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DARZALEX FASPRO®

(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

Medical Information

DARZALEX FASPRO - Minimal Residual Disease in Clinical Trials

Last Updated: 10/01/2025

SUMMARY

  • Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • CEPHEUS: phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).1-3
    • Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months, the overall minimal residual disease (MRD)-negativity (10-5 sensitivity with complete response or better [≥CR]) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; odds ratio [OR], 2.37; 95% confidence interval [CI], 1.58-3.55; P<0.0001). Similarly, the sustained MRD-negativity (10-5 sensitivity; ≥12 months) rate was significantly higher in the D-VRd vs VRd arm (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4; P<0.0001). The overall ≥CR rate was significantly higher with D-VRd vs VRd (81.2% vs 61.6%; OR, 2.73; 95% CI, 1.71-4.34; P<0.0001).
    • Zweegman et al (2024)4 presented an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for a stem cell transplant (SCT) or transplant deferred. The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free. Analyses of MRD-negativity (with ≥CR) rates in D-VRd vs VRd were generally consistent across prespecified subgroups.
    • Zweegman et al (2025)5 presented a subgroup analysis to assess efficacy and safety outcomes from the CEPHEUS study based on frailty status in patients with NDMM who were TIE or transplant deferred. The overall MRD-negativity rates
      (at 10-5 and 10-6 threshold) and sustained (≥12 months) MRD-negativity rates (10-5 threshold) were higher with D-VRd compared with VRd across the International Myeloma Working Group (IMWG) and Intergroupe Francophone de Myélome (IFM) frailty subgroups. A reduction in the risk of progression or death with D-VRd was reported to be 41% and 44% in the IMWG fit and intermediate-fit groups, and 42% and 49% in the IFM nonfrail and frail groups, respectively. Any grade 3/4 events reported in the D-VRd vs VRd arms were 89.5% vs 84.1% in the IMWG fit subgroup, 97.3% vs 88.9% in the IMWG intermediate fitness subgroup, 90.0% vs 84.6% in the IFM nonfrail subgroup, and 98.2% vs 89.7% in the IFM frail subgroup. Overall safety was consistent with the established profiles of DARZALEX FASPRO and VRd across frailty subgroups, with no detriment in health-related quality of life (HRQoL).
    • Facon et al (2025)6 presented a post hoc subgroup analysis of the CEPHEUS study that evaluated the efficacy and safety of D-VRd vs VRd in TIE patients with NDMM. D-VRd significantly increased the overall MRD-negativity with ≥CR rate compared to VRd (10-5 sensitivity threshold, 60.4% vs 39.3%; 10-6 sensitivity threshold, 45.8% vs 26.9%). D-VRd vs VRd showed higher ≥12 months (47.2% vs 28.3%), and ≥24 months (40.3% vs 22.8%) sustained MRD-negativity rates at 10-5 sensitivity threshold. Further, D-VRd vs VRd also showed higher ≥12 months (33.3% vs 16.6%) and ≥24 months (27.1% vs 13.8%) sustained MRD negativity rates at 10-6 sensitivity threshold. The treatment effect on the overall MRD-negativity with ≥CR (10-5 sensitivity threshold) remained consistent across predefined subgroups.
    • Bahlis et al (2025)7 presented the results of a post hoc analysis of the cytogenetic subgroup from the phase 3 CEPHEUS study. D-VRd vs VRd showed higher overall MRD-negativity and sustained MRD-negativity (≥12 months and ≥24 months) ≥CR rates at 10-5 sensitivity threshold. D-VRd vs VRd showed generally favorable treatment effects for DVRd for overall MRD-negativity ≥CR and sustained MRD-negativity rates (≥12 months and ≥24 months) at the 10⁻⁵ sensitivity threshold in subgroups with high-risk cytogenetic abnormalities (HRCAs) with exceptions among the protocol-defined high-risk subgroup. At 10-6 sensitivity threshold, D-VRd vs VRd showed higher overall MRD-negativity rates in the 1 revised HRCA, isolated amp(1q), and isolated gain/amp(1q) subgroups and a higher sustained (≥12 months) MRD-negativity ≥CR rate in the isolated gain/amp(1q) subgroup.
  • PERSEUS: ongoing phase 3 study evaluating the efficacy and safety D-VRd vs VRd induction and consolidation followed by maintenance with lenalidomide and daratumumab (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for autologous stem cell transplant (ASCT).8
    • Sonneveld et al (2023)8 reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. At a median follow-up duration of 47.5 months (range, 0-54.4), overall MRD-negativity of 75.2% vs 47.5% (P<0.0001) was higher with D-VRd vs VRd cohort.
    • Bertamini et al (2024)9 presented results from the PERSEUS study that highlighted the significance of circulating tumor cells (CTCs) as a biomarker in transplant-eligible NDMM patients. D-VRd vs VRd significantly improved patient outcomes, across both high and low CTC levels (P<0.0001). D-VRd vs VRd improved MRD-negativity rates (≥CR; 10-5 and 10-6 sensitivities) and sustained MRD-negativity rates (≥CR; 10-5 and 10-6 sensitivities; ≥12 months) in patients with both high and low CTC levels. D-VRd vs VRd improved PFS in patients with high cytogenetic risk and low CTC levels. However, there was no improvement in outcomes for patients with high cytogenetic risk combined with high CTC levels. Further, D-VRd vs VRd significantly improved PFS in patients with both high and low CTC levels (P<0.0001).
    • Moreau et al (2025)10 presented findings from the phase 3 PERSEUS study, highlighting the impact of sustained MRD-negativity on PFS and the incidence of functionally high-risk disease. D-VRd vs VRd more than doubled the rates of sustained MRD-negativity ≥CR (10-5 sensitivity threshold) at ≥12 months (64.8% vs 29.7%; OR, 4.42; 95% CI, 3.22-6.08; P<0.0001) and ≥24 months (55.8% vs 22.6%; OR, 4.36; 95% CI, 3.15-6.05; P<0.0001), respectively. DVRd was associated with higher rates of sustained MRD negativity (10‒5) ≥CR when compared to VRd across subgroups.
  • APOLLO: phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO + pomalidomide and dexamethasone (D-Pd) vs pomalidomide and dexamethasone (Pd) in patients with relapsed refractory multiple myeloma (RRMM).
    • Dimopoulos et al (2021)11 reported the primary analysis of this ongoing study with a median follow-up of 16.9 months. MRD-negativity rate was 9% in patients treated with D-Pd vs 2% with Pd (OR, 4.7; 95% CI, 1.3-16.9; P=0.010).
  • PLEIADES: 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).
    • Chari et al (2021)12 presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 3.9 months for D-VRd (primary analysis), 14.3 months for DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP), and 14.7 months for DARZALEX FASPRO in combination with lenalidomide and dexamethasone (D-Rd). MRD-negativity rates were 16.4% (90% CI, 9.4-25.7) in the D-VMP cohort and 15.4% (90% CI, 8.6-24.7) in the D-Rd cohort.
    • Moreau et al (2020)13 presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 9.2 months for DARZALEX FASPRO in combination with carfilzomib and dexamethasone (D-Kd; primary analysis), 25.7 months for D-Rd, and 25.2 months for D-VMP. MRD-negativity rates were evaluated via next-generation sequencing (NGS) at a sensitivity threshold of 10-5. MRD-negativity rates were 24.2% in the D-Kd cohort, 20% in the D-Rd cohort, and 25.4% in the D-VMP cohort.
    • MRD-negative ≥CR rates were 21.2% in the D-Kd cohort, 20% in the D-Rd cohort, and 25.4% in the D-VMP cohort.
  • AURIGA: ongoing phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment D-R vs R alone in patients with NDMM who are anti-cluster of differentiation (CD) 38 naïve, have a very good partial response or better (≥VGPR), and are MRD-positive following ASCT after standard-of-care induction/consolidation.14-16
    • Badros et al (2024)14,15,17 reported primary results from the phase 3 AURIGA study. The MRD-negativity (10-5 sensitivity) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; OR, 4.51; 95% CI, 2.37-8.57; P<0.0001). Similarly, the MRD-negativity (10-6) conversion rate by 12 months from initiation of maintenance was higher with D-R vs R (23.2% vs 5%; OR, 5.97; 95% CI, 2.15-16.58; P=0.0002). At a median follow-up of 32.3 months, the D-R vs R arm showed a higher overall MRD-negativity conversion rate (10-5 sensitivity, 60.6% vs 27.7%; 10-6 sensitivity, 36.4% vs 12.9%).
    • Anderson et al (2025)18 presented updated efficacy and safety results from the phase 3 AURIGA study at 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months. The MRD-negativity (10-5) conversion rate was significantly higher for D-R vs R (60.6% vs 28.7%; OR, 3.92; 95% CI, 2.16-7.14; P<0.0001). Similarly, the MRD-negativity (10-6) conversion rate was higher with D-R vs R (36.4% vs 13.9%; OR, 3.59; 95% CI, 1.78-7.23; P=0.0003). No new safety concerns were identified with the addition of DARZALEX FASPRO to R maintenance.
  • Several subgroup analyses that reported on MRD outcomes with the use of DARZALEX FASPRO were identified. These analyses are listed in the References section for your information.19-25

