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DARZALEX FASPRO®

(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)
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DARZALEX + DARZALEX FASPRO - Use in Combination with Bortezomib, Lenalidomide, and Dexamethasone in Multiple Myeloma

Last Updated: 06/04/2026

Summary

  • Johnson & Johnson does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • GRIFFIN was a 2-part, phase 2 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) compared to bortezomib, lenalidomide and dexamethasone (VRd) alone in patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT).1-3
    • Part 1: Voorhees et al (2021)4 reported the final analysis of the safety run-in cohort of the GRIFFIN study with a median follow-up of 40.8 months. By the end of D-VRd consolidation, 56.3% of patients achieved stringent complete response (sCR). After maintenance, 93.8% of patients achieved sCR. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 93.8% of patients.
    • Part 2: Voorhees et al (2023)5 reported the final efficacy and safety results at a median follow-up of 49.6 months. In the D-VRd vs VRd arm, respectively, sCR was achieved in 67% vs 48% of patients (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.22-3.89; 2-sided P=0.0079). In the D-VRd vs VRd arm, the most common (≥10%) grade 3/4 TEAEs were neutropenia (46% vs 23%), lymphopenia (23% in both arms), leukopenia (17% vs 8%), thrombocytopenia (16% vs 9%), pneumonia (12% vs 14%), and hypophosphatemia (10% vs 11%).
  • PERSEUS is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with VRd (D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO and lenalidomide (D-R) in the D-VRd group or lenalidomide alone (R) in the VRd group in patients with NDMM eligible for ASCT.6
    • Sonneveld et al (2024)6 reported efficacy and safety results from the PERSEUS study. At a median follow-up of 47.5 months, 14.1% of patients in the D-VRd arm vs 29.1% of patients in the VRd arm experienced disease progression or death (hazard ratio [HR], 0.42; 95% CI, 0.30-0.59; P<0.0001). The most common grade 3/4 adverse events (AEs) in the D-VRd vs VRd arm were neutropenia (62.1% vs 51%), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%).
  • CEPHEUS is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with VRd or VRd alone in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).7
    • Usmani et al (2026)8 presented the efficacy and safety results of the TIE population of the CEPHEUS study at a median follow-up of 76 months. Overall minimal residual disease (MRD) negativity (10-5) in patients with complete response or better (≥CR) was achieved in 61.1% of patients in the D-VRd arm vs 40.0% of patients in the VRd arm (OR, 2.35; 95% CI, 1.47-3.77). Grade 3/4 TEAEs occurred in 93.8% of patients in the D-VRd arm vs 88.7% in the VRd arm.
  • PLEIADES was a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care treatment regimens in patients with multiple myeloma (MM). One cohort included patients with transplant-eligible (TE) NDMM treated with DARZALEX FASPRO + VRd.9-12
    • Chari et al (2021)12 presented updated safety and efficacy results of the D-VRd cohort, among others. In the D-VRd group, the very good partial response or better (≥VGPR) rate was 71.6% vs 71.7% in the GRIFFIN study. Grade 3/4 TEAEs occurred in 58.2% of patients.
  • Other relevant literature regarding the use of DARZALEX and DARZALEX FASPRO in combination with VRd in patients with MM has been identified in addition to the data summarized above.13-20

PRODUCT LABELING

CLINICAL STUDIES

Phase 2 Study of DARZALEX in Combination with VRd in TE NDMM  

GRIFFIN (MMY2004; NCT02874742) was a 2-part, phase 2, randomized, active-controlled, open-label, multicenter, United States (US) study evaluating the safety and efficacy of D-VRd in patients with NDMM eligible for HDT and ASCT.1-3

Final Analysis of Part 1 (Safety Run-in Phase) of the GRIFFIN Study

Voorhees et al (2021)4 reported the final analysis of the safety run-in cohort of the GRIFFIN study at a median follow-up of 40.8 months.

Results

Baseline Characteristics

Baseline Characteristics4
Characteristic
D-VRd
(n=16)
Median age (range), years
62.5 (46-65)
   <65 years, n (%)
14 (87.5)
   ≥65 years, n (%)
2 (12.5)
Sex, n (%)
   Male
8 (50)
   Female
8 (50)
Race, n (%)
   White
11 (68.8)
   Black or African American
4 (25)
   Asian
1 (6.3)
ECOG performance statusa, n (%)
   0
3 (18.8)
   1
10 (62.5)
   2
3 (18.8)
ISS disease stageb, n (%)
   I
12 (75)
   II
2 (12.5)
   III
2 (12.5)
Cytogenetic risk profilec, n (%)
   Standard
12 (75)
   High risk
4 (25)
Median (range) time since diagnosis of multiple myeloma, months
1.6 (0-5)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization (locally tested); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) in those patients with cytogenetic risk data available.
  • Median follow-up was 40.8 months (range, 20.6-43) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.4
  • All patients in the safety run-in phase (N=16) completed induction therapy, stem cell mobilization, ASCT, consolidation, and entered maintenance therapy.4
  • A total of 87.5% of patients (n=14) completed study therapy, and 2 patients (12.5%) discontinued the therapy because of progressive disease (PD; n=1) or AE (n=1; neuralgia or thrombocytopenia) during maintenance therapy.4
Safety
  • During cycle 1, 3 of 16 patients developed 4 dose-limiting toxicities (DLTs): fatigue, gastroenteritis, hypotension, and pneumonitis.4
    • All DLTs were grade 3 and none resulted in treatment discontinuation during induction or consolidation therapy.
  • One patient had a TEAE leading to discontinuation of study treatment.4
  • Fourteen patients (87.5%) experienced any grade infections, and 5 patients (31.3%) experienced grade 3/4 infections.4
    • During the maintenance phase 31.3% of patients (n=5) experienced any grade infections, the most common being upper respiratory tract infections. One patient (6.3%) experienced a grade 3/4 infection (pneumonia and bronchitis).
  • Grade 1/2 infusion-related reactions (IRRs) occurred in 31.3% of patients (n=5).4
  • Eleven patients (68.6%) experienced a serious adverse event (SAE).
  • For the incidences of grade 3/4 TEAEs, see Table: Most Common Grade 3/4 TEAEs.4

