J&J Medical Connect
DARZALEX®

(daratumumab)

+ Save link
J&J Medical Connect

Connect with us

Connect with us

This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

DARZALEX® (daratumumab)

Medical Information

DARZALEX - Adverse Events - General in Patients with Multiple Myeloma

Last Updated: 07/24/2025

SUMMAry

  • Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.1
  • The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma (MM) including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy.1
  • The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion-related reactions (IRRs), thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.1
  • The most common (any grade) adverse events (AEs) are presented from the following studies:
    • CASSIOPEIA for newly diagnosed multiple myeloma (NDMM) patients eligible for autologous stem cell transplant (ASCT).2-5
    • GRIFFIN for NDMM patients eligible for high-dose therapy (HDT) and ASCT.6-10
    • MAIA and ALCYONE for NDMM patients ineligible for ASCT.11-13
    • POLLUX, CASTOR, CANDOR, GEN503, and EQUULEUS for relapsed/refractory multiple myeloma (RRMM) patients receiving DARZALEX in combination with background regimens.14-19
    • GEN501 and SIRIUS for patients with RRMM receiving DARZALEX as monotherapy.20,21
  • Please refer to the following sections of the full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS.

CLINICAL DATA - Newly diagnosed multiple myeloma - TRANSPLANT ELIGIBLE

Combination Treatment with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; NCT02541383) is an ongoing, open-label, 2-arm, multicenter, phase 3 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) in patients with NDMM who are eligible for HDT/ASCT.2,3 Moreau et al (2019)2 reported the results from Part 1 of this study. Moreau et al (2021)3 reported results from Part 2 of the CASSIOPEIA study (maintenance treatment). Moreau et al (2024)4 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.

Safety Results - Part 1  

  • AEs are presented in Table: Most Common AEs During Treatment in the Safety Population (CASSIOPEIA Part 1).
  • The most common any-grade AEs occurring in ≥20% of patients in either arm (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 (47%) patients in the D-VTd arm and 255 (47%) patients in the VTd arm. The most common SAEs (occurring in ≥3% of patients in either arm) were neutropenia (D-VTd, 4%; VTd, 1%), pneumonia (D-VTd, 4%; VTd, 2%), pyrexia (D-VTd, 3%; VTd, 4%), and pulmonary embolism (D-VTd, 1%; VTd, 4%).

Most Common AEs During Treatment in the Safety Population (CASSIOPEIA Part 1)a,2
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)
   Paraesthesia
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 IRR
190 (35)
19 (4)
NA
NA
Abbreviations: AE, adverse event; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; IRR,
infusion-related reaction; NA, not applicable; VTd, bortezomib + thalidomide + dexamethasone.
aAEs of any grade that were reported in at least 20% of patients in either treatment arm and grade 3/4 AEs that were reported in at least 10% of patients in either treatment arm are listed.

Safety Results - Part 2  

  • Any treatment-emergent adverse events (TEAEs) occurred in 95% (n=420) of patients in the DARZALEX monotherapy arm vs 89% (n=394) in the observation arm.
  • SAEs occurred in 23% (n=100) patients in the DARZALEX monotherapy arm vs 19% (n=84) in the observation arm.
  • SAEs that occurred in >1% of patients in the DARZALEX monotherapy vs observation arms were pneumonia (n=11 [3%] vs n=7 [2%]) and lung infection (n=6 [1%] vs n=7 [2%]), respectively.
  • Grade ≥3 TEAEs occurred in 28% (n=122) of patients in the DARZALEX monotherapy arm (who received at least 1 dose) vs 24% (n=108) in the observation arm.
  • IRRs occurred in 54.5% (n=115) of patients in the DARZALEX monotherapy arm.
  • Two AEs led to death in the DARZALEX monotherapy arm (septic shock and natural killer-cell lymphoblastic lymphoma, n=1 each); both were treatment-related.22
  • Safety data of patients in the DARZALEX monotherapy arm vs observation arm is presented in Table: Most Common AEs (≥10%) in CASSIOPEIA Part 2 Study.

Most Common AEs (≥10%) in CASSIOPEIA Part 2 Studya,3
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
   Cough
78 (18)
1 (<1)
0
40 (9)
0
0
   Nasopharyngitis
76 (17)
0
0
49 (11)
0
0
   Peripheral sensory
   neuropathy
65 (15)
4 (1)
0
46 (10)
5 (1)
0
   URTI
64 (15)
0
0
35 (8)
1 (<1)
0
   Asthenia
60 (14)
0
0
51 (11)
2 (<1)
   Diarrhea
56 (13)
1 (<1)
0
0
10 (2)
   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
   Herpes zoster
30 (7)
1 (<1)
0
63 (14)
2 (<1)
0
   Pneumonia
18 (4)
10 (2)
1 (<1)
13 (3)
6 (1)
0
   Hypertension
15 (3)
13 (3)
0
10 (2)
7 (2)
0
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.
aThe most common grade 3 or 4 TEAEs were lymphopenia, hypertension, and neutropenia.

Long-term Follow-up in CASSIOPEIA

Moreau et al (2024)4 reported the long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization.

Safety Results


Causes of Death During and After the Maintenance Phase by Induction/Consolidation Treatment in the Maintenance-Specific Safety Population5
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 Population5
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 the lung
0
0
1 (0.4)
0
      Testicular germ cell cancer
0
0
1 (0.4)
0
      Adenocarcinoma of the 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 the oral cavity
1 (0.4)
0
0
0
      Squamous cell carcinoma of the 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 the 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.

Combination Treatment with Bortezomib, Lenalidomide and Dexamethasone

GRIFFIN (MMY2004; NCT02874742)6-8 is a 2-part, phase 2, randomized, active-controlled US study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with NDMM eligible for HDT and ASCT. Vorhees et al (2021)23 reported the final analysis of the safety run-in cohort of this study (Part 1 safety run-in phase final analysis) at a median follow-up of 40.8 months. Voorhees et al (2020)8 presented the primary analysis (median follow-up, 13.5 months) and updated analysis of the randomized portion (median follow-up, 22.1 months) of this study. Sborov et al (2022)24 presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median follow-up, 49.6 months). Chari et al (2024)9,10 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study at a median follow-up duration of 49.6 months

Part 1: Safety Run-in Phase Final Analysis

Vorhees et al (2021)23 reported the final analysis of the safety run-in cohort of this study (Part 1 safety run-in phase final analysis) at a median follow-up of 40.8 months.

Safety Results

  • Eleven patients (68%) experienced a SAE. For the incidences of grade 3/4 TEAEs. See Table: Most Common Grade 3/4 TEAEs (GRIFFIN; Part 1).
  • One patient had a TEAE leading to discontinuation of study treatment.
  • Fourteen (87.5%) patients experienced any grade infections and 5 (31.3%) patients experienced grade 3/4 infections.
    • During the maintenance phase, 31.3% (n=5) of patients experienced any grade infections, the most common being upper respiratory tract infections. One (6.3%) patient experienced a grade 3/4 infection (pneumonia and bronchitis).
  • Grade 1/2 IRRs occurred in 31.3% (n=5) of patients. IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.

Most Common Grade 3/4 TEAEs (GRIFFIN; Part 1)23
Patients, n (%)
D-VRd (n=16)
Grade 3/4a
Total
15 (93.8)
Most commonly occurring
   Neutropenia
7 (43.8)
   Pneumonia
5 (31.3)
   Lymphopenia
5 (31.3)
   Thrombocytopenia
4 (25)
   Hypertension
3 (18.8)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone, TEAE, treatment-emergent adverse event.
aNo Grade 5 TEAEs were reported.