CLINICAL DATA

CEPHEUS (MMY3019; NCT03652064) is an ongoing, randomized, open-label, multicenter, phase 3 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).1-3 Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study.

Results

Patient Characteristics


Baseline Demographics and Clinical Characteristics of the ITT Populationa,3
Characteristic
D-VRd (n=197)
VRd (n=198)
Median age (range), years
70 (42-79)
70 (31-80)
   <65 years, n (%)
36 (18.3)
35 (17.7)
   65 to <70 years, n (%)
52 (26.4)
53 (26.8)
   ≥70 years, n (%)
109 (55.3)
110 (55.6)
Age or transplant eligibility, n (%)
   <70 years and transplant ineligible
35 (17.8)
35 (17.7)
   <70 years and transplant deferred
53 (26.9)
53 (26.8)
   ≥70 years
109 (55.3)
110 (55.6)
Maleb, n (%)
87 (44.2)
111 (56.1)
Raceb, n (%)
   White
162 (82.2)
156 (78.8)
   Black or African American
10 (5.1)
9 (4.5)
   Asian
11 (5.6)
14 (7.1)
   Native Hawaiian or other Pacific Islander
0 (0)
1 (0.5)
   Other
1 (0.5)
2 (1)
   Not reported
13 (6.6)
16 (8.1)
ECOG PSc, n (%)
   0
71 (36)
84 (42.4)
   1
103 (52.3)
100 (50.5)
   2
23 (11.7)
14 (7.1)
Frailty scored, n (%)
   0 (fit)
124 (62.9)
132 (66.7)
   1 (intermediate fitness)
73 (37.1)
66 (33.3)
Type of measurable disease, n (%)
   Detected in serum only
120 (60.9)
108 (54.5)
      IgG
89 (45.2)
76 (38.4)
      IgA
27 (13.7)
31 (15.7)
      Othere
4 (2)
1 (0.5)
   Detected in serum and urine
41 (20.8)
45 (22.7)
   Detected in urine only
20 (10.2)
24 (12.1)
   Detected in serum FLCs only
16 (8.1)
21 (10.6)
ISS disease stagef, n (%)
   I
68 (34.5)
68 (34.3)
   II
73 (37.1)
75 (37.9)
   III
56 (28.4)
55 (27.8)
Cytogenetic risk profileg, n (%)
   Standard risk
149 (75.6)
149 (75.3)
   High risk
25 (12.7)
27 (13.6)
   Indeterminateh
23 (11.7)
22 (11.1)
Median time since diagnosis of MM (range), months
1.2 (0.4-5.8)
1.3 (0.3-8)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone.
aThe ITT population was defined as all patients who underwent randomization.
bSex and race were reported by the patient.
cECOG PS is scored on a scale of 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability.
dTotal 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/).
eIncludes IgD, IgM, IgE, and biclonal.fBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
gAssessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).
hIndeterminate includes patients with missing or unevaluable samples.