Most Common Grade 3/4 TEAEs4
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.
Efficacy
  • At a median follow-up of 40.8 months, disease progression occurred in 3 patients.4
  • Median time to first response was 0.77 months (range, 0.1-2.1), and median duration of response was not estimable (NE).4
  • Median time to ≥CR was 7.36 months (range, 2.8-18.5), and median duration of ≥CR was NE.4
  • Estimated 24-month progression-free survival (PFS) and overall survival (OS) rate was 93.8%.4
  • Estimated 36-month PFS and OS rates were 78.1% and 93.8%, respectively.4
  • MRD-negativity rates at 10-5 sensitivity threshold and 10-6 sensitivity threshold, respectively4:
    • By end of D-VRd induction: 18.8% (n=3) vs 0%
    • By end of D-VRd consolidation: 50% (n=8) vs 0%
    • At the last follow-up: 81.3% (n=13) vs 31.3% (n=5)
  • MRD-negativity rates at 10-5 were sustained for ≥12 months in 8 patients (50%).4
  • Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort.4

Updated Response Rates Over Time for the Safety Run-in Cohorta,4
Patients, %
By end of
D-VRd induction
By end of
D-VRd consolidation
By last follow-up
D-R Maintenance
sCR
-
56.3
93.8
CR
12.5
12.5
-
≥CR
12.5
68.8
93.8
VGPR
56.3
31.3
6.3
PR
31.3
-
-
Abbreviations: CR, complete response; D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
Response data are shown for the response-evaluable population (N=16).
aPercentages do not add up to 100% due to rounding.

Final Analysis of Part 2 (Randomized Phase) of the GRIFFIN Study

Voorhees et al (2023)5 reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment, died, or withdrew from study participation at a median follow-up of 49.6 months.

Results

Baseline Characteristics

Patient Demographics in the Randomized Phase (ITT)3
Characteristic
D-VRd
(n=104)
VRd
(n=103)
Age
   Median (range), years
59 (29-70)
61 (40-70)
   ≥65 years
28 (26.9)
28 (27.2)
Male, n (%)
58 (55.8)
60 (58.3)
ECOG statusa, n (%)
n=101
n=102
   0
39 (38.6)
40 (39.2)
   1
51 (50.5)
52 (51)
   2
11 (10.9)
10 (9.8)
ISS stageb, n (%)
   I
49 (47.1)
50 (48.5)
   II
40 (38.5)
37 (35.9)
   III
14 (13.5)
14 (13.6)
Baseline creatinine clearance, n (%)
   30-50 mL/minute
9 (8.7)
9 (8.7)
   >50 mL/minute
95 (91.3)
94 (91.3)
Cytogenetic profilec, n (%)
n=98
n=97
   Standard risk
82 (83.7)
83 (85.6)
   High risk
16 (16.3)
14 (14.4)
Time since diagnosis of MM
n=103
n=102
   Median (range), months
0.7 (0-12)
0.9 (0-61)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone.
aECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum-β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization, high risk was defined as the presence of del17p, t(4:14), or t(14:16) among patients with available cytogenetic risk data.
  • The median follow-up was 49.6 months (interquartile range [IQR], 47.4-52.1).5
  • The median duration of treatment in the D-VRd and VRd arms was 32.5 months (IQR, 31.1-33.4) and 27.5 months (IQR, 2.9-32.7), respectively.5
    • In the D-VRd arm, among the 90 patients who received D-R maintenance therapy, 21% (n=19) switched from DARZALEX to DARZALEX FASPRO and received ≥1 cycle of DARZALEX FASPRO (median number, 3 [IQR, 3-5]).
  • By the final analysis, 25% of patients in the D-VRd arm and 51% in the VRd arm discontinued treatment.5
Efficacy
  • At the final analysis, among response-evaluable patients in the D-VRd (n=100) vs VRd (n=98) arm, respectively, sCR was achieved in 67% vs 48% of patients (OR, 2.18; 95% CI, 1.22-3.89; 2-sided P=0.0079) and ≥CR in 83% vs 60% of patients (P=0.0005). Response data over time are summarized in Table: Summary of Response Over Time.5,21

Summary of Response Over Time5
Timepoint, %
D-VRd
VRd
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
End of inductiona
12
7
19
53
26
2
7
6
13
43
35
8
End of post-ASCT consolidationa
42
9
52
39
8
1
32
10
42
31
19
8
Final analysisb
67
16
83
13
3
1
48
12
60
17
14
8
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IQR, interquartile range; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
Rates shown are the number of patients with each type of response divided by the response-evaluable population.aResponse rates were from the primary analysis cutoff (median follow-up, 13.5 months) and the response-evaluable population comprised 196 patients (D-VRd, n=99; VRd, n=97).
bResponse rates were also evaluated at the time of the final analysis (median follow-up 49·6 months; IQR 47·4-52·1), and the response-evaluable population comprised 198 patients (D-VRd, n=100; VRd, n=98).