Part 2: Randomized Phase

Voorhees et al (2020)8 presented the primary analysis (median follow-up, 13.5 months) and updated analysis of the randomized portion (median follow-up, 22.1 months) of this study. Sborov et al (2022)24 presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median
follow-up, 49.6 months).

Safety Results

  • In the updated safety and efficacy analysis, any grade infections occurred in 91% of patients in the D-VRd arm and 62% of patients in the VRd arm, the most common being grade 1/2 upper respiratory tract infections; grade 3/4 infections were seen in 23% of patients in the D-VRd arm vs 22% of patients in the VRd arm. See Table: Most Common TEAEs (GRIFFIN; Part 2).
  • Pneumonia was reported in 13% of patients in the D-VRd arm and 15% of patients in the VRd arm.

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

Final Safety Analysis of Maintenance Therapy in GRIFFIN

Sborov et al (2022)24 presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment (median follow-up,
49.6 months).

  • TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33%; VRd, 31%). One patient in each arm died due to TEAEs unrelated to study treatment.
  • Rates of infections leading to treatment discontinuation were similar across treatment arms (D-VRd, 2%; VRd, 3%).
    • The most common infection was upper respiratory tract infection in both arms.
    • In the D-VRd vs VRd arms, Coronavirus Disease 2019 (COVID-19) infections were reported in 5 vs 2 patients.
  • TEAEs occurring in ≥30% of patients in the safety population are summarized in Table: Most Common TEAEs (Final Analysis of GRIFFIN).
  • A total of 14 patients (D-VRd, n=7; VRd, n=7) died, of whom 9 patients (D-VRd, n=5; VRd, n=4) died due to PD.

Most Common TEAEs (Final Analysis of GRIFFIN)a,24
TEAEs, n (%)
D-VRd (n=99)
VRd (n=102)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
63 (64)
46 (46)
41 (40)
23 (23)
   Thrombocytopenia
44 (44)
16 (16)
36 (35)
9 (9)
   Leukopenia
39 (39)
17 (17)
30 (29)
8 (8)
   Anemia
37 (37)
9 (9)
33 (32)
6 (6)
   Lymphopenia
31 (31)
23 (23)
29 (28)
23 (23)
Non-hematologic
   Fatigue
71 (72)
7 (7)
63 (62)
6 (6)
   Upper respiratory tract infection
67 (68)
4 (4)
51 (50)
2 (2)
   Diarrhea
66 (67)
7 (7)
56 (55)
5 (5)
   Peripheral neuropathyb
62 (63)
7 (7)
78 (76)
9 (9)
   Cough
53 (54)
0
31 (30)
0
   Nausea
52 (53)
2 (2)
51 (50)
1 (1)
   Constipation
51 (52)
2 (2)
42 (41)
1 (1)
   Pyrexia
48 (48)
3 (3)
33 (32)
3 (3)
   Insomnia
45 (45)
2 (2)
31 (30)
1 (1)
   Back pain
41 (41)
2 (2)
36 (35)
3 (3)
   Arthralgia
39 (39)
1 (1)
38 (37)
2 (2)
   Peripheral edema
36 (36)
2 (2)
37 (36)
3 (3)
   Headache
33 (33)
5 (5)
24 (24)
1 (1)
   Vomiting
32 (32)
3 (3)
29 (28)
0
   Muscle spasms
30 (30)
2 (2)
20 (20)
1 (1)
   Dyspnea
24 (24)
2 (2)
31 (30)
5 (5)
IRRc
49 (49)
7 (7)
-
-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse events; VRd, bortezomib + lenalidomide + dexamethasone.
aAny grade TEAEs occurring in ≥30% of patients in either group are listed. The safety analysis population included all randomized patients who received ≥1 dose of the study treatment; analysis was according to treatment received.
bPeripheral neuropathy includes the preferred terms of peripheral neuropathy and peripheral sensory neuropathy. cThere were no grade 4 or 5 IRRs.

Final Analysis in Clinically Relevant Subgroups

Chari et al (2024)9,10 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study at a median follow-up duration of 49.6 months.

Safety Results

  • A summary of the most common (>30%) TEAEs in the safety analysis population separated by age <65 years and ≥65 years is provided in Table: Most Common (>30%) Any Grade TEAEs by Age (<65 Years and ≥65 Years).
  • Among patients aged <65 years (84.7% vs 80.0%) and ≥65 years (88.9% vs 77.8%), the rates of grade 3/4 TEAEs were slightly higher for D-VRd vs VRd.
  • The incidence of serious TEAEs was lower in D-VRd vs VRd among patients <65 years, 41.7% vs 56.0% respectively.
  • The incidence of serious TEAEs was higher in the D-VRd vs VRd among patients ≥65 years, 59.3% vs 40.7% respectively.
  • Two deaths due to TEAE occurred and were considered unrelated to study treatment.
    • <65 years (VRd, n=1; cause unknown)
    • ≥65 years (D-VRd, n=1; pneumonia)

Most Common (>30%)a Any Grade TEAEs by Age (<65 Years and ≥65 Years)9
Most common TEAEs, n (%)
<65 Years
≥65 Years
D-VRd
(n=72)
VRd
(n=75)
D-VRd
(n=27)
VRd
(n=27)
Hematologic
   Neutropenia
47 (65.3)
29 (38.7)
16 (59.3)
12 (44.4)
   Thrombocytopenia
 30 (41.7)
24 (32.0)
14 (51.9)
12 (44.4)
   Leukopenia
29 (40.3)
21 (28.0)
10 (37.0)
9 (33.3)
   Anemia
25 (34.7)
25 (33.3)
12 (44.4)
8 (29.6)
   Lymphopenia
23 (31.9)
23 (30.7)
8 (29.6)
6 (22.2)
Nonhematologic
   Upper respiratory tract
   infection
51 (70.8)
37 (49.3)
16 (59.3)
14 (51.9)
Diarrhea
48 (66.7)
39 (52.0)
18 (66.7)
17 (63.0)
Fatigue
48 (66.7)
45 (60.0)
23 (85.2)
18 (66.7)
Peripheral neuropathyb
41 (56.9)
56 (74.7)
21 (77.8)
22 (81.5)
Nausea
38 (52.8)
37 (49.3)
14 (51.9)
14 (51.9)
Constipation
37 (51.4)
29 (38.7)
14 (51.9)
13 (48.1)
Insomnia
36 (50.0)
25 (33.3)
9 (33.3)
6 (22.2)
Cough
35 (48.6)
26 (34.7)
18 (66.7
5 (18.5)
Pyrexia
34 (47.2)
27 (36.0)
14 (51.9)
6 (22.2)
Back pain
30 (41.7
29 (38.7)
11 (40.7)
7 (25.9)
Arthralgia
27 (37.5)
26 (34.7)
12 (44.4)
12 (44.4)
Headache
27 (37.5)
18 (24.0)
6 (22.2)
6 (22.2)
Muscle spasms
26 (36.1)
11 (14.7)
4 (14.8)
9 (33.3)
Vomiting
25 (34.7)
21 (28.0)
7 (25.9)
8 (29.6)
Peripheral edema
24 (33.3)
25 (33.3)
12 (44.4)
12 (44.4)
Hypokalemia
19 (26.4)
20 (26.7
9 (33.3)
7 (25.9)
Pain in extremity
19 (26.4)
13 (17.3)
3 (11.1)
9 (33.3)
Dyspnea
14 (19.4)
24 (32.0)
10 (37.0)
7 (25.9)
Dizziness
15 (20.8)
16 (21.3)
8 (29.6)
9 (33.3)
Pneumonia
14 (19.4)
16 (21.3)
10 (37.0)
2 (7.4)
Dysgeusia
14 (19.4)
14 (18.7)
9 (33.3)
5 (18.5)
Abbreviations: D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; VRd, lenalidomide + bortezomib + dexamethasone.
aIncludes TEAEs occurring in ≥30% of patients aged <65 years or ≥65 years in either treatment group from the safety analysis population (all randomized patients who received ≥1 dose of study treatment).
bIncludes preferred terms neuropathy peripheral and peripheral sensory neuropathy.

clinical data - newly diagnosed multiple myeloma Transplant-INELIGIBLE

Combination Treatment with Lenalidomide and Dexamethasone

MAIA (MMY3008; NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for HDT and ASCT (N=737).11,25,26 Facon et al (2019)11 presented the pre-specified interim results of this ongoing study with a median follow-up of 28.0 months including updated overall survival (OS) results (median follow-up, 73.6 months). Facon et al (2025)26 reported the updated efficacy and safety results at a long-term median follow-up of 64.5 months. Facon et al (2024)12 presented the results of the updated efficacy and safety analysis at a median follow-up of 89.3 months (range, 0-102.2).

