.
      • Serum free light-chain ratio >100.
      • > 1 focal bone lesion by magnetic resonance imaging (MRI).

Results

Baseline Characteristics
  • CRAB subgroup: n=1,004 (n=507) D-VTd vs (n=497) VTd.
  • Slim subgroup: n=81 (n=36) D-VTd vs (n=45) VTd.
  • ECOG PS score of ≥1: 22 % slim only group vs 54% CRAB group.
  • ISS stage III disease: 4% slim only group vs 16% CRAB group.
  • High risk cytogenetics: 11% slim only group vs 16% CRAB group.
Efficacy
  • Efficacy data for slim-only vs CRAB patients are presented in Table: Efficacy Outcomes in Slim-only vs CRAB Patients.
  • ORRs were similar for slim-only (90%) and CRAB patients (91%).
    • Rates of sCR (25% vs 25%) and CR (32 vs 33%) were similar for slim-only and CRAB patients.
  • MRD-negativity rates were similar for slim only (46%) and CRAB patients (54%).
  • At 18.8-month median follow-up, PFS was not significantly different in slim-only and CRAB patients.
  • Efficacy data for D-VTd vs VTd in slim-only and CRAB patients are presented in Table: Efficacy Outcomes for D-VTd vs VTd in Slim-only and CRAB Patients.
  • In slim-only patients, ORR was significantly higher for D-VTd vs VTd (97% vs 84%; P=0.0377).
    • In slim-only patients, sCR (36% vs 16%; P=0.0083) and >CR (50% cs 18%; P=0.0003 were significantly higher for D-VTd vs VTd.
  • In CRAB patients, ORR was similar for D-VTd vs VTd (92% vs 90%).
    • In CRAB patients, sCR (28% vs 21%; P=0.0048) and >CR (38% vs 27%; P=0.0001) were improved for D-VTd vs VTd.
  • MRD-negativity rates were significantly higher in D-VTd vs VTd in slim-only and CRAB patients (both P<0.0001).
  • In slim-only patients, median PFS was not reached in either group for D-VTd vs VTd and did not significantly differ (HR, 1.19; 95% CI, 0.30-4.78; P=0.8023).
    • In slim-only patients, 18-month PFS rates were 96% versus 89% and 24-month PFS rates were 89% vs 76% for D-VTd and VTd, respectively.
  • In CRAB patients, median PFS was not reached in either group, with a significant reduction in risk of PD or death with D-VTd vs VTd (HR, 0.44; 95% CI, 0.30-0.64; P<0.0001).
    • In CRAB patients, 18-month PFS rates were 92% vs 84% and 24-month PFS rates were 89% vs 76%, for D-VTd vs VTd, respectively.

Efficacy Outcomes in Slim-only vs CRAB Patientsa,10
Slim-Only (n=81)
CRAB (n=1,004)
P value
Response, %
   ORR
90
91
0.4053
   ≥CR
32
33
0.9690
   sCR
25
25
0.9776
   CR
7
8
-
   >VGPR
78
81
0.4974
   VGPR
46
49
-
   PR
12
10
-
MRD (10-5)
   MRD-negative, %
46
54
   MRD OR (95% CI)
0.70 (0.44-1.11)
0.1261
PFS
   Median PFS, months
NR
NR
   HR (95% CI)
0.73 (0.36-1.50)
0.3888
   18-month PFS, %
93
88
   24-month PFS, %
90
83
Abbreviations: CI, confidence interval; CR, complete response; HR, hazard ratio; MRD, minimal residual disease; NR, not reached; OR, odds ratio; ORR, overall response rate; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
aMeasured post-consolidation.