Response Duration Among Patients in the D-VRd vs VRd Arm5
Parameter
D-VRd
VRd
Median duration to first response (ORR), months (95% CI)
0.8 (0.8-0.8)
0.8 (0.8-1)
Median duration to sCR, months (95% CI)
10.2 (8.8-13)
14.3 (9.2-21.7)
   HR (95% CI)
1.26 (0.86-1.83)
P value
0.2339
Median duration to ≥VGPR, months (95% CI)
2.2 (2.1-2.7)
3 (2.2-6.3)
Median duration to ≥CR, months (95% CI)
8.9 (7.9-9.4)
9.6 (8.4-12.2)
Median DOR
NR
NR
   Estimated 48-month DOR, % (95% CI)
89 (79.9-94.3)
71 (55.8-81.4)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; DOR, duration of response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reached; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.

Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance5,21
Parameter
D-VRd
VRd
P value
Responsea, n
100
98
-
   ORR, n (%)
99 (99)
90 (92)
0.016b
      ≥CR
83 (83)
59 (60)
0.0005b
      CR
16 (16)
12 (12)
-
      sCR
67 (67)
47 (48)
0.0079b
      ≥VGPR
96 (96)
76 (78)
0.0002b
      VGPR
13 (13)
17 (17)
-
      PR
3 (3)
14 (14)
-
   SD, n (%)
1 (1)
8 (8)
-
   PD, n (%)
0
0
-
MRD negative
   ITT population, n
104
103
-
      10-5 sensitivity, n (%)
67 (64)
31 (30)
<0.0001c
         OR (95% CI)
4.23 (2.35-7.62)
      10-6 sensitivity, n (%)
37 (36)
16 (16)
0.0013c
         OR (95% CI)
2.95 (1.52-5.75)
   In patients achieving ≥CR, n
83
59
-
      10-5 sensitivity, n (%)
64 (77)
28 (47)
0.0004c
      10-6 sensitivity, n (%)
35 (42)
14 (24)
0.031c
Durable MRD-negativity
   Lasting ≥12 months, n
104
103
-
      10-5 sensitivity, n (%)
46 (44)
14 (14)
<0.0001c
         OR (95% CI)
5 (2.50-9.99)
      10-6 sensitivity, n (%)
10 (10)
4 (4)
0.16c
         OR (95% CI)
2.48 (0.76-8.07)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; MRD, minimal residual disease; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; ≥VGPR, very good partial response or better; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
The predefined per protocol final analysis occurred after all patients completed ≥1 year of long-term follow-up after the end-of-study treatment, died, or withdrew from study participation, whichever occurred first.
aResponse rate is based on the response-evaluable population, which included randomized patients who had a confirmed diagnosis of MM, had measurable disease at baseline, received ≥1 dose of study treatment, and had ≥1 postbaseline disease assessment. The response-evaluable population for the primary analysis included 99 patients in the D-VRd group and 97 patients in the VRd group.
bP value was calculated using the Cochran-Mantel-Haenszel Chi-square test stratified by ISS disease stage (I, II, or III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.
cP value was calculated using Fisher’s exact test.
  • By the end of the 2-year maintenance therapy, 14% of patients (n/N=15/104) and 10% of patients (n/N=10/103) in the D-VRd and VRd arms, respectively, who were previously MRD-positive at the end of the consolidation phase, converted to MRD-negative (10-5). MRD-negativity rates continuously improved over time and were consistently higher in the D-VRd vs VRd arm. See Table: Summary of MRD-Negativity Rates Over Time (ITT Population).5,21

Summary of MRD-Negativity Rates Over Time (ITT Population)a,5,21
Timepoint, %
D-VRd
VRd
MRD-Negativity (10-5)
MRD-Negativity (10-6)
MRD-Negativity (10-5)
MRD-Negativity (10-6)
End of induction
22
1
8
0
Post-ASCT consolidation
50
11
20
3
End of study
64
36
30
16
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; sCR, stringent complete response; VRd, bortezomib + lenalidomide + dexamethasone. aMRD was evaluated by NGS using the clonoSEQ assay. MRD assessments occurred at the first evidence of suspected CR or sCR, after induction (but before stem cell collection), after consolidation, and after 12 and 24 months of maintenance, regardless of response.
  • No patient in either treatment arm with sustained MRD-negativity 10-5 lasting ≥12 months became MRD-positive later.5
  • The median time to MRD-negativity in the D-VRd vs VRd arm at sensitivity thresholds of 10-5 and 10-6, respectively, was 8.5 vs 34.6 months (HR, 2.70; 95% CI, 1.72-4.23; P<0.0001) and 33.9 months vs not reached (not reaches [NR]; HR, 1.93; 95% CI, 1.05-3.54; P=0.031).5
  • Efficacy and survival outcomes are summarized in Table: Efficacy and Survival Outcomes (ITT Population).5,21