Safety Results


Most Common AEs and Second Primary Cancers in the Safety Population (Prespecified Interim Results; MAIA)a,11
Event, n (%)
D-Rd (n=364)
Rd (n=365)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
207 (56.9)
182 (50)
154 (42.2)
129 (35.3)
   Anemia
126 (34.6)
43 (11.8)
138 (37.8)
72 (19.7)
   Leukopenia
68 (18.7)
40 (11)
34 (9.3)
18 (4.9)
   Lymphopenia
66 (18.1)
55 (15.1)
45 (12.3)
39 (10.7)
Non-hematologic
   Infections
314 (86.3)
117 (32.1)
268 (73.4)
85 (23.3)
   Pneumonia
82 (22.5)
50 (13.7)
46 (12.6)
29 (7.9)
   Diarrhea
207 (56.9)
24 (6.6)
168 (46)
15 (4.1)
   Constipation
149 (40.9)
6 (1.6)
130 (35.6)
1 (0.3)
   Fatigue
147 (40.4)
29 (8)
104 (28.5)
14 (3.8)
   Peripheral edema
140 (38.5)
7 (1.9)
107 (29.3)
2 (0.5)
   Back pain
123 (33.8)
11 (3)
96 (26.3)
11 (3)
   Asthenia
117 (32.1)
16 (4.4)
90 (24.7)
13 (3.6)
   Nausea
115 (31.6)
5 (1.4)
84 (23)
2 (0.5)
Second primary cancerb
32 (8.8)
NA
26 (7.1)
NA
   Invasive second primary cancer
12 (3.3)
NA
13 (3.6)
NA
Any IRR
149 (40.9)
10 (2.7)
NA
NA
Abbreviations: AE, adverse event; D-Rd, DARZALEX + lenalidomide + dexamethasone; IRR, infusion-related reaction; NA, not applicable; Rd, lenalidomide + dexamethasone.
aThe safety population included all patients who received at least 1 dose of the trial treatment. AEs of any grade that were reported in >30% of patients in either treatment arm and grade 3/4 AEs that were reported in >10% of patients in either treatment arm are listed.
bThe presence of a second primary cancer was prespecified in the statistical analysis plan as an AE of clinical interest.

Updated Analysis of the MAIA Study

Facon et al (2025)26 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months.

Safety Results

  • At clinical cutoff, 52 patients from the D-Rd arm discontinued lenalidomide ± dexamethasone but remained on the rest of the study treatment; 46 (88.5%) of these patients discontinued due to AEs.26
    • The median time to lenalidomide discontinuation was 37.8 months (range, 1-70).
    • The median duration of DARZALEX treatment was 66.2 months (range, 56-77).
    • The estimated 60-month PFS and OS rates were 98.1% and 100.0%, respectively.
    • Of the aforementioned 52 patients, 13 (25.0%) discontinued lenalidomide but continued DARZALEX + dexamethasone and 39 (75.0%) discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy.
      • In the 39 patients who discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy, the median time to discontinuation was 39.1 months (range, 3-67) and the median DARZALEX treatment duration was 65.6 months (range, 56-73). The estimated 60-month PFS and OS rates were 97.4% and 100.0%, respectively.
      • One patient in the D-Rd arm stopped DARZALEX after 15 days due to AEs but continued lenalidomide treatment without progression at the clinical cutoff.
  • No new safety concerns were observed with a longer follow-up.26
    • Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively.
    • Grade 3/4 infections occurred in 42.6% vs 29.6% of patients from the D-Rd vs Rd arm, respectively.
    • Serious TEAEs occurred in 78.8% vs 71.0% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (18.7% vs 10.7%, respectively).
      • Among patients aged ≥75 years, serious TEAEs occurred in 80.9% vs 79.2% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (19.7% vs 12.6%, respectively).
      • Among patients aged ≥80 years, serious TEAEs occurred in 81.5% vs 82.9% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (24.6% vs 8.6%, respectively).
    • The overall discontinuation rate due to TEAEs was lower in the D-Rd vs Rd arm (14.6% vs 23.8%).
      • Discontinuation of lenalidomide due to TEAEs was reported in 36.8% vs 24.4% of patients from the D-Rd vs Rd arm, respectively.
      • Discontinuation of dexamethasone due to TEAEs was reported in 39.8% vs 36.2% of patients from the D-Rd vs Rd arm, respectively.
      • Discontinuation of DARZALEX due to TEAEs was reported in 14.6% of patients.
      • Among patients aged ≥75 years, treatment discontinuation due to TEAEs was reported in 15.3% vs 27.7% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥80 years, treatment discontinuation due to TEAEs was reported in 6.2% vs 20.0% of patients from the D-Rd vs Rd arm, respectively.
    • TEAEs leading to death were reported in 9.9% vs 9.3% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥75 years, TEAEs leading to death were reported in 11.5% vs 13.2% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥80 years, TEAEs leading to death were reported in 12.3% vs 11.4% of patients from the D-Rd vs Rd arm, respectively.

Most Common Any-Grade or Grade 3/4 TEAEs in the Safety Populationa,26
TEAE, n (%)
D-Rd (n=364)
Rd (n=365)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
224 (61.5)
197 (54.1)
166 (45.5)
135 (37.0)
   Anemia
154 (42.3)
62 (17.0)
150 (41.1)
79 (21.6)
Nonhematologic
   Diarrhea
240 (65.9)
33 (9.1)
188 (51.5)
22 (6.0)
   Fatigue
164 (45.1)
33 (9.1)
114 (31.2)
17 (4.7)
   Constipation
157 (43.1)
6 (1.6)
137 (37.5)
2 (0.5)
   Peripheral edema
155 (42.6)
10 (2.7)
117 (32.1)
3 (0.8)
   Back pain
155 (42.6)
14 (3.8)
109 (29.9)
14 (3.8)
   Asthenia
136 (37.4)
19 (5.2)
101 (27.7)
18 (4.9)
   Nausea
133 (36.5)
7 (1.9)
88 (24.1)
2 (0.5)
   Insomnia
125 (34.3)
11 (3.0)
116 (31.8)
14 (3.8)
   Bronchitis
124 (34.1)
12 (3.3)
87 (23.8)
7 (1.9)
   Cough
123 (33.8)
2 (0.5)
65 (17.8)
0 (0.0)
   Dyspnea
119 (32.7)
12 (3.3)
63 (17.3)
4 (1.1)
   Pneumonia
113 (31.0)
71 (19.5)
66 (18.1)
39 (10.7)
   Weight decreased
112 (30.8)
10 (2.7)
69 (18.9)
11 (3.0)
   Peripheral sensory neuropathy
111 (30.5)
9 (2.5)
66 (18.1)
2 (0.5)
   Muscle spasms
111 (30.5)
2 (0.5)
86 (23.6)
5 (1.4)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
aAny-grade TEAEs that are listed are those that occurred in ≥30% of patients in either group.