Efficacy Outcomes for D-VTd vs VTd in Slim-only and CRAB Patients10
Slim-Only
CRAB
D-VTd (n=36)
VTd (n=45)
P-value
D-VTd (n=507)
VTd (n=497)
P value
Response, %
   ORR
97
84
0.0377
92
90
0.2771
   ≥CR
50
18
0.0003
38
27
0.0001
   CR
14
2
-
10
6
-
   sCR
36
16
0.0083
28
21
0.0048
>VGPR
89
69
0.0078
83
79
0.0946
   VGPR
39
51
-
45
52
-
   PR
8
16
-
9
12
-
MRD-negative Status (10-5)
   MRD-negative, %
67
29
64
45
-
   MRD OR (95% CI)
7.83 (2.53-24.22)
<0.0001
2.12 (1.65-2.73)
<0.0001
PFS
   Median PFS, months
NR
NR
NR
NR
   HR (95% CI)
1.19 (0.30-4.78)
P=0.8023
0.44 (0.30-0.64)
P<0.0001
   18-month PFS, %
96
89
92
84
   24-month PFS, %
89
89
89
76
Abbreviations: CI, confidence interval; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR; hazard ratio; MRD, minimal residual disease; NR, not reached; OR, odds ratio; ORR, overall response rate; PFS; progression-free survival; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.

Health-Related Quality of Life Outcomes from Part 1 of CASSIOPEIA

Roussel et al (2020)11 reported the results of the PRO data collected during treatment in Part 1 of the CASSIOPEIA study up to post-consolidation (day 100 after ASCT).

Results

  • Compliance rates for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires were 93% at baseline and remained high and similar between treatment groups in the post-induction and post-consolidation assessments.
  • Mean changes in the global health score (GHS) from baseline to post-consolidation were similar between treatment groups.
  • Both treatment groups had improvement from baseline in EORTC QLQ-C30 GHS and in EQ-5D-5L visual analog scale scores in post-consolidation scores.
  • Post-consolidation scores presented significantly lesser reductions in cognitive functioning, greater improvement in constipation, emotional functioning, and greater mean decreases in pain in the D-VTd group vs VTd group.

EQ-5D-5L: Least Squares Mean Between Groups Differences of Change from Baseline (95% CI)11
Post-induction
Post-consolidation
D-VTd
VTd
P Valuea
D-VTd
VTd
P Valuea
Visual analog scale
2.7
(0.5 to 4.8)
2.2
(0.1 to 4.4)
0.70
8.6
(6.5 to 10.8)b
7.7
(5.5 to 9.9)b
0.44
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer quality of life questionnaire core 30-item; EQ-5D-5L, EuroQol 5-dimensional descriptive system; VTd, bortezomib + thalidomide + dexamethasone.
ap-value was calculated using a mixed-effects model with repeated measures.
bClinically meaningful change.