Efficacy and Survival Outcomes (ITT Population)5,21
Parameter
D-VRd
VRd
Median PFS, months
NR
NR
   3-year PFS rate, %
89
80.7
   4-year PFS rate, %
87.2
70
   PFS HR (95% CI); P value
0.45 (0.21-0.95); 0.032
Median PFS in patients who received lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who received SoC lenalidomide therapy after study completion, %
96
80
Median PFS in patients who did not receive lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who did not receive SoC lenalidomide therapy after study completion, %
100
86
Median OS, months
NR
NR
   3-year OS rate, %
92.7
92.2
   4-year OS rate, %
92.7
92.2
   OS HR (95% CI); P value
0.90 (0.31-2.56); 0.84a
Disease progression or death, n/N (%)
11/104 (11)
18/103 (17)
   HR (95% CI)
0.45 (0.21-0.95)
P value
0.032
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; ITT, intention-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival; SoC, standard of care; VRd, bortezomib + lenalidomide + dexamethasone.
aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, and III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.
An HR <1 indicates an advantage for D-VRd. P value is based on the log-rank test stratified with ISS staging and baseline CrCl at randomization.
Safety
  • Among safety-evaluable patients in the D-VRd (n=99) vs VRd (n=102) arms, grade 3/4 TEAEs occurred in 86% (n=85) vs 79% (n=81), respectively.5
  • In the D-VRd vs VRd arm, serious TEAEs occurred in 46% (n=46) vs 52% (n=53) of patients, respectively.5
    • The most common serious TEAEs included pneumonia (15% vs 14%) and pyrexia (11% vs 10%).
  • TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33% [n=33]; VRd, 31% [n=32]). One patient in each arm died due to TEAEs unrelated to study treatment.5
  • Any-grade infections were more common in the D-VRd vs VRd arm (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment arms for grade 3/4 infections (D-VRd, 29%; VRd, 26%) and infections leading to treatment discontinuation (D-VRd, 2%; VRd, 3%).5
    • During maintenance therapy (cycle 7 and onwards) in the D-VRd vs VRd arm, any-grade infections occurred in 35% (n/N=31/89) vs 32% (n/N=23/71) of patients and grade 3/4 infections occurred in 18% (n=16) vs 21% (n=15) of patients.
    • In the D-VRd vs VRd arm, coronavirus disease 2019 (COVID-19) infections were reported in 5% (n=5) vs 2% (n=2) of patients, respectively. Of these, 1 patient in each arm had a grade 3 COVID-19-related event (including 1 serious event in the D-VRd arm).
  • TEAEs occurring in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.5,21
  • During maintenance therapy, second primary malignancies with first onset after the start of maintenance therapy were reported in 4 of 89 evaluable patients (4%) in the D-VRd arm and 3 of 71 (4%) evaluable patients in the VRd arm.5
  • A total of 14 (D-VRd, n=7; VRd, n=7) patients died, of whom 9 (D-VRd, n=5; VRd, n=4) patients died due to PD.5
  • There were 39 (39%) IRRs reported at the initial infusion, 2 (2%) IRRs at the second infusion, and 14 (14%) IRRs at the subsequent infusions.21

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

Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TE NDMM

PERSEUS (MMY3014; NCT03710603) is a phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in D-VRd group or lenalidomide in VRd arm in patients with NDMM eligible for ASCT.

Primary Analysis of the PERSEUS Study

Sonneveld et al (2024)6 reported efficacy and safety results from the PERSEUS study at a median follow-up of 47.5 months (range, 0-54.4).

Results

Patient Characteristics
  • A total of 709 patients were randomized into the D-VRd (n=355) and VRd (n=354) groups.6 
  • The baseline characteristics were well balanced between treatment arms.6 
    • Across treatment arms, the median age was 60 years (range, 31-70), 14.8% of patients had International Staging System (ISS) stage III disease, and 21.7% had high cytogenetic risk (del[17p], t[4;14], or t[14;16]).
  • A total of 698 patients (D-VRd, n=351; VRd, n=347) received ≥1 dose of treatment.6 
  • As of the clinical data cutoff date of August 1, 2023, 322 patients (91.7%) vs 300 patients (86.5%) in the D-VRd vs VRd group who started the induction therapy phase continued into the maintenance therapy phase.6 
    • A total of 207/322 patients in the D-VRd group who were receiving maintenance therapy discontinued DARZALEX FASPRO per protocol after receiving ≥24 months of maintenance therapy, achieving ≥CR, and having sustained MRD-negativity for ≥12 months.
  • A total of 315 patients (89.7%) vs 302 patients (87.0%) in the D-VRd vs VRd group received ASCT.6 
  • The median duration of treatment was 45.7 months (range, 0.5-54.3) in the D-VRd arm and 42.2 months (range, 0.1-53.9) in the VRd arm.6 
Efficacy
  • A total of 50 patients (14.1%) vs 103 patients (29.1%) experienced disease progression or death in the D-VRd vs VRd arm of the intent-to-treat (ITT) population (HR, 0.42; 95% CI, 0.30-0.59; P<0.0001), respectively, crossing the prespecified stopping boundary for superiority at the first interim analysis (P=0.0126).6 
  • The estimated 48-month PFS rate for the D-VRd vs VRd arm was 84.3% (95% CI, 79.5-88.1) vs 67.7% (95% CI, 62.2-72.6), respectively.6 
  • Analyses of overall ≥CR rates and overall MRD-negativity rates (at 10-5) in prespecified subgroups appeared to favor D-VRd over VRd across clinically relevant subgroups.6 
  • In the D-VRd group, 96.6% of patients achieved an overall response (95% CI, 94.2-98.2) vs 93.8% (95% CI, 90.7-96.1) in the VRd group, with 87.9% vs 70.1% (P<0.001) achieving ≥CR, respectively.6 
  • In the D-VRd arm, 75.2% of patients were MRD-negative (10-5 sensitivity) compared with 47.5% of patients in the VRd arm (P<0.001).6 
  • Prespecified subgroup analyses suggested a consistent benefit for progression-free survival in the D-VRd group as compared with the VRd group across various subgroups, including patients with ISS stage III disease or those with high cytogenetic risk.6 
Safety
  • The most common grade 3/4 AEs recorded in the D-VRd vs VRd arm were neutropenia (62.1% vs 51%), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%). See Table: Most Common AEs During Treatment in the Safety Population.6