Most Common Any-Grade or Grade 3/4 TEAEs Among Patients Aged ≥75 Years and ≥80 Years in the Safety Populationa,27
TEAE, n (%)
Patients Aged ≥75 Years
Patients Aged ≥80 Years
D-Rd (n=157)
Rd (n=159)
D-Rd (n=65)
Rd (n=70)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
109 (69.4)
98
(62.4)
81
(50.9)
66
(41.5)
45
(69.2)
37
(56.9)
34
(48.6)
26
(37.1)
   Anemia
71 (45.2)
32 (20.4)
73 (45.9)
40 (25.2)
31 (47.7)
12 (18.5)
35 (50.0)
19 (27.1)
   Thrombocytopenia
39 (24.8)
16 (10.2)
43 (27.0)
19 (11.9)
21 (32.3)
7 (10.8)
20 (28.6)
8 (11.4)
   Lymphopenia
37 (23.6)
33 (21.0)
25 (15.7)
20 (12.6)
10 (15.4)
8 (12.3)
13 (18.6)
10 (14.3)
Nonhematologic
   Diarrhea
98 (62.4)
16 (10.2)
80 (50.3)
8 (5.0)
37 (56.9)
5 (7.7)
35 (50.0)
3 (4.3)
   Peripheral edema
76 (48.4)
6 (3.8)
53 (33.3)
2 (1.3)
31 (47.7)
0 (0.0)
24 (34.3)
2 (2.9)
   Constipation
75 (47.8)
2 (1.3)
61 (38.4)
1 (0.6)
27 (41.5)
0 (0.0)
27 (38.6)
1 (1.4)
   Fatigue
73 (46.5)
15 (9.6)
48 (30.2)
8 (5.0)
26 (40.0)
7 (10.8)
19 (27.1)
3 (4.3)
   Back pain
65 (41.4)
7 (4.5)
53 (33.3)
6 (3.8)
24 (36.9)
2 (3.1)
21 (30.0)
2 (2.9)
   Asthenia
58 (36.9)
8 (5.1)
43 (27.0)
10 (6.3)
25 (38.5)
3 (4.6)
26 (37.1)
8 (11.4)
   Weight decreased
49 (31.2)
6 (3.8)
31 (19.5)
5 (3.1)
19 (29.2)
2 (3.1)
16 (22.9)
2 (2.9)
   Bronchitis
48 (30.6)
7 (4.5)
31 (19.5)
4 (2.5)
18 (27.7)
2 (3.1)
15 (21.4)
1 (1.4)
   Nausea
48 (30.6)
2 (1.3)
40 (25.2)
0 (0.0)
21 (32.3)
1 (1.5)
20 (28.6)
0 (0.0)
   Pneumonia
44 (28.0)
32 (20.4)
33 (20.8)
23 (14.5)
22 (33.8)
17 (26.2)
13 (18.6)
8 (11.4)
   Pyrexia
44 (28.0)
6 (3.8)
22 (13.8)
3 (1.9)
20 (30.8)
4 (6.2)
7 (10.0)
0 (0.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
aAny-grade TEAEs that are listed are those that occurred in ≥30% of patients in either group.

Final Survival Analysis of the MAIA Study

Facon et al (2024)12 presented the results of the updated efficacy and safety analysis of the MAIA study at a median follow-up of 89.3 months (range, 0-102.2).

Safety and Tolerability Results

  • Among the safety population, 78.3% (n=285) of patients in the D-Rd arm and 94.5% (n=345) in the Rd arm discontinued study treatment.
    • Progressive disease was the primary reason for discontinuation in both the D-Rd (32.7%) and Rd arms (38.6%).
    • A lower proportion of patients in the D-Rd (16.5%) and Rd arms (25.8%) discontinued study treatment due to AEs.
  • In the D-Rd vs Rd arm, 33% reduction in the risk of death was reported.

Summary of Death and Causes of Death in the Safety Populationa,12
n (%)
D-Rd
(n=364)
Rd
(n=365)
Total number of patients who died during the study
173 (47.5)
218 (59.7)
   Primary cause of death
      Disease progression
76 (20.9)
88 (24.1)
      Adverse events
44 (12.1)
40 (11.0)
         Related to study treatmentb
14 (3.8)
10 (2.7)
         Unrelated to study treatment
28 (7.7)
29 (7.9)
         Othersc
53 (14.6)
90 (24.7)
         Infections/infestations
9 (2.5)
30 (8.2)
         General disorders/administration site conditionsd
11 (3.0)
5 (1.4)
         Neoplasms (benign, malignant, or unspecified)
11 (3.0)
4 (1.1)
         Cardiac disorders
1 (0.3)
8 (2.2)
         Nervous system disorders
3 (0.8)
5 (1.4)
         Unknown
13 (3.6)
27 (7.4)
Deaths within 30 days of the last study treatment dose
31 (8.5)
35 (9.6)
   Primary cause of death
      Disease progression
1 (0.3)
1 (0.3)
      Adverse events
29 (8.0)
32 (8.8)
         Related to study treatmentb
11 (3.0)
10 (2.7)
         Unrelated to study treatment
18 (4.9)
22 (6.0)
         Othere
1 (0.3)
2 (0.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide/dexamethasone.
aThe safety population included all randomized patients who received ≥1 dose of study treatment.
bAdverse events were related to ≥1 of the 3 components of study treatment: DARZALEX, lenalidomide, and dexamethasone.
cOther reasons were reported in ≥1% of patients in either treatment group.
dAll events were related to the general health condition of the patient.
eIncludes a nervous system disorder in 1 patient in the D-Rd group and a blood and lymphatic system disorder and general disorder/administration site condition in 1 patient each in the Rd group.

Combination Treatment with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; NCT02195479) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the safety and efficacy of DARZALEX when administered in combination with bortezomib, melphalan, and prednisone (D-VMP) compared with administration of VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.13,28 Mateos et al (2018)13 reported results of a planned interim analysis of this study with a median follow-up of 16.5 months. Mateos et al (2025)29 reported the final efficacy and safety analysis results at a median follow-up of 86.7 months.

Safety Results

  • Summary of on-treatment AEs (median follow-up, 16.5 months) are summarized in Table: Most Common Any Grade (≥20%) and Grade 3/4 (≥10%) On-Treatment AEs (Safety Population; Planned Interim Analysis in ALCYONE).
  • Grade 3/4 infections were more frequent in the D-VMP arm than in the VMP arm (23.1% vs 14.7%), with pneumonia being the most common grade 3/4 infection (11.3% vs 4.0%). In the D-VMP and VMP arms, respectively:
    • Infections, including pneumonia, resolved in 87.9% and 86.5% of patients.
    • Rates of treatment discontinuation because of infections were 0.9% and 1.4%.
    • Infection-related deaths occurred in 5 (1.4%) patients and 4 (1.1%) patients.
  • Rates of SAEs were 41.6% in the D-VMP arm and in 32.5% in the VMP arm, with pneumonia being the most common SAE (10.1% and 3.1%, respectively).
  • Tumor lysis syndrome occurred in 2 (0.6%) patients in each treatment arm.
  • Second primary malignancy occurred in 8 (2.3%) patients in the D-VMP arm and in 9 (2.5%) in the VMP arm.
  • Fatal AEs within a month after the last study treatment occurred in 14 (4.0%) patients in the D-VMP arm and in 16 (4.5%) in the VMP arm.