EORTC-QLQ-C30: Least Squares Mean Between Groups Differences of Change from Baseline (95% CI)11
Post-induction
Post-consolidation
D-VTd
VTd
P Valuea
D-VTd
VTd
P Valuea
Global health status
3.8
(1.6 to 6.0)
2.9
(0.7 to 5.1)
0.43
9.7
(7.4 to 11.9)b
8.7
(6.5 to 11.0)b
0.45
Functioning
   Physical
2.2
(0.0 to 4.4)
0.6
(-1.7 to 2.8)
0.16
6.9
(4.7 to 9.2)
6.5
(4.2 to 8.8)
0.74
   Role
5.6
(2.1 to 9.1)
1.9
(-1.6 to 5.4)
0.051
13.1
(9.5 to 16.7)b
11.0
(7.4 to 14.6)b
0.27
   Emotional
6.4
(3.9 to 8.9)
7.6
(5.0 to 10.0)
0.40
13.0
(10.4 to 15.5)b
9.5
(6.9 to 12.1)
0.013
   Cognitive
-6.2
(-8.8 to -3.7)
-6.6
(-9.2 to -4.0)
0.80
-5.0
(-7.6 to -2.4)
-7.9
(-10.6 to -5.3)
0.036
   Social
-1.7
(-4.9 to 1.4)
-3.0
(-6.1 to 0.2)
0.476
5.6
(2.4 to 8.8)
3.5
(0.2 to 6.7)
0.22
Symptoms
   Fatigue
0.8
(-2.1 to 3.7)
3.6
(0.6 to 6.5)
0.079
-5.2
(-8.1 to -2.2)
-4.3
(-7.4 to -1.3)
0.60
   Nausea and
   vomiting
-0.5
(-2.2 to 1.2)
0.3
(-1.4 to 1.9)
0.41
-1.9
(-3.5 to -0.2)
-0.9
(-2.7 to 0.8)
0.33
   Pain
-16.0
(-19.2 to -12.7)b
-13.8
(-17.1 to-10.5)b
0.22
-23.3
(-26.6 to -20.0)b
-19.7
(-23.0 to -16.3)b
0.042
Single item
   Dyspnea
2.3
(-1.2 to 5.8)
6.3
(2.8 to 9.8)
0.031
1.5
(-2.1 to 5.0)
2.7
(-0.9 to 6.3)
0.51
   Insomnia
-9.8
(-13.5 to -6.2)
-7.6
(-11.2 to -3.9)
0.26
-12.2
(-15.9 to -8.5)b
-13.6
(-17.4 to -9.8)b
0.50
   Appetite
   loss
-5.8
(-8.4 to -3.3)
-8.0
(-10.6 to -5.4)
0.12
-10.2
(-12.8 to -7.6)b
-11.6
(-14.3 to -8.9)b
0.33
   Constipation
8.1
(4.1 to 12.1)
11.6
(7.5 to 15.7)b
0.11
-3.2
(-7.3 to 0.9)
1.8
(-2.4 to 6.0)
0.025
   Diarrhea
-2.3
(-4.4 to -0.1)
-4.1
(-6.3 to -2.0)
0.12
-1.3
(-3.5 to 0.9)
-2.9
(-5.2 to -0.7)
0.19
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer quality of life questionnaire core 30-item; VTd, bortezomib + thalidomide + dexamethasone.
aP-value was calculated using a mixed-effects model with repeated measures.
bClinically meaningful change.

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 03 June 2025.

 

References

Show
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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. [published online ahead of print June 14, 2024]. Lancet Oncol. 2024. doi:10.1016/s1470-2045(24)00282-1.  
5 Corre J, Vincent L, Moreau P, et al. Daratumumab/bortezomib/thalidomide/dexamethasone in newly diagnosed myeloma: CASSIOPEIA minimal residual disease results. [Published online March 24, 2025]. Blood. 2025. doi:10.1182/blood.2024027620.  
6 Avet-Loiseau H, Sonneveld P, Moreau P, et al. Daratumumab (DARA) with bortezomib, thalidomide, and dexamethasone (VTd) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) negativity in CASSIOPEIA part 1 and part 2. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.  
7 Avet-Loiseau H, Moreau P, Attal M, et al. Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: analysis of the CASSIOPEIA trial. Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2019; Chicago, IL.  
8 Sonneveld P, Attal M, Perrot A, et al. Daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (NDMM): subgroup analysis of high-risk patients (pts) in CASSIOPEIA. presented at: 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
9 Moreau P, Zweegman S, Perrot A, et al. Evaluation of the prognostic value of positron emission tomography-computed tomography (PET-CT) at diagnosis and follow-up in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients treated in the phase 3 CASSIOPEIA* study: results of the CASSIOPET companion study. Oral presentation presented at: American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.  
10 Touzeau C, Moreau P, Perrot A, et al. Daratumumab + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM): baseline slimCRAB-based subgroup analysis of CASSIOPEIA. Poster presented at: American Society of Clinical Oncology (ASCO) 2020 Scientific Program; May 29-31, 2020; Virtual.  
11 Roussel M, Moreau P, Hebraud B, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial. Lancet Haematol. 2020;7(12):e874-873.  
12 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.  
13 Corre J, Vincent L, Moreau P, et al. Supplement to: Daratumumab/bortezomib/thalidomide/dexamethasone in newly diagnosed myeloma: CASSIOPEIA minimal residual disease results. [Published online March 24, 2025]. Blood. 2025. doi:10.1182/blood.2024027620.  
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