Most Common AEs During Treatment in the Safety Population6
Most Common (≥20%) Any Grade AEs
Most Common (≥10%) Grade 3/4 AEs
Hematologic
  • Neutropenia
  • Thrombocytopenia
  • Anemia

Nonhematologic
  • Diarrhea
  • Peripheral sensory neuropathy
  • Constipation
  • Pyrexia
  • Insomnia
  • Asthenia
  • Cough
  • Fatigue
  • Rash
  • Back pain
  • Peripheral edema
  • Nausea
  • Infections*
Hematologic
  • Neutropenia
  • Thrombocytopenia
  • Febrile neutropenia

Nonhematologic
  • Diarrhea
  • Infections**
Abbreviation: AE, adverse event.*Including COVID-19, upper respiratory tract infection, and pneumonia
**Including pneumonia
  • Grade 3/4 peripheral neuropathy occurred in 6% vs 4.9% of patients in the D-VRd vs VRd arm, respectively.6
  • A second primary malignancy was observed in 37 patients (10.5%) in the D-VRd arm and 25 patients (7.2%) in the VRd arm.6
  • The number of deaths recorded due to COVID-19 in the D-VRd vs VRd arm was 4 patients (1.1%) vs 1 patient (0.3%), respectively.6
  • A total of 25.9% vs 54.2% of patients in the D-VRd vs VRd arm discontinued treatment, respectively.6
    • The most common reasons for treatment discontinuation over all phases of the study were AEs (D-VRd, 9.1%; VRd, 22.5%) and PD (D-VRd, 8.3%; VRd, 20.7%).
  • A total of 34 vs 44 patients died in the D-VRd vs VRd arm, respectively.6
    • A total of 7 patients died due to COVID-19 (D-VRd, n=4; VRd, n=3).
  • SAEs occurred in 57.0% vs 49.3% of patients in the D-VRd vs VRd arms, respectively. The most common SAEs (occurring in ≥2% of patients in either group) were6: 
    • Infections: 35.0% (D-VRd) vs 27.4% (VRd) 
      • Includes pneumonia, COVID-19, COVID-19 pneumonia, lower respiratory tract infection, sepsis, and upper respiratory tract infection.  
    • Febrile neutropenia: 4.6% (D-VRd) vs 4.6% (VRd) 
    • Pyrexia: 3.7% (D-VRd) vs 4.6% (VRd) 
    • Pulmonary embolism: 2.6% (D-VRd) vs 1.4% (VRd) 
    • Atrial fibrillation: 2.6% (D-VRd) vs 0.6% (VRd) 
    • Diarrhea: 2.0% (D-VRd) vs 2.6% (VRd)
  • The proportion of patients proceeding to ASCT in the D-VRd vs VRd arm was 89.7% vs 87%, respectively.6

Phase 3 Study of DARZALEX FASPRO in Combination with VRd in TIE NDMM

CEPHEUS (MMY3019; NCT03652064) is a phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of D-VRd vs VRd in patients with NDMM who are TIE or for whom transplant is not planned as initial therapy (transplant deferred).7

Final Analysis of TIE Patients in the CEPHEUS Study

Usmani et al (2026)8 reported the final analysis of TIE patients in the CEPHEUS study at a median follow-up of 76 months.

Results

Patient Characteristics

Baseline Characteristics of TIE Population22
Characteristic
D-VRd (n=144)
VRd (n=145)
Median age (range), years
72 (58-79)
72 (51-80)
   <70 years, n (%)
35 (24.3)
35 (24.1)
   70 to <75 years, n (%)
68 (47.2)
65 (44.8)
   ≥75 years, n (%)
41 (28.5)
45 (31.0)
Male, n (%)
65 (45.1)
82 (56.6)
ECOG PSa, n (%)
   0
52 (36.1)
57 (39.3)
   1
75 (52.1)
78 (53.8)
   2
17 (11.8)
10 (6.9)
IMWG frailty scoreb, n (%)
   0 (fit)
82 (56.9)
88 (60.7)
   1 (intermediate fitness)
62 (43.1)
57 (39.3)
IFM frailty score, n (%)
   Nonfrail (0-1)
96 (66.7)
110 (75.9)
   Frail (≥2)
48 (33.3)
35 (24.1)
Type of myeloma by immunofixation or serum FLC assay, n (%)
   IgG
92 (63.9)
78 (53.8)
   IgA
26 (18.1)
42 (29.0)
   IgD
2 (1.4)
2 (1.4)
   Light chain
20 (13.9)
19 (13.1)
   Biclonal
4 (2.8)
3 (2.1)
   Unknown
0
1 (0.7)
Extramedullary plasmacytomas, n (%)
9 (6.3)
12 (8.3)
ISS disease stagec, n (%)
   I
50 (34.7)
48 (33.1)
   II
54 (37.5)
57 (39.3)
   III
40 (27.8)
40 (27.6)
Cytogenetic risk profiled, n (%)
   Standard
105 (72.9)
111 (76.6)
   High
20 (13.9)
18 (12.4)
   Unevaluable or missing
19 (13.2)
16 (11.0)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; IFM, Intergroupe Francophone du Myelome; Ig, immunoglobulin; IMWG, International Myeloma Working group; ISS, International Staging System; TIE, transplant-ineligible; VRd, bortezomib + lenalidomide + dexamethasone.
aECOG PS is scored on a scale of 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bTotal additive frailty is scored on a scale of 0-5 based on age, comorbidities, and cognitive and physical conditions, with 0 indicating fit, 1 indicating intermediate fitness, and ≥2 indicating frail, per the Myeloma Geriatric Assessment score (http://www.myelomafrailtyscorecalculator.net/).
cBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
dBased on fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).
Efficacy
  • Overall MRD negativity rates (10-5) in patients with ≥CR was higher in the D-VRd arm vs the VRd arm, with 61.1% of patients in the D-VRd arm achieving overall MRD negativity vs 40.0% in the VRd arm (OR, 2.35; 95% CI, 1.47-3.77). See Table: Summary of MRD Negativity Rates (TIE Subgroup).8
    • Sustained MRD negativity rate at ≥12 and ≥24 months was higher in the D-VRd arm vs the V-Rd arm.