Most Common On-Treatment AEs of Any Grade and Grade 3/4 (Safety Population; Planned Interim Analysis in ALCYONE)13
Event, n (%)
D-VMP
(n=346)
VMP
(n=354)
Any Gradea
Grade 3/4b
Any Gradea
Grade 3/4b
Hematologic
   Neutropenia
172 (49.7)
138 (39.9)
186 (52.5)
137 (38.7)
   Thrombocytopenia
169 (48.8)
119 (34.4)
190 (53.7)
133 (37.6)
   Anemia
97 (28)
55 (15.9)
133 (37.6)
70 (19.8)
Non-hematologic
   Infections
231 (66.8)
80 (23.1)
170 (48)
52 (14.7)
      Upper respiratory tract infection
91 (26.3)
7 (2)
49 (13.8)
5 (1.4)
      Pneumonia
53 (15.3)
39 (11.3)
17 (4.8)
14 (4)
   Peripheral sensory neuropathy
98 (28.3)
5 (1.4)
121 (34.2)
14 (4)
   Diarrhea
82 (23.7)
9 (2.6)
87 (24.6)
11 (3.1)
   Pyrexia
80 (23.1)
2 (0.6)
74 (20.9)
2 (0.6)
   Nausea
72 (20.8)
3 (0.9)
76 (21.5)
4 (1.1)
Any IRR
96 (27.7)
15 (14.3)
NA
NA
Abbreviations: AE, adverse event; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; IRR, infusion-related reaction; NA, not applicable; VMP, bortezomib + melphalan + prednisone.
aReported in ≥20% of patients in either treatment arm.
aReported in ≥10% of patients in either treatment arm.

Final Analysis of the ALCYONE Study

Mateos et al (2025)29 reported the final efficacy and safety analysis results at a median follow-up of 86.7 months.

Safety Results

  • No new safety concerns were identified with a longer follow-up.29 
  • TEAEs were experienced by 98% of patients in the D-VMP group and 97% of patients in the VMP group. The most common TEAEs are summarized in Table: Summary of the Most Common TEAEs.29
    • Grade 3 or 4 TEAEs occurred in 83% of patients receiving D-VMP and 77% of patients receiving VMP.29
    • The most common grade 3 or 4 infection in both treatment groups was pneumonia (D-VMP, 16%; VMP, 5%).29
    • Infusion-related reactions (IRRs) of any grade were reported in 29% of patients in the D-VMP group, including a grade 3 reaction in 4% and a grade 4 reaction in 1% of patients.29
      • In the D-VMP group, IRRs of any grade, grade 3 and serious TEAE were reported in <1% of patients.30
      • No IRR of any grade was reported in the VMP group.30
    • The D-VMP group experienced a higher rate of serious TEAEs compared to the VMP group (21% vs 16%). The most common serious TEAE observed in D-VMP vs VMP group was pneumonia (5% vs 2%).29
  • The rate of treatment discontinuation due to TEAEs was 9% in both the D-VMP and VMP groups. TEAEs in both groups are detailed in Table: Summary of Treatment Discontinuation Due to TEAEs.29,30

Summary of the Most Common TEAEs29
Event, n (%)
D-VMP
(n=346)
VMP
(n=354)
Any Gradea
Grade 1-2
Grade
3
Grade
4
Grade
5
Any Gradea
Grade
1-2
Grade
3
Grade
4
Grade
5
Any TEAEs
338
(98)
47
(14)
184
(53)
77
(22)
30
(9)
342 (97)
65
(18)
180
(51)
77
(22)
20
(6)
Hematologic AE
   Neutropenia
175
(51)
35
(10)
107
(31)
33
(10)
0
186
(53)
48
(14)
103
(29)
35
(10)
0
   Thrombocytopenia
173
(50)
53
(15)
83
(24)
37
(11)
0
190
(54)
56
(16)
83
(23)
51
(14)
0
   Anemia
112
(32)
49
(14)
61
(18)
2
(1)
0
131
(37)
61
(17)
68
(19)
2
(1)
0
Nonhematological AE
   Peripheral sensory
   neuropathy
100
(29)
95
(27)
4
(1)
1
(<1)
0
122
(34)
108
(31)
14
(4)
0
0
   Diarrhea
101
(29)
92
(27)
9
(3)
0
0
87
(25)
76
(21)
11
(3)
0
0
   Pyrexia
89
(26)
87
(25)
2
(1)
0
0
74
(21)
72
(20)
2
(1)
0
0
   Nausea
76
(22)
73
(21)
3
(1)
0
0
76
(21)
72
(20)
4
(1)
0
0
   Back pain
73
(21)
65
(19)
8
(2)
0
0
42
(12)
38
(11)
4
(1)
0
0
   Cough
71
(21)
70
(20)
1
(<1)
0
0
27
(8)
26
(7)
1
(<1)
0
0
   Upper respiratory
   tract infection
107
(31)
99
(29)
7
(2)
0
1
(<1)
50
(14)
44
(12)
6
(2)
0
0
   Bronchitis
77
(22)
66
(19)
11
(3)
0
0
27
(8)
24
(7)
3
(1)
0
0
   Pneumonia
78
(23)
19
(5)
53
(15)
4
(1)
2
(1)
 19
(5)
3
(1)
15
(4)
1
(<1)
0
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone; AE, adverse event.
aPreferred terms for any grade of TEAEs with an occurrence of ≥20% are reported.

Summary of Treatment Discontinuation Due to TEAEs29,30
TEAEs
D-VMP
n=346
VMP
n=354
Patients with TEAEs leading to treatment discontinuation, n (%)
31 (9)
33 (9)
TEAEs leading to treatment discontinuationa, n (%)
   Pneumonia
4 (1)
1 (<1)
   Upper respiratory tract infection
2 (1)
0
   Acute respiratory failure
2 (1)
0
   Fatigue
1 (<1)
2 (1)
   Peripheral sensory neuropathy
0
6 (2)
   Neuralgia
0
2 (1)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intent to treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone; TEAE, treatment-related adverse event.
aTEAEs leading to treatment discontinuation in at least 2 patients in either treatment group are reported.
  • The incidence of second primary malignancies in the D-VMP vs VMP group was 8% vs 6%, respectively.29
    • The most frequently reported second primary malignancies in the D-VMP vs VMP group were basal cell carcinoma (1.2% vs 0.6%, respectively) and myelodysplastic syndrome (1.2% vs 0.6%, respectively).29,30
  • Deaths due to an adverse event considered related to at least 1 of 4 study treatment components occurred in 5 (1%) of 346 D-VMP patients (due to pneumonia, acute myocardial infarction, neuroendocrine tumor, tumor lysis syndrome, and acute respiratory failure [1 each]) and in 3 (1%) of 354 VMP patients (due to acute myeloid leukemia, pulmonary embolism, and bacterial pneumonia [1 each]).29

clinical data in Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

POLLUX (MMY3003; NCT02076009) is a phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the safety and efficacy of DRd compared with administration of Rd alone in patients with RRMM (N=569).16 Dimopoulos et al (2016)16 reported safety and efficacy results of a prespecified interim analysis of this study (median follow-up, 13.5 months). Dimopoulos et al (2023)31 reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months.

Safety Results

  • After a median follow-up of 13.5 months:
    • Any grade infusion reactions were reported in 49% of patients who received DARZALEX. Infusion reactions were mostly grade 1/2 (grade 3 were observed in 5% of patients) and most (92%) occurred during the first infusion. No grade 4 infusion reactions were reported.
    • SAEs were reported in 49% and 42% of patients in the DARZALEX + Rd and Rd arms, respectively.
    • AEs leading to discontinuation were reported in 7% of patients who received D-Rd and 8% in patients who received Rd. The most common of these across both arms were pneumonia, pulmonary embolism, and deterioration of general physical health.
    • AEs leading to death [most commonly (≤1%) acute kidney injury, septic shock, and pneumonia] occurred in 11 (4%) patients in the D-Rd arm and 15 (5%) patients in the Rd arm.