Efficacy

  • A summary of the MRD status and response rates in the ITT population is presented in Table: Summary of MRD Status and Response Rates in the ITT Population.
    • D-VRd vs VRd significantly increased the overall MRD-negativity rate (10-5 sensitivity with ≥CR; 60.9% vs 39.4%) and ≥CR rate (81.2% vs 61.6%).3
    • Patients in the D-VRd vs VRd arm showed a higher MRD-negativity rate at 10-6 sensitivity (46.2% vs 27.3%) and a significantly higher sustained (≥12 months) MRD-negativity rate at 10-5 sensitivity (48.7% vs 26.3%).3
    • The treatment effect on the overall MRD-negativity rate remained consistent across the predefined subgroups and is summarized in Table: Prespecified Subgroup Analysis of Overall MRD-Negativity Rates.

Summary of MRD Status and Response Rates in the ITT Population3
Parameter
D-VRd (n=197)
VRd (n=198)
OR (95% CI)
P Value
Overall MRD-negativitya, %
   10-5 sensitivity
60.9
39.4
2.37 (1.58-3.55)
<0.0001
   10-6 sensitivity
46.2
27.3
2.24 (1.48-3.40)
0.0001
Sustained MRD-negativity
(10‒5) for ≥12 months, %
48.7
26.3
2.63 (1.73-4)
<0.0001
Responseb, n
191
184
-
-
   ORR, % (95% CI)
97 (93.5-98.9)
92.9 (88.4-96.1)
-
0.0698
      sCR, n (%)
128 (65)
88 (44.4)
-
<0.0001
      CR, n (%)
32 (16.2)
34 (17.2)
-
-
      VGPR, n (%)
23 (11.7)
50 (25.3)
-
-
      PR, n (%)
8 (4.1)
12 (6.1)
-
-
   ≥CR, n (%)
160 (81.2)
122 (61.6)
2.73 (1.71-4.34)
<0.0001
   ≥VGPR, n (%)
183 (92.9)
172 (86.9)
-
0.0495
   SD, n (%)
5 (2.5)
7 (3.5)
-
-
   PD, n (%)
0 (0)
0 (0)
-
-
   Response could not be evaluated, n (%)
1 (0.5)
7 (3.5)
-
-
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IMWG, International Myeloma Working Group; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aMRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity (10-5 threshold) and ≥CR.
bResponse rates at any time during the study. Response was assessed based on IMWG response criteria. P values were calculated using the stratified Cochran-Mantel-Haenszel chi-squared test.

Prespecified Subgroup Analysis of Overall MRD-Negativity Rates3
Subgroup
D-VRd
VRd
OR (95% CI)
Number of Patients With MRD-Negativity/
Total Number of Patients (%)
Sex
   Male
54/87 (62.1)
39/111 (35.1)
3.02 (1.69-5.41)
   Female
66/110 (60)
39/87 (44.8)
1.85 (1.04-3.26)
Age
   <70 years
59/88 (67)
36/88 (40.9)
2.94 (1.59-5.44)
   ≥70 years
61/109 (56)
42/110 (38.2)
2.06 (1.20-3.53)
Region
   Europe
69/120 (57.5)
46/116 (39.7)
2.06 (1.23-3.46)
   North America
21/37 (56.8)
13/31 (41.9)
1.82 (0.69-4.77)
   Other
30/40 (75)
19/51 (37.3)
5.05 (2.03-12.60)
Weight
   ≤65 kg
40/58 (69)
22/63 (34.9)
4.14 (1.94-8.86)
   >65-85 kg
58/101 (57.4)
31/88 (35.2)
2.48 (1.38-4.47)
   >85 kg
22/38 (57.9)
25/47 (53.2)
1.21 (0.51-2.87)
ISS staging
   I
45/68 (66.2)
30/68 (44.1)
2.48 (1.24-4.96)
   II
47/73 (64.4)
29/75 (38.7)
2.87 (1.47-5.59)
   III
28/56 (50)
19/55 (34.5)
1.89 (0.88-4.07)
Cytogenetic risk
   High risk
12/25 (48)
15/27 (55.6)
0.74 (0.25-2.20)
   Standard risk
95/149 (63.8)
57/149 (38.3)
2.84 (1.78-4.54)
   Indeterminate
13/23 (56.5)
6/22 (27.3)
3.47 (0.99-12.09)
ECOG PS score
   0
41/71 (57.7)
36/84 (42.9)
1.82 (0.96-3.45)
   ≥1
79/126 (62.7)
42/114 (36.8)
2.88 (1.71-4.87)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.

Expanded Analysis of MRD Outcomes - Results From the CEPHEUS Study

Zweegman et al (2024)4 presented an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for SCT or for whom transplant was deferred.

Results

Patient Characteristics

  • A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.4

Efficacy

  • A summary of the cumulative and sustained MRD-negativity (≥CR) rates is presented in Table: Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis.
    • D-VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints.4
    • D-VRd almost doubled sustained MRD-negativity (≥) CR rates at 12, 24, and 36 months.4
    • Among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.4
  • D-VRd vs VRd showed PFS benefit regardless of the MRD-negativity status (10-6 sensitivity).4
    • The overall MRD-negativity rate (10-6 sensitivity) for D-VRd vs VRd was 46.2% vs 27.3%, respectively, and the overall MRD-positivity rate (10-6 sensitivity) was 53.8% vs 72.7%, respectively.
    • At 54 months, the estimated PFS by MRD-negativity status (10-6 sensitivity) was 86.2% vs 79% and by MRD-positivity status was 51% vs 36.5% for D-VRd vs VRd, respectively.
  • Analyses of MRD-negativity (with ≥CR) rates in prespecified subgroups appeared to consistently favor D-VRd over VRd across these prespecified subgroups and are summarized in Table: MRD-Negativity (≥CR) Rates in Prespecified Subgroups.

Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis4
Parameter
D-VRd
(n=197)
VRd
(n=198)
OR (95% CI)
P Value
Cumulative MRD-negativity (10-5 sensitivity; ≥CR), %
   12 months
43.1
28.3
-
-
   24 months
56.9
35.9
-
-
   36 months
59.9
37.4
-
-
   48 months
60.9
38.4
-
-
Cumulative MRD-negativity (10-6 sensitivity; ≥CR), %
   12 months
22.8
11.1
-
-
   24 months
38.1
22.2
-
-
   36 months
40.6
25.3
-
-
   48 months
45.2
27.3
-
-
Sustained MRD-negativity (10-5 sensitivity; ≥CR)a, %
   ≥12 monthsb
49.2
27.3
2.56 (NR)
<0.0001
   ≥24 monthsc
42.1
22.7
2.47 (NR)
<0.0001
   ≥36 monthsd
29.9
15.2
2.37 (NR)
0.0005
Sustained MRD-negativity (10-6 sensitivity; ≥CR)a, %
   ≥12 monthsb
34
16.2
NR
NR
   ≥24 monthsc
27.9
13.6
NR
NR
   ≥36 monthsd
18.8
8.6
NR
NR
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; NR, not reported; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aAt any time during the study.
bProportion of patients who achieved ≥CR and achieved an MRD-negative status at 2 bone marrow assessments that are 12 month apart with an allotted window of ±1 month, without an MRD-positive status in between.
cAchieving an MRD-negative status at 2 bone marrow assessments that are 24 months apart with an allotted window of ±3 months, without an MRD-positive status in between.
dAchieving an MRD-negative status at 2 bone marrow assessments that are 36 months apart with an allotted window of ±3 months, without an MRD-positive status in between.

MRD-Negativity (≥CR) Rates in Prespecified Subgroups4
Subgroups,
n/N (%)
D-VRd
VRd
OR
(95% CI)
D-VRd
VRd
OR
(95% CI)
10-5 Sensitivity
10-6 Sensitivity
Sex
   Male
54/87
(62.1)
39/111
(35.1)
3.02
(1.69-5.41)
42/87
(48.3)
28/111
(25.2)
2.77
(1.52-5.04)
   Female
66/110
(60)
39/87
(44.8)
1.85
(1.04-3.26)
49/110
(44.5)
26/87
(29.9)
1.88
(1.04-3.41)
Age
   <70 years
59/88
(67)
36/88
(40.9)
2.94
(1.59-5.44)
44/88
(50)
25/88
(28.4)
2.52
(1.35-4.70)
   ≥70 years
61/109
(56)
42/110
(38.2)
2.06
(1.20-3.53)
47/109
(43.1)
29/110
(26.4)
2.12
(1.20-3.74)
Region
   Europe
69/120
(57.5)
46/116
(39.7)
2.06
(1.23-3.46)
57/120
(47.5)
34/116
(29.3)
2.18
(1.28-3.73)
   North America
21/37
(56.8)
13/31
(41.9)
1.82
(0.69-4.77)
14/37
(37.8)
9/31
(29)
1.49
(0.54-4.13)
   Other
30/40
(75)
19/51
(37.3)
5.05
(2.03-12.60)
20/40
(50)
11/51
(21.6)
3.64
(1.46-9.04)
Weight
   ≤65 kg
40/58
(69)
22/63
(34.9)
4.14
(1.94-8.86)
31/58
(53.4)
18/63
(28.6)
2.87
(1.35-6.09)
   >65-85 kg
58/101
(57.4)
31/88
(35.2)
2.48
(1.38-4.47)
45/101
(44.6)
19/88
(21.6)
2.92
(1.54-5.54)
   >85 kg
22/38
(57.9)
25/47
(53.2)
1.21
(0.51-2.87)
15/38
(39.5)
17/47 (36.2)
1.15
(0.48-2.78)
ISS staging
   I
45/68
(66.2)
30/68
(44.1)
2.48
(1.24-4.96)
32/68
(47.1)
22/68
(32.4)
1.86
(0.93-3.73)
   II
47/73
(64.4)
29/75
(38.7)
2.87
(1.47-5.59)
37/73
(50.7)
17/75
(22.7)
3.51
(1.73-7.13)
   III
28/56
(50)
19/55
(34.5)
1.89
(0.88-4.07)
22/56
(39.3)
15/55
(27.3)
1.73
(0.78-3.84)
Cytogenetic risk
   High risk
12/25
(48)
15/27
(55.6)
0.74
(0.25-2.20)
8/25
(32)
12/27
(44.4)
0.59
(0.19-1.83)
   Standard risk
95/149
(63.8)
57/149
(38.3)
2.84
(1.78-4.54)
71/149
(47.7)
37/149
(24.8)
2.76
(1.69-4.50)
ECOG PS score
   0
41/71
(57.7)
36/84
(42.9)
1.82
(0.96-3.45)
28/71
(39.4)
27/84
(32.1)
1.37
(0.71-2.66)
   ≥1
79/126
(62.7)
42/114
(36.8)
2.88
(1.71-4.87)
63/126
(50)
27/114
(23.7)
3.22
(1.85-5.61)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.

Analysis of Sustained MRD-negativity from the Phase 3 PERSEUS Study

Moreau et al (2025)10 presented findings from the phase 3 PERSEUS study, highlighting the impact of sustained MRD-negativity on PFS and the incidence of functionally high-risk disease, defined as those experiencing relapse or progression within 18 months of treatment initiation, who often have poorer survival outcomes.

Results

Patient Characteristics

Sustained MRD Negativity ≥CR (10‒5) ≥12 Months Baseline Demographics and Clinical Characteristics10
Characteristic
Sustained (≥12 months) MRD negativity ≥CR
(10–5) D-VRd
(n=230)
Non-sustained (≥12 months) MRD negativity ≥CR (10-5) D-VRd
(n=125)
Median age, years
60.0
61.0
Male, n (%)
131 (57.0)
80 (64.0)
ECOG PS, n (%)
   0
150 (65.2)
71 (56.8)
   1
64 (27.8)
50 (40.0)
   ≥2
16 (6.9)
4 (3.2)
ISS staginga, n (%)
   I
128 (55.7)
58 (46.4)
   II
69 (30.0)
45 (36.0)
   III
33 (14.3)
22 (17.6)
Standard cytogenetic risk, n (%)
183 (79.6)
81 (64.8)
High cytogenetic riskb, n (%)
37 (16.1)
39 (31.2)
   del(17p)
14 (6.1)
22 (17.6)
   t(4;14)
17 (7.4)
16 (12.8)
   t(14;16)
7 (3.0)
4 (3.2)
Abbreviations: CR, complete response; D-VRd, daratumumab+bortezomib+lenalidomide+dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease.
aBased on the combination of serum β2-microglobulin and albumin levels
bBased on fluorescence in situ hybridization.