Summary of MRD Negativity Rates (TIE Subgroup)8
Parameter, n (%)
D-VRd
(n=144)
VRd
(N=145)
OR (95% CI)
P-value
Overall MRD negativity (≥CR) ratea
   10-5 threshold
61.1
40.0
2.35 (1.47-3.77)
0.0004
   10-6 threshold
46.5
27.6
2.27 (1.39-3.71)
0.0010
Sustained MRD negativity (≥CR) rate ≥12 monthsb
   10-5 threshold
49.3
29.0
2.40 (1.47-3.91)
0.0005
   10-6 threshold
37.5
16.6
3.01 (1.73-5.24)
<0.0001
Sustained MRD negativity (≥CR) rate ≥24 monthsb
   10-5 threshold
44.4
23.4
2.62 (1.58-4.36)
0.0002
   10-6 threshold
30.6
15.2
2.45 (1.38-4.37)
0.0020
Abbreviations: CI, confidence interval, CR, complete response; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; OR, odds ratio; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone.
aThe proportion of patients who achieved MRD negativity and ≥CR.
bSustained MRD negativity was defined as 2 consecutive MRD negative reads ≥12 months (±1) or 24 months (±3) apart with no MRD-positive result in between.

Prespecified Subgroup Analysis of MRD Negativity (TIE Subgroup)8
Subgroup
D-VRd
VRd
OR (95% CI)
MRD negativity (≥CR; 10-5), n/N (%)
Sex
   Male
43/65 (66.2)
29/82 (35.4)
3.57 (1.80-7.08)
   Female
45/79 (57.0)
29/63 (46.0)
1.55 (0.80-3.02)
Age
   <70 years
26/35 (74.3)
15/35 (42.9)
3.85 (1.40-10.59)
   ≥70 years
62/109 (56.9)
43/110 (39.1)
2.06 (1.20-3.52)
Region
   Europe
55/96 (57.3)
37/90 (41.1)
1.92 (1.07-3.44)
   North America
20/31 (64.5)
12/28 (42.9)
2.42 (0.85-6.92)
   Other
13/17 (76.5)
9/27 (33.3)
6.50 (1.64-25.76)
Baseline ISS
   I
33/50 (66.0)
20/48 (41.7)
2.72 (1.20-6.17)
   II
32/54 (59.3)
26/57 (45.6)
1.73 (0.82-3.68)
   III
23/40 (57.5)
12/40 (30.0)
3.16 (1.26-7.94)
Cytogenetic Risk
   High risk
10/20 (50.0)
9/18 (50.0)
1.00 (0.28-3.57)
   Standard risk
67/105 (63.8)
44/111 (39.6)
2.68 (1.55-4.66)
Baseline ECOG PS
   0
30/52 (57.7)
26/57 (45.6)
1.63 (0.76-3.47)
   ≥1
58/92 (63.0)
32/88 (36.4)
2.99 (1.63-5.48)
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance score; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone.

Prespecified Subgroup Analysis of PFS (TIE Subgroup)8
Subgroup
D-VRd
VRd
HR (95% CI)
Events/N
Median PFS, months
Events/N
Median PFS, months
Sex
   Male
23/65
NE
47/82
47.9
0.43 (0.26-0.70)
   Female
31/79
NE
29/63
59.9
0.76 (0.46-1.26)
Age
   <70 years
15/35
NE
20/35
59.9
0.60 (0.31-1.18)
   ≥70 years
39/109
NE
56/110
49.4
0.54 (0.36-0.82)
Region
   Europe
36/96
NE
48/90
49.6
0.55 (0.36-0.85)
   North America
11/31
NE
13/28
50.2
0.49 (0.22-1.10)
   Other
7/17
NE
15/27
68.0
0.78 (0.32-1.91)
Baseline ISS
   I
17/50
NE
25/48
60.5
0.52 (0.28-0.97)
   II
19/54
NE
30/57
49.4
0.50 (0.28-0.88)
   III
18/40
66.4
21/40
43.8
0.66 (0.35-1.24)
Cytogenetic Risk
   High risk
11/20
58.0
12/18
31.7
0.82 (0.36-1.87)
   Standard risk
35/105
NE
50/111
61.6
0.58 (0.38-0.89)
Baseline ECOG PS
   0
13/52
NE
28/57
59.9
0.33 (0.17-0.64)
   ≥1
41/92
74.8
48/88
47.2
0.70 (0.46-1.06)
Abbreviations: CI, confidence interval; D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance score; HR, hazard ratio; ISS, International Staging System; NE, not estimable; PFS, progression-free survival; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone.
  • OS favored D-VRd vs VRd (HR, 0.84; 95% CI, 0.57-1.24) and when censoring for COVID-19-related deaths (HR, 0.74; 95% CI, 0.49-1.12).8
    • Deaths from COVID-19 occurred in 8 patients (5.6%) in the D-VRd arm and 3 patients (2.1%) in the VRd arm.
    • Deaths from progressive disease occurred in 8 patients (5.6%) in the D-VRd arm vs 17 patients (12.0%) in the VRd arm.
Safety