>Six-year Follow-up Update on Safety and Efficacy Outcomes

Dimopoulos et al (2023)31 reported results of the POLLUX study, including OS, at a median follow-up of 79.7 months. Safety results from this updated analysis are summarized below.

Safety Results


Most common (>15% of Patients) and Grade 3/4 (>5% of Patients) TEAEs in the Safety Population (Updated Analysis of POLLUX)31
TEAE, %
All Grades
Grade 3/4
D-Rd
(n=283)
Rd
(n=281)
D-Rd
(n=283)
Rd
(n=281)
Hematologic
   Neutropenia
185 (65.4)
136 (48.4)
163 (57.6)
117 (41.6)
   Anemia
121 (42.8)
117 (41.6)
56 (19.8)
63 (22.4)
   Thrombocytopenia
93 (32.9)
90 (32.0)
44 (15.5)
44 (15.7)
   Lymphopenia
20 (7.1)
17 (6.0)
17 (6.0)
12 (4.3)
   Febrile neutropenia
18 (6.4)
8 (2.8)
18 (6.4)
8 (2.8)
Non-hematologic
   Diarrhea
170 (60.1)
108 (38.4)
29 (10.2)
11 (3.9)
   URTI
125 (44.2)
79 (28.1)
6 (2.1)
5 (1.8)
   Fatigue
119 (42.0)
87 (31.0)
20 (7.1)
12 (4.3)
   Cough
107 (37.8)
43 (15.3)
1 (0.4)
0
   Nasopharyngitis
100 (35.3)
62 (22.1)
0
0
   Constipation
95 (33.6)
77 (27.4)
4 (1.4)
2 (0.7)
   Muscle spasms
87 (30.7)
61 (21.7)
3 (1.1)
5 (1.8)
   Nausea
87 (30.7)
53 (18.9)
6 (2.1)
2 (0.7)
   Insomnia
80 (28.3)
65 (23.1)
6 (2.1)
6 (2.1)
   Pneumonia
80 (28.3)
49 (17.4)
49 (17.3)
31 (11.0)
   Back pain
77 (27.2)
59 (21.0)
10 (3.5)
5 (1.8)
   Pyrexia
77 (27.2)
41 (14.6)
9 (3.2)
7 (2.5)
   Arthralgia
75 (26.5)
56 (19.9)
4 (1.4)
4 (1.4)
   Peripheral edema
72 (25.4)
50 (17.8)
3 (1.1)
4 (1.4)
   Dyspnea
67 (23.7)
39 (13.9)
15 (5.3)
2 (0.7)
   Vomiting
66 (23.3)
20 (7.1)
3 (1.1)
4 (1.4)
   Bronchitis
63 (22.3)
50 (17.8)
9 (3.2)
9 (3.2)
   Cataract
61 (21.6)
35 (12.5)
21 (7.4)
13 (4.6)
   Asthenia
59 (20.8)
47 (16.7)
10 (3.5)
9 (3.2)
   Hypokalemia
58 (20.5)
35 (12.5)
19 (6.7)
12 (4.3)
   Headache
57 (20.1)
23 (8.2)
0
0
   Rash
51 (18.0)
36 (12.8)
1 (0.4)
0
   Decreased appetite
50 (17.7)
37 (13.2)
6 (2.1)
1 (0.4)
   Pain in extremity
48 (17.0)
42 (14.9)
0
1 (0.4)
   Influenza
46 (16.3)
24 (8.5)
11 (3.9)
3 (1.1)
   Hypophosphatemia
22 (7.8)
14 (5.0)
16 (5.7)
8 (2.8)
   Syncope
16 (5.7)
4 (1.4)
15 (5.3)
4 (1.4)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE,
treatment-emergent adverse event; URTI, upper respiratory infection.

Serious TEAEs and TEAEs Leading to Treatment Discontinuation or Deaths (Updated Analysis of POLLUX)31
TEAEs
D-Rd
(n=283)
Rd
(n=281)
Serious TEAEs, %
72.4
52.7
   Pneumonia
17.0
11.4
TEAEs leading to treatment discontinuation, %
19.1
16.0
   Infections, n (%)
13 (4.6)
11 (3.9)
TEAEs leading to death, n (%)
35 (12.4)
24 (8.5)
   Septic shock, %
1.4
0.4
   Cardiac arrest, %
1.1
0.4
   Sudden death, %
1.1
0.4
   Pneumonia, %
0.7
1.1
   Acute kidney injury, %
0.4
1.1
   Sepsis, %
0
1.1
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE,
treatment-emergent adverse event.

Combination Treatment with Bortezomib and Dexamethasone

CASTOR (MMY3004; NCT02136134) is an open-label, randomized, multicenter, active-controlled, phase 3 study which evaluated the safety and efficacy of Vd alone compared to D-Vd in patients with RRMM (N=498). Palumbo et al (2016)18 reported prespecified interim results from this study at a median follow-up of 7.4 months. Sonneveld et al (2023)32 reported updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months.

Safety Results

  • At a median follow-up of 7.4 months, overall grade 3/4 AEs were experienced more frequently in the D-Vd arm vs the Vd arm (76% vs 62%, respectively).
  • IRRs occurred in 45% of patients in the D-Vd arm:
    • IRRs were mostly grade 1/2. No grade 4 reactions were reported.
    • 98% of patients with IRRs experienced the events with the first infusion.
    • Two patients discontinued treatment due to IRRs (bronchospasm in 1 patient; bronchospasm, laryngeal edema, and skin rash in the other patient).
  • Treatment was discontinued due to AEs in 7% of D-Vd patients and 9% in Vd patients. The most common AEs (>1% in either arm) leading to discontinuation were peripheral sensory neuropathy and pneumonia.
  • A total of 13 (5%) patients in the D-Vd arm and 14 (6%) patients in the Vd arm experienced an AE leading to death.

>Six-year Follow-up Update on Safety and Efficacy Outcomes in CASTOR

Sonneveld et al (2023)32 presented updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months. Safety results from this updated analysis are summarized below.

Safety Results

  • Summary of TEAEs (median follow-up, 72.6 months) are presented in Table: Most common (>15% of patients) and Grade 3/4 TEAEs (>5% of patients) in the Safety Population (Updated Analysis of CASTOR).
  • Grade 3/4 infections were reported in 72 (29.6%) patients vs 45 (19%) patients in the D-Vd vs Vd arms, respectively.
  • TEAEs leading to treatment discontinuations were reported in 10.7% vs 9.3% in the D-Vd vs Vd arms, respectively.
  • Deaths due to TEAEs were reported in 17 (7%) patients vs 14 (5.9%) patients in the D-Vd vs Vd arms, respectively.
    • The most frequent TEAEs leading to death were pneumonia (0.8% in both arms) and general physical health deterioration (D-Vd, 0.4%; Vd, 1.3%).
    • Three patients (D-Vd, n=1; Vd, n=2) died during the study due to COVID-19 disease.
  • With extended follow-up, second primary malignancies (cutaneous, invasive, and hematologic) were reported in 20 (8.2%) vs 5 (2.2%) patients in the D-Vd vs Vd arm, respectively.