Functionally High-Risk Subgroup Baseline Demographics and Clinical Characteristics10
Characteristic
Functionally high-risk subgroupa
(n=35)
ITT population
(N=709)
Median age, years
60.0
60.0
ECOG PS, n (%)
   0
21 (60.0)
451 (63.6)
   1
12 (34.3)
222 (31.3)
   ≥2
2 (5.7)
36 (5.1)
ISS stagingb, n (%)
   I
13 (37.1)
364 (51.4)
   II
13 (37.1)
239 (33.8)
   III
9 (25.7)
105 (14.8)
Standard cytogenetic riskc, n (%)
14 (40.0)
530 (74.8)
High cytogenetic riskc, n (%)
20 (57.1)
154 (21.7)
   del(17p)
13 (37.1)
70 (9.9)
   t(4;14)
2 (5.7)
71 (10.0)
   t(14;16)
7 (20.0)
25 (3.5)
CRAB criteria, n (%)
32 (91.4)
589 (83.1)
Abbreviations: CRAB, calcium, renal, anemia, bone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat.
aDefined as those experiencing relapse or progression within 18 months of treatment initiation
bBased on the combination of serum β2-microglobulin and albumin levels
cBased on fluorescence in situ hybridization.
Efficacy
  • D-VRd vs VRd more than doubled the rates of sustained MRD-negativity ≥CR (10-5 sensitivity threshold) at ≥12 months (64.8% vs 29.7%; OR, 4.42; 95% CI, 3.22-6.08; P<0.0001) and ≥24 months (55.8% vs 22.6%; OR, 4.36; 95% CI, 3.15-6.05; P<0.0001), respectively.10

Summary of Sustained MRD-negativity Rates (10-5 Sensitivity Threshold) by Subgroups10
Subgroup
D-VRd
VRd
OR (95% CI)
Number of Patients With MRD-Negativity/
Total Number of Patients (%)
Sustained MRD negativity (10-5) ≥12 months
   Sex
      Male
131/211 (62.1)
62/205 (30.2)
3.78 (2.51-5.68)
      Female
99/144 (68.8)
43/149 (28.9)
5.42 (3.29-8.94)
   Age
      <65 years
180/261 (69.0)
78/267 (29.2)
5.38 (3.71-7.81)
      ≥65 years
50/94 (53.2)
27/87 (31.0)
2.53 (1.37-4.64)
   Race
      White
216/330 (65.5)
93/323 (28.8)
4.69 (3.37-6.52)
      Other
14/25 (56.0)
12/31 (38.7)
2.02 (0.69-5.88)
   ISS staging
      I
128/186 (68.8)
58/178 (32.6)
4.57 (2.94-7.10)
      II
69/114 (60.5)
35/125 (28.0)
3.94 (2.29-6.78)
      III
33/55 (60.0)
12/50 (24.0)
4.75 (2.04-11.05)
   Type of MM
      lgG
136/204 (66.7)
50/185 (27.0)
5.40 (3.49-8.35)
      Non-lgG
52/78 (66.7)
31/96 (32.3)
4.19 (2.22-7.92)
   Cytogenetic risk
      Standard risk
183/264 (69.3)
83/266 (31.2)
4.98 (3.45-7.20)
      High risk
37/76 (48.7)
20/78 (25.6)
2.75 (1.40-5.42)
      Intermediate
10/15 (66.7)
2/10 (20.0)
8.00 (1.21-52.69
   ECOG PS score
      0
150/221 (67.9)
71/230 (30.9)
4.73 (3.18-7.04)
      ≥1
80/134 (59.7)
34/124 (27.4)
3.92 (2.32-6.62)
Sustained MRD negativity (10-5) ≥24 months
   Sex
      Male
105/211 (49.8)
44/205 (21.5)
3.62 (2.36-5.57)
      Female
77/144 (53.5)
30/149 (20.1
4.56 (2.72-7.65)
   Age
      <65 years
141/261 (54.0)
54/267 (20.2)
4.63 (3.15-6.81)
      ≥65 years
41/94 (43.6)
20/87 (23.0)
2.59 (1.36-4.94)
   Race
      White
172/330 (52.1)
68/323 (21.1)
4.08 (2.89-5.76)
      Other
10/25 (40.0)
6/31 (19.4)
2.78 (0.84-9.20)
   ISS staging
      I
105/186 (56.5)
44/178 (24.7)
3.95 (2.52-6.17)
      II
53/114 (46.5)
21/125 (16.8)
4.30 (2.37-7.81)
      III
24/55 (43.6)
9/50 (18.0)
3.53 (1.44-8.65)
   Type of MM
      lgG
105/204 (51.5)
35/185 (18.9)
4.55 (2.87-7.19)
      Non-lgG
46/78 (59.7)
19/96 (19.8)
5.83 (2.97-11.44
   Cytogenetic risk
      Standard risk
143/264 (54.2)
58/266 (21.8)
4.24 (2.90-6.19)
      High risk
29/76 (38.2)
14/78 (17.9)
2.82 (1.34-5.92)
      Intermediate
10/15 (66.7)
2/10 (20.0)
8.00 (1.21-52.69)
   ECOG PS score
      0
121/221 (54.8)
49/230 (21.3)
4.47 (2.96-6.75)
      ≥1
61/134 (45.5)
25/124 (20.2)
3.31 (1.90-5.76)

DARZALEX FASPRO in Combination with Lenalidomide

AURIGA (MMY3021; NCT03901963) is an ongoing, open-label, active-controlled, multicenter, randomized, phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with D-R vs lenalidomide alone in patients with NDMM who are MRD-positive after ASCT.14-16 Badros et al (2024)14,15 reported primary results from the phase 3 AURIGA study. Anderson et al (2025)18 presented updated efficacy and safety results from the phase 3 AURIGA study at 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months.