Safety Overview (TIE Subgroup)8
Event, n (%)
D-VRd
(n=144)
VRd
(n=142)
Any TEAE
144 (100.0)
142 (100.0)
   Grade 3/4
135 (93.8)
126 (88.7)
   Grade 5 non-COVID-19
18 (12.5)
13 (9.2)
   Grade 5 COVID-19a
6 (4.2)
1 (0.7)
Any serious TEAE
109 (75.7)
99 (69.7)
TEAE leading to discontinuation of study treatment
14 (9.7)
33 (23.2)
Exposure-adjusted grade 5 TEAE rate, patient-monthsb
0.30/100
0.26/100
Second primary malignancies
20 (13.9)
20 (14.1)
Most common (≥5%) grade 3/4 TEAEs of interest
   Neutropenia
65 (45.1)
47 (33.1)
   Thrombocytopenia
44 (30.6)
33 (23.2)
   Anemia
16 (11.1)
14 (9.9)
   Diarrhea
20 (13.9)
15 (10.6)
   Fatigue
13 (9.0)
15 (10.6)
   COVID-19c
14 (9.7)
5 (3.5)
   Pneumonia
26 (18.1)
19 (13.4)
   Peripheral sensory neuropathy
Any grade: 86 (59.7)
Grade 3/4: 14 (9.7)
Any grade: 91 (64.1)
Grade 3/4: 12 (8.5)
Abbreviations: D-VRd, DARZLEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; TIE, transplant ineligible; VRd, bortezomib + lenalidomide + dexamethasone.
aDeaths on or within 30 days of treatment.
bExposure-adjusted incidence rate: number of subjects with event per 100 patient-months at risk. Patient-months at risk = sum of exposure time until first TEAE occurrence or end of treatment for subjects without the event.cGroup term.

Phase 2 Study of DARZALEX FASPRO in Combination with Various Treatment Regimens in MM

PLEIADES (MMY2040; NCT03412565) was a phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM.9-12

Updated Analysis of the D-VRd, D-VMP, and D-Rd Cohorts of the PLEIADES Study

Chari et al (2021)12 presented updated safety and efficacy results of the D-VRd, DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP), and DARZALEX FASPRO in combination with lenalidomide and dexamethasone (D-Rd) arms in the PLEIADES study. Results specific to the D-VRd cohort are summarized below.

Results: D-VRd Cohort

Patient Characteristics

Baseline Demographics and Patient Characteristicsa,12
Transplant-eligible NDMM
D-VRd (n=67)
Age, years
   Median (range)
59 (33-76)
   18 to <65, n (%)
54 (80.6)
   65 to <75, n (%)
12 (17.9)
   ≥75, n (%)
1 (1.5)
Male, n (%)
48 (71.6)
Median (range) body weight, kg
77 (43-148)
Race, n (%)
   White
38 (56.7)
   Black or African American
5 (7.5)
   Asian
0 (0)
ECOG PS score, n (%)
   0
40 (59.7)
   1
26 (38.8)
   2
1 (1.5)
Median (range) number of prior lines of therapy, n
N/A
ISS stagingb,n (%)
   I
30 (44.8)
   II
23 (34.3)
   III
14 (20.9)
Cytogenetic riskc,d
   N
53
   Standard risk, n (%)
40 (75.5)
   High risk, n (%)
13 (24.5)
      t(4;14)
9 (17)
      t(14;16)
1 (1.9)
      del17p
5 (9.4)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; NDMM, newly diagnosed multiple myeloma.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bBased on the combination of serum β2-microglobulin and albumin at screening.
cBased on fluorescence in situ hybridization or karyotyping testing conducted locally.
dHigh cytogenetic risk was defined as having ≥1 of t(4;14), t(14;16) or del17p abnormalities.
Efficacy
  • Median follow-up was 3.9 months for the D-VRd cohort.12
  • Primary endpoints were met for the D-VRd cohort with available data and response rates were similar to DARZALEX results in the GRIFFIN study.2
  • In the D-VRd cohort (n=67)12:
    • ≥VGPR was 71.6% vs 71.7% in the GRIFFIN study
    • Overall response rate (ORR) was 97% vs 98%
    • PR was 25.4% vs 26.3%
    • CR was 7.5% vs 12.1%
    • sCR was 9% vs 7.1%
Safety
  • Treatment discontinuation due to TEAEs occurred in 2% of patients in the D-VRd arm. A summary of TEAEs in the D-VRd cohort is presented in Table: Safety Summary.12

