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DARZALEX® (daratumumab)

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DARZALEX + DARZALEX FASPRO - Minimal Residual Disease in Clinical Trials

Last Updated: 02/13/2025

SUMMARY

DARZALEX for intravenous (IV) use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd). Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.

DARZALEX

CASSIOPEIA: phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM).¹^,²
- Part 1: Moreau et al (2019)¹ reported the results from Part 1 of CASSIOPEIA study. The proportion of patients with minimal residual disease (MRD)-negative status at a 10^-5 sensitivity threshold following consolidation was larger in the D-VTd arm than in the bortezomib, thalidomide, and dexamethasone (VTd) arm (64% vs 44%; P<0.0001).
  - Avet-Loiseau et al (2019)³ evaluated MRD status and its association with progression-free survival (PFS) in transplant-eligible NDMM patients in Part 1 of the CASSIOPEIA study. Adding DARZALEX to VTd induction and consolidation resulted in significant increases in MRD-negativity rates in all patients, regardless of response, as well as in patients who achieved complete response or better (≥CR). Deeper post-consolidation responses with D-VTd led to improved outcomes, with MRD-negativity associated with prolonged PFS.
  - Touzeau et al (2020)⁴ evaluated slimCRAB baseline characteristics and its association with efficacy outcomes in NDMM patients in Part 1 of the CASSIOPEIA study. Response rates, MRD-negativity rates, and PFS did not differ significantly between slim-only and CRAB subgroups. Significantly higher response and MRD-negativity rates were seen with D-VTd vs VTd for both slim-only and CRAB subgroups.
- Part 2: Moreau et al (2021)²^,⁵ reported results from Part 2 of the CASSIOPEIA study. MRD-negativity status (at 10^-5 sensitivity by next-generation sequencing [NGS] in patients with ≥CR) was achieved by 58.6% of patients in the DARZALEX monotherapy group vs 47.1% in the observation group (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.33-2.43; P=0.0001).
  - Avet-Loiseau et al (2021)⁶ presented MRD results from Part 1 and Part 2 of the CASSIOPEIA study to demonstrate the impact of DARZALEX maintenance therapy on MRD-negativity. MRD-negativity rates and sustained MRD-negativity rates were significantly higher after D-VTd induction and consolidation. D-VTd induction/consolidation followed by DARZALEX maintenance resulted in the numerically highest MRD-negativity rates.
- Moreau et al (2024)⁷ reported long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization. At any time point in the D-VTd cohort, MRD-negativity at 10^-5sensitivity threshold was achieved by 65.1% of patients in the DARZALEX subgroup and by 58.1% of patients in the observation subgroup (P=0.080), respectively; and MRD-negativity at 10^-6sensitivity threshold was achieved by 58.1% of patients in the DARZALEX subgroup and by 48.9% of patients in the observation subgroup (P=0.031), respectively. At any time point in the VTd cohort, MRD-negativity at 10^-5sensitivity threshold was achieved by 53.5% of patients in the DARZALEX subgroup and by 36.3% of patients in the observation subgroup (P=0.0001), respectively; and MRD-negativity at 10^-6sensitivity threshold was achieved by 43.7% of patients in the DARZALEX subgroup and by 26.5% of patients in the observation subgroup (P<0.0001), respectively.
MAIA: phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared to Rd in transplant-ineligible NDMM patients.⁸
- Kumar et al (2022)⁹ presented updated efficacy and safety results of MAIA study with a median follow-up of 64.5 months. The MRD-negativity rates for D-Rd vs Rd were 32.1% vs 11.1%, respectively.
- San-Miguel et al (2022)¹⁰ evaluated the predictive and prognostic role of MRD-negativity and durability in patients treated in the MAIA study. The MRD-negativity (10^-5 sensitivity) rates for D-Rd vs Rd were 28.8% vs 9.2% (P<0.0001) in the intent-to-treat (ITT) population, and 58.2% vs 34% (P=0.0001) in patients who achieved ≥CR.
ALCYONE: phase 3 study evaluating the safety and efficacy of DARZALEX, bortezomib, melphalan, and prednisone (D-VMP) and VMP in NDMM patients ineligible for high-dose chemotherapy with autologous stem-cell transplantation (ASCT).¹¹
- Mateos et al (2022)¹² presented an updated efficacy and safety results of the ALCYONE study with a median follow-up of 78.8 months. The MRD-negativity rates for D-VMP vs VMP were 28.3% vs 7%, respectively.
- San-Miguel et al (2022)¹⁰ evaluated the predictive and prognostic role of MRD-negativity and durability in patients treated in the ALCYONE study. The MRD-negativity (10^-5 sensitivity) rates for D-VMP vs VMP were 26.9% vs 7% (P<0.0001) in the ITT population, and 58.8% vs 27.8% (P<0.0001) in patients who achieved ≥CR.
GRIFFIN: phase 2 study evaluating the safety and efficacy of D-VRd in patients with NDMM eligible for high-dose therapy (HDT) and ASCT.¹³
- Part 1: Voorhees et al (2021)¹⁴ reported the final analysis of the safety run-in cohort (N=16) of the GRIFFIN study with a median follow-up of 40.8 months. By the end of D-VRd consolidation, 50% of patients were MRD-negative (10^-5sensitivity threshold). After maintenance, 81.3% of patients were MRD-negative (10^-5sensitivity threshold).
- Part 2: Voorhees et al (2023)¹⁵ 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. The median duration of followup was 49.6 months. At the end of the study, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and bortezomib, lenalidomide, and dexamethasone (VRd) arms, respectively, who were previously MRD-positive at the end of the consolidation phase, converted to MRD-negative (10^-5 sensitivity).
POLLUX: phase 3 study evaluating the safety and efficacy of D-Rd vs Rd in patients with relapsed or refractory multiple myeloma (RRMM).¹⁶
- Dimopoulos et al (2023)¹⁷ reported the updated efficacy and safety results of the POLLUX study at a median follow-up of 79.7 months. The MRD-negativity rate (10^-5 sensitivity) in the D-Rd vs Rd arm was 33.2% vs 6.7%, respectively (P<0.0001).
CASTOR: phase 3 study evaluating the safety and efficacy of bortezomib and dexamethasone (Vd) alone and DARZALEX + Vd (D-Vd) in patients with RRMM.¹⁸
- Sonneveld et al (2022)¹⁹ reported updated efficacy and safety results from CASTOR at a median follow-up of 72.6 months. The MRD-negativity rates (10^-5 sensitivity) were for D-Vd vs Vd were 15.1% vs 1.6%, respectively.
CANDOR: phase 3 study evaluating the efficacy and safety of DARZALEX use in combination with carfilzomib and dexamethasone (D-Kd) vs Kd in patients with RRMM.²⁰
- Usmani et al (2023)²¹ reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. The MRD-negativity rate was 18.3% in the D-Kd arm and 5.2% in the Kd arm.
- Landgren et al (2020)²² presented results from a post-hoc analyses of the best overall MRD-negative status at any time point and MRD-negative CR at various cutoffs from the CANDOR study. In each analysis, MRD-negativity rates were higher in the D-Kd arm. At the 12month landmark, D-Kd vs Kd treatment resulted in greater proportion of CR rates (26.9% vs 9.7%) and deeper MRD responses. With a median follow-up of 6 months from the 12-month landmark, no patient with MRDnegative CR response progressed.