Results

Patient Characteristics

  • A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.14
  • The median duration of treatment was 30.7 (range, 0.7-37.5) months vs 20.6 (range, 0-37.7) months in the D-R vs R arm, respectively.14
  • The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the ITT Population.14
  • The median follow-up was 32.3 months.14
  • Patients in the D-R vs R arm received a median of 33 (range, 1-36) vs 21.5 (range, 1-36) maintenance cycles, respectively.14
  • Overall, 85 of 96 (88.5%) vs 77 of 98 (78.6%) patients in the D-R vs R arm completed ≥12 maintenance cycles, respectively.14

Baseline Demographics and Disease Characteristics of the ITT Population14
D-R (n=99)
R (n=101)
Median age (range), years
63 (35-77)
62 (35-78)
   <65 years, n (%)
61 (61.6)
61 (60.4)
   65-70 years, n (%)
23 (23.2)
21 (20.8)
   ≥70 years, n (%)
15 (15.2)
19 (18.8)
Sex, n (%)
   Male
61 (61.6)
58 (57.4)
   Female
38 (38.4)
43 (42.6)
Race, n (%)
   White
67 (67.7)
68 (67.3)
   Black or African American
20 (20.2)
24 (23.8)
   Asian
5 (5.1)
1 (1)
   American Indian or Alaska Native
0 (0)
1 (1)
   Othera
5 (5.1)
5 (5)
   NR
2 (2)
2 (2)
ECOG PS, n (%)
   0
45 (45.5)
55 (54.5)
   1
52 (52.5)
44 (43.6)
   2
2 (2)
2 (2)
ISS disease stageb, n (%)
   I
40 (44)
38 (38.8)
   II
28 (30.8)
37 (37.8)
   III
23 (25.3)
23 (23.5)
Median induction cycles (range)c, n
5 (4-8)
5 (4-8)
Cytogenetic risk at diagnosisd, n (%)
   Standard risk
63 (68.5)
66 (74.2)
   High riske
22 (23.9)
15 (16.9)
      del(17p)
13 (14.1)
3 (3.4)
      t(4;14)
10 (10.9)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
   Unknown
7 (7.6)
8 (9)
Revised cytogenetic risk at diagnosisf, n (%)
   Standard risk
52 (55.9)
53 (59.6)
   High riskg
32 (34.4)
30 (33.7)
      del(17p)
13 (14)
3 (3.4)
      t(4;14)
10 (10.8)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
      t(14;20)
1 (1.1)
2 (2.2)
      gain/amp(1q21)
16 (17.2)
22 (24.7)
   Unknown
9 (9.7)
6 (6.7)
Abbreviations: D-R, DARZALEX FASPRO+lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; NR, not reported; R, lenalidomide.
aPatients reporting multiple races.
bD-R vs R: n=91 vs n=98, respectively.
cD-R vs R: n=98 vs n=99, respectively.
dD-R vs R: n=92 vs n=89, respectively.
eHigh risk is defined as positive for any of del(17p), t(14;16), or t(4;14).
fD-R vs R: n=93 vs n=89, respectively.
gRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).

Efficacy

  • The MRD status in the ITT population are summarized in Table: Summary of MRD Status in the ITT Population.14,15
    • The MRD-negativity (10-5 sensitivity) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; OR, 4.51; 95% CI, 2.37-8.57; P<0.0001).
    • The D-R arm yielded ~2.5 times greater sustained MRD-negativity (10-5 sensitivity) rates at ≥6 months (35.4% vs 13.9%) and relatively higher sustained MRD-negativity (10-5 sensitivity) rates at ≥12 months (17.2% vs 5%) than the R arm.
  • Subgroup analyses of MRD-negativity (10-5 sensitivity) conversion rates at 12 months appeared to consistently favor D-R over R across most clinically relevant subgroups, including patients with a standard or high cytogenetic risk and older patients; the results are summarized in Table: Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population.14

Summary of MRD Status in the ITT Population14,15
Parameter
D-R (n=99)
R (n=101)
ORa (95% CI)
P-Valueb
Overall MRD-negativity conversion ratec, n (%)
   10-5 sensitivity
60 (60.6)
28 (27.7)
4.12 (2.26-7.52)
<0.0001
   10-6 sensitivity
36 (36.4)
13 (12.9)
3.91 (1.91-7.99)
0.0001
MRD-negativity conversion rate at 12 months from start of maintenance, n (%)
   10-5 sensitivity
50 (50.5)
19 (18.8)
4.51 (2.37-8.57)
<0.0001
   10-6 sensitivity
23 (23.2)
5 (5)
5.97 (2.15-16.58)
0.0002
Sustained MRD-negativity (10-5), n (%)
   ≥6 monthsd
35 (35.4)
14 (13.9)
3.40 (1.69-6.83)
0.0005
   ≥12 monthsd
17 (17.2)
5 (5)
4.08 (1.43-11.62)
0.0065
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide.
aMantel-Haenszel estimate of the common OR for stratified tables was used. The stratification factor was the baseline cytogenetic risk per investigator assessment (high vs standard/unknown) as used for randomization. An OR of >1 indicates an advantage for the D-R arm.
bAll parameters, except ≥CR were assessed using Fisher’s exact test.
cAt a median follow-up of 32.3 months.
dSustained MRD-negativity at ≥6 months and ≥12 months is defined as an MRD-negative status (at 10-5 sensitivity threshold) in 2 bone marrow aspirate assessments spaced a minimum of 6 months and 12 months apart, respectively, without any assessment showing an MRD-positive status in between the assessments.

Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population14
Subgroup, n/N (%)
D-R (n=99)
R (n=101)
OR (95% CI)
ITT (overall)
50/99 (50.5)
19/101 (18.8)
4.51 (2.37-8.57)
Sex
   Male
32/61 (52.5)
11/58 (19)
4.71 (2.06-10.78)
   Female
18/38 (47.4)
8/43 (18.6)
3.94 (1.45-10.68)
Age
   <65 years
30/61 (49.2)
12/61 (19.7)
3.95 (1.76-8.85)
   ≥65 years
20/38 (52.6)
7/40 (17.5)
5.24 (1.86-14.74)
Race
   White
31/67 (46.3)
14/68 (20.6)
3.32 (1.55-7.10)
   Black
12/20 (60)
4/24 (16.7)
7.50 (1.85-30.34)
   Other
7/12 (58.3)
1/9 (11.1)
11.20 (1.04-120.36)
Weight
   ≤70 kg
12/23 (52.2)
4/18 (22.2)
3.82 (0.96-15.18)
   >70 kg
38/76 (50)
15/81 (18.5)
4.40 (2.14-9.03)
Baseline ECOG PS score
   0
20/45 (44.4)
9/55 (16.4)
4.09 (1.62-10.31)
   ≥1
30/54 (55.6)
10/46 (21.7)
4.50 (1.86-10.88)
ISS staging at diagnosis
   I
19/40 (47.5)
8/38 (21.1)
3.39 (1.25-9.19)
   II
13/28 (46.4)
7/37 (18.9)
3.71 (1.23-11.25)
   III
15/23 (65.2)
3/23 (13)
12.50 (2.83-55.25)
Cytogenetic risk at diagnosis
   High riska
7/22 (31.8)
1/15 (6.7)
6.53 (0.71-60.05)
   Standard risk
35/63 (55.6)
14/66 (21.2)
4.64 (2.15-10.04)
Revised cytogenetic risk at diagnosis
   High riskb
14/32 (43.8)
4/30 (13.3)
5.06 (1.43-17.88)
   Standard risk
28/52 (53.8)
12/53 (22.6)
3.99 (1.72-9.26)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO+lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide.
aHigh risk is defined as positive for any of the following abnormalities: del(17p), t(14;16), or t(4;14).
bRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).

Updated Efficacy and Safety Results

Anderson et al (2025)18 presented updated efficacy and safety results from the phase 3 AURIGA study 24 months from the start of maintenance therapy, with a median follow-up of 40.3 months.

Efficacy

Summary of MRD Status and Conversion Rates in the ITT Population18 

Parameter
D-R
R
ORa (95% CI)
P Valueb
Overall MRD-negativity conversion rate, %c
   10-5 sensitivity
60.6
28.7
3.92 (2.16-7.14)
<0.0001
   10-6 sensitivity
36.4
14
3.59 (1.78-7.23)
0.0003
Overall MRD-negativity (≥CR) conversion rate, %c
   10-5 sensitivity
55.6
23.8
4.11 (2.23-7.59)
<0.0001
   10-6 sensitivity
35.4
10.9
4.55 (2.14-9.66)
<0.0001
MRD-negativity accumulative conversion rate at 12 months from start of maintenance, %
   10-5 sensitivity
50.5
18.8
4.51 (2.37-8.57)
<0.0001
   10-6 sensitivity
23.2
5.0
5.97 (2.15-16.58)
0.0002
MRD-negativity accumulative conversion rate at 18 months from start of maintenance, %
   10-5 sensitivity
56.6
21.8
4.81 (2.57-9.00)
<0.0001
   10-6 sensitivity
30.3
8.9
4.44 (1.98-9.96)
0.0001
MRD-negativity accumulative conversion rate at 24 months from start of maintenance, %
   10-5 sensitivity
60.6
26.7
4.33 (2.36-7.94)
<0.0001
   10-6 sensitivity
35.4
10.9
4.51 (2.13-9.56)
<0.0001
Sustained MRD-negativity (10-5), %
   ≥6 monthsd
42.4
17.8
3.45 (1.80-6.61)
0.0002
   ≥12 monthsd
29.3
7.9
4.88 (2.09-11.38)
0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide.
aMantel–Haenszel estimate of the common OR for stratified tables was used. The stratification factor was BL cytogenetic risk per investigator assessment (high vs standard/unknown), as used for randomization. An OR >1 indicates an advantage for D-R.
bP value from Fisher’s exact test.
cAt a median follow-up of 40.3 months.
dDefined as those who achieved MRD-negative status (at 10–5) in 2 bone marrow aspirate assessments with a minimum of 6 or 12 months apart (based on specified endpoint), without any assessment showing MRD-positive status in between assessments.

Subgroup Analysis of MRD-Negativity (10-5) Conversion Rates in Patient Subgroups18 

Subgroup, n/N (%)
D-R
R
OR (95% CI)
Sex
   Male
37/61 (60.7)
17/58 (29.3)
3.72 (1.73-7.98)
   Female
23/38 (60.5)
12/43 (27.9)
3.96 (1.56-10.05)
Age
   <65 years
35/61 (57.4)
19/61 (31.1)
2.98 (1.42-6.25)
   ≥65 years
25/38 (65.8)
10/40 (25.0)
5.77 (2.16-15.38)
Race
   White
36/67 (53.7)
21/68 (30.9)
2.60 (1.29-5.25)
   Black or African American
16/20 (80.0)
7/24 (29.2)
9.71 (2.38-39.61)
   Other
8/12 (66.7)
1/9 (11.1)
16.00 (1.45-176.45)
Weight
   ≤70 kg
15/23 (65.2)
4/18 (22.2)
6.56 (1.61-26.72)
   >70 kg
45/76 (59.2)
25/81 (30.9)
3.25 (1.69-6.27)
Baseline ECOG PS score
   0
27/45 (60.0)
12/55 (21.8)
5.37 (2.24-12.89)
   ≥1
33/54 (61.1)
17/46 (37.0)
2.68 (1.19-6.03)
ISS staging at diagnosis
   I
22/40 (55.0)
14/38 (36.8)
2.10 (0.85-5.19)
   II
15/28 (53.6)
11/37 (29.7)
2.73 (0.98-7.59)
   III
18/23 (78.3)
3/23 (13.0)
24.00 (5.01-114.97)
Cytogenetic risk at diagnosis
   High riska
11/22 (50.0)
3/15 (20.0)
4.00 (0.88-18.22)
   Standard risk
40/63 (63.5)
20/66 (30.3)
4.00 (1.92-8.33)
Revised cytogenetic risk at diagnosis
   High riskb
19/32 (59.4)
6/30 (20.0)
5.85 (1.87-18.27)
   Standard risk
32/52 (61.5)
18/53 (34.0)
3.11 (1.40-6.90)
Cytogenic risk per IMS 2024 criteria
   High riskc
9/17 (52.9)
0/8 (0)
NE (NE-NE)
   Standard risk
42/67 (62.7)
25/68 (36.8)
2.89 (1.44-5.81)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; R, lenalidomide.
aHigh-risk cytogenetics are defined as ≥1 abnormality including del(17p), t(4;14), and/or t(14;16).
bRevised high-risk cytogenetics are defined as ≥1 abnormality including del(17p), t(4;14), t(14;16), t(14;20), and/or gain/amp(1q21).
cHigh risk per the modified IMS 2024 criteria is defined as the presence of ≥20% del(17p), or the association of ≥2 of the following: t(4;14) or t(14;16) or t(14;20); gain/amp(1q21); or del(1p32) [in the AURIGA study, data were not available on TP53 mutations, baseline ß2M, and creatinine levels and differentiation between monoallelic versus biallelic del(1p32)].