Most common (>15% of Patients) and Grade 3/4 TEAEs (>5% of Patients) in the Safety Population (Updated Analysis of CASTOR)32
TEAE, %
All Grades
Grade 3/4
D-Vd
(n=243)
Vd
(n=237)
D-Vd
(n=243)
Vd
(n=237)
Hematologic
   Thrombocytopenia
145 (59.7)
105 (44.3)
112 (46.1)
78 (32.9)
   Anemia
73 (30.0)
75 (31.6)
39 (16.0)
38 (16.0)
   Neutropenia
48 (19.8)
23 (9.7)
33 (13.6)
11 (4.6)
   Lymphopenia
33 (13.6)
9 (3.8)
25 (10.3)
6 (2.5)
Non-hematologic
   Peripheral sensory neuropathy
122 (50.2)
90 (38.0)
11 (4.5)
16 (6.8)
   Upper respiratory tract infection
90 (37.0)
43 (18.1)
6 (2.5)
1 (0.4)
   Diarrhea
88 (36.2)
53 (22.4)
10 (4.1)
3 (1.3)
   Cough
71 (29.2)
30 (12.7)
0 (0)
0 (0)
   Fatigue
57 (23.5)
58 (24.5)
13 (5.3)
8 (3.4)
   Constipation
56 (23.0)
38 (16.0)
0 (0)
2 (0.8)
   Back pain
54 (22.2)
24 (10.1)
6 (2.5)
3 (1.3)
   Arthralgia
49 (20.2)
14 (5.9)
4 (1.6)
0 (0)
   Peripheral edema
48 (19.8)
20 (8.4)
1 (0.4)
0 (0)
   Dyspnea
47 (19.3)
21 (8.9)
10 (4.1)
2 (0.8)
   Pyrexia
46 (18.9)
28 (11.8)
5 (2.1)
3 (1.3)
   Insomnia
44 (18.1)
36 (15.2)
2 (0.8)
3 (1.3)
   Pneumonia
40 (16.5)
32 (13.5)
26 (10.7)
24 (10.1)
   Bronchitis
38 (15.6)
15 (6.3)
7 (2.9)
3 (1.3)
   Nausea
37 (15.2)
27 (11.4)
2 (0.8)
0
   Hypertension
30 (12.3)
8 (3.4)
18 (7.4)
2 (0.8)
   Asthenia
27 (11.1)
37 (15.6)
2 (0.8)
5 (2.1)
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; Vd,
bortezomib + dexamethasone.

Combination Treatment with Carfilzomib and Dexamethasone

CANDOR (NCT03158688) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.19 Dimopoulos et al (2020)15 reported the primary results at a median follow-up of approximately 17 months. Usmani et al (2023)33 reported the final efficacy and safety results after a median follow-up for approximately 50 months.

Safety Results


Treatment-Emergent Adverse Events (CANDOR)15
AEs, n (%)
D-Kd (n=308)
Kd (n=153)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
TEAEs
306 (99)
147 (96)
Hematologica
   Thrombocytopenia
115 (37)
49 (16)
26 (8)
45 (29)
19 (12)
6 (4)
   Anemia
101 (33)
48 (16)
3 (1)
48 (31)
21 (14)
1(1)
   Neutropenia
43 (14)
24 (8)
2 (1)
15 (10)
7 (5)
2 (1)
   Lymphopenia
27 (9)
9 (3)
12 (4)
12 (8)
9 (6)
2(1)
Non-hematologica
   Diarrhea
97 (31)
12 (4)
0
22 (14)
1 (1)
0
   Hypertension
94 (31)
54 (18)
0
42 (27)
20 (13)
0
   URTI
90 (29)
7 (2)
1 (<1)
35 (23)
2 (1)
0
   Fatigue
75 (24)
23 (7)
1(<1)
28 (18)
7 (5)
0
   Dyspnea
61 (20)
12 (4)
0
34 (22)
4 (3)
0
   Pneumonia
55 (18)
32 (10)
5 (2)
19 (12)
12(8)
1 (1)
Serious
173 (56)
70 (46)
Leading to treatment discontinuation
69 (22)
38 (25)
Leading to treatment dose reduction
119 (39)
53 (35)
Abbreviations: AE, adverse event; D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.
aHematologic and non-hematologic AEs of all grades were reported for those that occurred in ≥20% of patients in either arm. Grade ≥3 events reported for those that occurred in >5% of patients in either arm.

AEs of Interest in CANDOR Study15
AEs, n (%)
D-Kd (n=308)
Kd (n=153)
All Grades
Grade 3
(≥5%)
Grade 4
(≥5%)
All Grades
Grade 3
(≥5%)
Grade 4
(≥5%)
Acute renal failure
18 (5.8)
5 (2)
4 (1)
12 (8)
6(4)
4 (3)
Cardiac failurea
23 (7)
9 (3)
1 (<1)
16 (10)
10 (7)
3 (2)
Ischemic heart disease
13 (4)
7 (2)
2 (1)
5 (3)
4 (3)
0
Respiratory tract infection
225 (73)
77 (25)
7 (2)
84 (55)
22 (14)
1 (1)
Peripheral neuropathy
53 (17)
3 (1)
0
13 (8)
0
0
DARZALEX-related infusion reactions
56 (18)
7 (2)
0
0
0
0
Viral infections
63 (20)
19 (6)
0
22 (14)
2 (1)
0
Abbreviations: AE, adverse event; D-Kd, DARZAELX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.
aIncidence of cardiac failure leading to carfilzomib discontinuation was 3.9% in the D-Kd arm vs 4.6% in Kd arm.

AEs Leading to Treatment Discontinuation (CANDOR)15
D-Kd (n=308)
Kd (n=153)
AEs leading to treatment discontinuation, n (%)
69 (22)
38 (25)
AEs leading to carfilzomib discontinuation, n (%)
65 (21)
33 (22)
AEs leading to DARZALEX discontinuation, n (%)
28 (9)
-
Abbreviations: AE, adverse event; D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.
  • The most common AE leading to DARZALEX treatment discontinuation was pneumonia (D-Kd, n=4; Kd, n=0) and cardiac failure for carfilzomib treatment discontinuation (D-Kd, n=6; Kd, n=3).

Fatal Events (CANDOR)15
Event, n (%)
D-Kd (n=308)
Kd (n=153)
Treatment-emergent
30 (10)a
8 (5)
Treatment-related
5 (1.6)b
0
Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.
aGenerally reported in older and more frail patients.
bDue to pneumonia, sepsis with Clostridium difficile enterocolitis, septic shock in the setting of Pneumocystis carinii pneumonia; Acinetobacter infection, and cardiorespiratory arrest (n=1 each).

>4-Years Follow-up Update on Safety Outcomes in CANDOR

Usmani et al (2023)33 reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. Safety results from this final analysis are summarized below.

Safety Results

  • The safety results were consistent with previous reports, and no new safety signals were identified with the longer follow-up. See Table: Safety Overview (Final Analysis of CANDOR).
  • Grade ≥3 infections and infestations occurred in 46% (n=142) vs 32% (n=49) of patients in the DKd vs Kd arm and led to carfilzomib discontinuation in 22% (n=69) vs 20% (n=30) of patients, respectively.
  • TEAEs related to COVID-19 occurred in 11% (n=33) vs 4% (n=6) of patients in the DKd vs Kd arm, and deaths related to COVID-19 occurred in 2% (n=6) vs 1% (n=1) of patients, respectively.
  • The incidence of carfilzomib and DARZALEX discontinuation due to TEAEs decreased over time, with most discontinuations due to TEAEs occurring in the first 18 months. See Table: TEAEs Leading to Treatment Discontinuation (Final Analysis of CANDOR).
  • The most common causes of fatal TEAEs were infections (DKd, 7% [n=21]; Kd, 3% [n=5]) and cardiac disorders (DKd, 2% [n=6]; Kd, 0%).
    • In the DKd vs Kd arm, the exposure-adjusted rates of fatal TEAEs were 6.5 vs 5.6 per 100 patients-years, respectively.
    • In the DKd vs Kd arm, the fatal infection rates were 7% (n=21) vs 3% (n=5), and the exposure-adjusted fatal infection rates were 3.5 vs 2.55 per 100 patient-years, respectively.
  • TEAEs are summarized in Tables: TEAEs in the Safety Population (Final Analysis of CANDOR), TEAEs of Interest (Final Analysis of CANDOR), and Fatal TEAEs (Final Analysis of CANDOR).