Safety Summary12
Transplant-eligible NDMM
D-VRd (n=67)
Any TEAE, n (%)
67 (100)
Serious
19 (28.4)
Grade 3/4
39 (58.2)
Grade 5
1 (1.5)
TEAEs leading to treatment discontinuation
1 (1.5)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; NDMM, newly diagnosed multiple myeloma; TEAE, treatment emergent adverse event.
  • Any-grade IRRs occurred in 7.5% of patient across all cohorts.12
  • Across all 3 cohorts with available data, any grade IRRs occurred in 7.5% (15/199) of patients. IRRs were mild (grade 1/2), one patient had grade 3 IRR and no patients reported grade 4 IRR.12
  • Median time to onset of IRRs was 4.4 hours in the D-VRd cohort.12
  • Across all 3 cohorts with available data local injection site reactions occurred in 7.5% (15/199) of patient (all grade 1/2).12
  • A summary of most common TEAEs is presented in Table: Most Common TEAEs (≥5% in D-VRd Cohort).12

Most common TEAEs (≥5% in D-VRd Cohort)a,12
Event, n (%)
Transplant-eligible NDMM
D-VRd (n=67)
Neutropenia
19 (28.4)
Lymphopenia
11 (16.4)
Thrombocytopenia
10 (14.9)
Leukopenia
5 (7.5)
Anemia
3 (4.5)
Pneumonia
2 (3)
Hypertension
1 (1.5)
Hyperglycemia
1 (1.5)
Hypokalemia
0 (0)
Any-Grade IRR
6 (9)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; NDMM, newly diagnosed multiple myeloma; TEAE, treatment-emergent adverse event. aThe all-treatedpopulation included all patients who received ≥1 dose of study treatment.

LITERATURE SEARCH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 02 June 2026. In response to your specific request, summarized in this response is the relevant data from company-sponsored studies pertaining to this topic.

 

References

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1 Voorhees P, 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 Annual Meeting of the American Society of Hematology (ASH); December 9-12, 2017; Atlanta, GA.  
2 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.  
3 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.  
4 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.  
5 Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
6 Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313.  
7 Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study. Nat Med. 2025;31(4):1195-1202.  
8 Usmani S, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide,  and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma: final analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. Oral presentation presented at: The American Society of Clinical Oncology (ASCO) Annual Meeting; May 29-June 2, 2026; Chicago, USA.  
9 Chari A, Goldschmidt H, San-Miguel J, et al. Subcutaneous (SC) daratumumab (DARA) in combination with standard multiple myeloma (MM) treatment regimens: an open-label, multicenter phase 2 study (PLEIADES). Oral Presentation presented at: The 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
10 Chari A, Goldschmidt H, Yang S, et al. Subcutaneous daratumumab plus carfilzomib and dexamethasone in relapsed/refractory multiple myeloma: an open-label, multicenter, phase 2 study (PLEIADES). Poster presented at: The 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
11 Chari A, Miguel J, McCarthy H, et al. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy: PLEIADES study update. Poster presented at: Poster presented at: The 61st American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.  
12 Chari A, Rodriguez-Otero P, McCarthy H, et al. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label phase II study. Br J Haematol. 2021;192(5):869-878.  
13 Nooka AK, Kaufman JL, Rodriguez C, et al. Post hoc analysis of daratumumab plus lenalidomide, bortezomib, and dexamethasone in black patients from final data of the GRIFFIN study. Br J Haematol. 2024;00:1-6.  
14 Callander NS, Silbermann R, Kaufman JL, et al. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer J. 2024;14(1):69.  
15 Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA)/ bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Poster presented at: The European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain.  
16 Rodriguez-Otero P, Voorhees P, Boccadoro M, et al. Daratumumab for newly diagnosed multiple myeloma: pooled analysis of patients aged ≥65 years from GRIFFIN and PERSEUS. [Published online ahead of print April 11, 2025]. Clin Lymphoma Myeloma Leuk. doi:10.1016/j.clml.2025.04.007.  
17 Zweegman S, Usmani SZ, Hungria V, et al. The phase 3 CEPHEUS trial of daratumumab plus bortezomib, lenalidomide, and dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: frailty subgroup analysis. Oral Presentation presented at: The 6th European Myeloma Network (EMN) Meeting; April 10-12, 2025; Athens, Greece.  
18 Bahlis NJ, Usmani SZ, Facon T, et al. Daratumumab + bortezomib, lenalidomide, and dexamethasone vs bortezomib, lenalidomide, and dexamethasone in transplant-ineligible/ transplant-deferred newly diagnosed multiple myeloma: phase 3 CEPHEUS trial cytogenetic subgroup analysis. Poster presented at: The American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2025; Chicago, USA.  
19 Moreau P, Sonneveld P, Einsele H, et al. Subcutaneous daratumumab (Dara) + bortezomib/lenalidomide/dexamethasone with Dara + lenalidomide maintenance in transplant-eligible patients with newly diagnosed multiple myeloma: analysis of sustained minimal residual disease negativity in the phase 3 PERSEUS trial. Oral Presentation presented at: The American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2025; Chicago, USA.  
20 San-Miguel J, Usmani S, Zweegman S, et al. Patient-reported outcomes (PROs) and safety in patients (pts) with NDMM achieving MRD negativity and ≥CR (MRDneg) in the phase 3 PERSEUS and CEPHEUS trials. Oral Presentation presented at: 22nd International Myeloma Society (IMS) Annual Meeting; September 17-20, 2025; Toronto, Canada.  
21 Voorhees PM, Sborov DW, Laubach J, et al. Supplement to: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
22 Facon T, Zweegman S, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) in patients with newly diagnosed multiple myeloma (NDMM): Subgroup analysis of transplant-ineligible (TIE) patients in the phase 3 CEPHEUS study. Oral Presentation presented at: The American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2025; Chicago, USA.  

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