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 26 September 2025. For purposes of streamlining, this scientific response has been limited to phase 2/3 clinical studies.

In response to your specific request, summarized in this response are the relevant data from company-sponsored studies pertaining to this topic.

 

References

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1 Zweegman S, Usmani S, Chastian K, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab in patients with newly diagnosed multiple myeloma for whom transplant is not planned as initial therapy: a multicenter, randomized, phase 3 study (CEPHEUS). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO). May 31-June 4, 2019; Chicago, IL.  
2 Janssen Research & Development, LLC. A study comparing daratumumab, velcade (bortezomib), lenalidomide, and dexamethasone (D-VRd) with velcade, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 September 26]. Available from: https://clinicaltrials.gov/ct2/show/NCT03652064 NML Identifier: NCT03652064.  
3 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.  
4 Zweegman S, Facon T, Hungria V, et al. Daratumumab + bortezomib, lenalidomide and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma ineligible for SCT or for whom SCT is not planned as initial therapy: analysis of minimal residual disease in the phase 3 CEPHEUS trial. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
5 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.  
6 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.  
7 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.  
8 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.  
9 Bertamini L, Fokkema C, Rodriguez-Otero P, et al. Circulating tumor cells as a biomarker to identify high-risk transplant-eligible myeloma patients treated with bortezomib, lenalidomide, and dexamethasone with or without daratumumab during induction/consolidation, and lenalidomide with or without daratumumab during maintenance: results from the PERSEUS study. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
10 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.  
11 Dimopoulos M, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812.  
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 Moreau P, Chari A, Haenel M, et al. Subcutaneous daratumumab (DARA SC) plus standard-of-care (SoC) regimens in multiple myeloma (MM) across lines of therapy in the phase 2 PLEIADES study: initial results of the DARA SC plus carfilzomib/dexamethasone (D-Kd) cohort, and updated results for the DARA SC plus bortezomib/melphalan/prednisone (D-VMP) and DARA SC plus lenalidomide/dexamethasone (D-Rd) cohorts. Poster presented at: The 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual.  
14 Badros A, Foster L, Anderson LD Jr, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310.  
15 Badros A, Foster L, Anderson LD Jr, et al. Subcutaneous daratumumab plus lenalidomide versus lenalidomide alone as maintenance therapy in newly diagnosed multiple myeloma after transplant: primary results from the phase 3 AURIGA study. Oral Presentation presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
16 Janssen Research & Development, LLC. A study of daratumumab plus lenalidomide versus lenalidomide alone as maintenance treatment in participants with newly diagnosed multiple myeloma who are minimal residual disease positive after frontline autologous stem cell transplant (AURIGA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 September 26]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03901963 NLM Identifier: NCT03901963.  
17 Badros A, Foster L, Anderson LD Jr, et al. Supplement to: Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood. 2025;145(3):300-310.  
18 Anderson LD Jr, Chung A, Foster L, et al. Updated efficacy and safety results of subcutaneous daratumumab plus lenalidomide versus lenalidomide alone  as maintenance therapy in newly diagnosed multiple myeloma after transplant: AURIGA study. Poster presented at: 22nd International Myeloma Society (IMS) Annual Meeting; September 17-20, 2025; Toronto, Canada.  
19 Rodriguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) with DARA-R (D-R) maintenance in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) in the PERSEUS trial. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL, USA.  
20 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.  
21 Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA SC)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance in transplant-eligible (TE) newly diagnosed myeloma (NDMM): PERSEUS cytogenetic risk analysis. Oral Presentation presented at: 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.  
22 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. Clin Lymphoma Myeloma Leuk. 2025;25(10):746-758.e6.  
23 Foster L, Anderson LD Jr, Chung A, et al. Daratumumab plus lenalidomide (D-R) versus lenalidomide (R) alone as maintenance therapy in newly diagnosed multiple myeloma (NDMM) after transplant: analysis of the phase 3 AURIGA study among clinically relevant subgroups. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
24 Rodriguez-Otero P, Voorhees PM, Boccadoro M, et al. Daratumumab for newly diagnosed multiple myeloma: pooled analysis of patients aged ≥65 years from GRIFFIN and PERSEUS. Clin Lymphoma Myeloma Leuk. 2025.  
25 Mian H, Facon T, Cook G, et al. Dynamic frailty analysis of transplant-ineligible patients with NDMM in the phase 3 MAIA and CEPHEUS trials of daratumumab (Dara) + lenalidomide-dexamethasone (Rd) and bortezomib-Rd (VRd). Oral Presentation presented at: 22nd International Myeloma Society  (IMS) Annual Meeting; September 17-20, 2025; Toronto, Canada.