Safety Overview (Final Analysis of CANDOR)34
Parameter 
DKd (n=308)
Kd (n=153)
Median relative dose intensity, % (range)a
   Carfilzomib
88.3 (21.6-106.0)
91.4 (34.3-105.9)
   DARZALEX
94.9 (24.0-102.3)
-
Dose reductions due to TEAE, n (%)
141 (45.8)
59 (38.6)
   Carfilzomib
95 (30.8)
38 (24.8)
   DARZALEX
4 (1.3)
-
Grade ≥3 TEAEs, n (%)
273 (88.6)
120 (78.4)
   Exposure-adjusted rate (95% CI), per PY
149.6 (132.9-168.5)
144.7 (121.0-173.1)
Serious TEAEs, n (%)
211 (68.5)
80 (52.3)
   Exposure-adjusted rate (95% CI)
60.4 (52.7-69.1)
59.0 (47.4-73.4)
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; PY, patient years; TEAE, treatment-emergent adverse event.
aRelative dose intensity is the actual dose intensity/planned dose intensity×100, where actual (planned) dose intensity is the actual (planned) cumulative dose (mg/kg) divided by the actual (planned) duration of drug administration (weeks).

TEAEs in the Safety Population (Final Analysis of CANDOR)33
Adverse Events, n (%)
DKd (n=308)
Kd (n=153)
Any Gradea
Grade ≥3b
Any Gradea
Grade ≥3b
All TEAEs
306 (99.4)
273 (88.6)
149 (97.4)
120 (78.4)
Hematologic
   Thrombocytopenia
119 (38.6)
76 (24.7)
46 (30.1)
25 (16.3)
   Anemia
114 (37)
54 (17.5)
52 (34)
25 (16.3)
   Neutropenia
49 (15.9)
31 (10.1)
15 (9.8)
10 (6.5)
   Lymphopenia
29 (9.4)
22 (7.1)
13 (8.5)
11 (7.2)
Nonhematologic
   Diarrhea
118 (38.3)
18 (5.8)
28 (18.3)
1 (0.7)
   Hypertension
115 (37.3)
72 (23.4)
49 (32)
27 (17.6)
   Upper respiratory tract infection
105 (34.1)
12 (3.9)
37 (24.2)
2 (1.3)
   Fatigue
81 (26.3)
25 (8.1)
29 (19)
7 (4.6)
   Pneumonia
79 (25.6)
57 (18.5)
24 (15.7)
14 (9.2)
   Dyspnea
70 (22.7)
16 (5.2)
35 (22.9)
4 (2.6)
   Pyrexia
66 (21.4)
6 (1.9)
27 (17.6)
2 (1.3)
   Insomnia
64 (20.8)
16 (5.2)
19 (12.4)
3 (2)
   Back pain
63 (20.5)
7 (2.3)
21 (13.7)
2 (1.3)
   Nausea
62 (20.1)
0
22 (14.4)
1 (0.7)
   Hyperglycemia
31 (10.1)
16 (5.2)
13 (8.5)
5 (3.3)
   Cataract
34 (11)
15 (4.9)
13 (8.5)
8 (5.2)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.
aAny grade TEAEs occurring in ≥20% of patients.
bGrade ≥3 TEAEs occurring in ≥5% of patients.

TEAEs of Interest (Final Analysis of CANDOR)33
Adverse Events, n (%)
DKd (n=308)
Kd (n=153)
Any Gradea
Grade ≥3b
Any Gradea
Grade ≥3b
Respiratory tract infection
243 (78.9)
117 (38.0)
90 (58.8)
27 (17.6)
Infusion reaction (on same day as any carfilzomib dosing)
142 (46.1)
47 (15.3)
50 (32.7)
12 (7.8)
Peripheral neuropathy
66 (21.4)
6 (1.9)
15 (9.8)
1 (0.7)
Cardiac failure
29 (9.4)
12 (3.9)
17 (11.1)
13 (8.5)
Acute renal failure
25 (8.1)
11 (3.6)
14 (9.2)
10 (6.5)
Ischemic heart disease
19 (6.2)
16 (5.2)
8 (5.2)
5 (3.3)
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.
aAny grade TEAEs occurring in ≥20% of patients.
bGrade ≥3 TEAEs occurring in ≥5% of patients.

TEAEs Leading to Treatment Discontinuation (Final Analysis of CANDOR)34
Parameter 
DKd (n=308)
Kd (n=153)
Discontinuation due to TEAE, n (%)
105 (34.1)
41 (26.8)
   Carfilzomib
98 (31.8)
37 (24.2)
   DARZALEX
43 (14)
-
Abbreviations: DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; TEAE, treatment-emergent adverse event.

Fatal Events (Final Analysis of CANDOR)33,34
Fatal AEs, n (%)
DKd (n=308)
Kd (n=153)
Treatment-emergenta
35 (11.4)
9 (5.9)
Treatment-related
5 (2)b
-
Abbreviations: CI, confidence interval; DKd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone.
aExcludes the fatal TEAE of plasma cell myeloma.
bDue to pneumonia, sepsis, septic shock, Acinetobacter infection, and cardiorespiratory arrest (n=1 each).

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 13 July 2025.

 

References

Show
1 DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
2 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;394:29-38.  
3 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. Lancet Oncol. 2021;22:1378-1390.  
4 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.  
5 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.  
6 Voorhees PM, Costa L, Reeves B, et al. Interim safety analysis of a phase 2 randomized study of daratumumab (Dara), lenalidomide (R), bortezomib (V), and dexamethasone (d; Dara-RVd) vs RVd in patients (pts) with newly diagnosed multiple myeloma (MM) eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) (GRIFFIN). Poster presented at: The 59th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA.  
7 Voorhees P, Kaufman J, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Oral Presentation presented at: 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
8 Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945.  
9 Chari A, Kaufman JL, Laubach J, et al. Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 2024;14(1):107.  
10 Chari A, Kaufman JL, Laubach J, et al. Supplement to: Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 2024;14(1):107.  
11 Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115.  
12 Facon T, Kumar SK, Orlowski R, et al. Final survival analysis of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: MAIA study. Poster presented at: The European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain.  
13 Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.  
14 Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981.  
15 Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.  
16 Dimopoulos M, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.  
17 Plesner T, Arkenau HT, Gimsing P, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016;128(14):1821-1828.  
18 Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.  
19 Usmani SZ, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: results of the randomized phase 3 study CANDOR (NCT03158688). Oral Presentation presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.  
20 Lokhorst H, Plesner T, Laubach J, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-1219.  
21 Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-1560.  
22 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.  
23 Voorhees PM, Rodriguez C, Reeves B, et al. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021;5(4):1092-1096.  
24 Sborov D, Laubach J, Kaufman JL, et al. Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Oral Presentation presented at: 19th International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA.  
25 Facon T, Kumar S, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Poster presented at: 60th American Society of Hematology (ASH) Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA.  
26 Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950.  
27 Facon T, Moreau P, Weisel K, et al. Supplement to: Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950.  
28 Mateos MV, San-Miguel J, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 ALCYONE study. Poster presented at: The 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
29 Mateos MV, San-Miguel J, Cavo M, et al. Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2025;26(5):596-608.  
30 Mateos MV, San-Miguel J, Cavo M, et al. Supplement to: Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2025;26(5):596-608.  
31 Dimopoulos MA, Oriol A, Nahi H, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1590-1599.  
32 Sonneveld P, Khan AC, Weisel K, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41:1600-1609.  
33 Usmani SZ, Quach H, Mateos MV, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.  
34 Usmani S, Quach H, Mateos M, et al. Supplement to: Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.