DARZALEX FASPRO

PERSEUS: ongoing phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd induction and consolidation followed by maintenance with lenalidomide and daratumumab (D-R) in DVRd group or lenalidomide (R) in VRd group in patients with NDMM eligible for ASCT.²³
- Sonneveld et al (2023)²³ 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)²⁴ presented (at the 66^th American Society of Hematology [ASH] Annual Meeting) 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 minimal residual disease (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 progression-free survival (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).
APOLLO: phase 3 study evaluating the safety and efficacy of DARZALEX FASPRO + pomalidomide and dexamethasone (D-Pd) vs Pd in patients with RRMM. Dimopoulos et al (2021)²⁵ 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 MM.
- Chari et al (2021)²⁶ 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 D-VMP, and 14.7 months for 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)²⁷ presented updated safety and efficacy results of the PLEIADES study with a median follow-up of 9.2 months for D-Kd (primary analysis), 25.7 months for D-Rd, and 25.2 months for D-VMP.
AURIGA: ongoing phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs lenalidomide (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. A total of 200 patients were randomized (D-R, n=99; R, n=101).²⁸^-³⁰
- Badros et al (2024)²⁸^,²⁹^,³¹ 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%; odds ratio [OR], 4.51; 95% confidence interval [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%).
CEPHEUS: phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.³²^-³⁴
- Usmani et al (2025)³⁴ reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall minimal residual disease (MRD)-negativity (10^-5 sensitivity with ≥CR) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; OR, 2.37; 95% 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)³⁵ presented (at the 66^th ASH Annual Meeting) 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.
Several subgroup analyses that reported on MRD outcomes with the use of DARZALEX or DARZALEX FASPRO were identified. These analyses are listed in the References section for your information.³⁶^-⁴⁸

PRODUCT LABELING

DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf.
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

CLINICAL DATA

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone in Previously Untreated MM

CASSIOPEIA (MMY3006; clinicaltrials.gov identifier: NCT02541383) is an ongoing, open-label, 2-arm, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VTd in patients with NDMM who are eligible for high-dose chemotherapy and ASCT.¹^,² Moreau et al (2019)¹ reported the results from part 1 of this study. Moreau et al (2021)² reported results from Part 2 of the CASSIOPEIA study (maintenance treatment).

Study Design/Methods

Primary endpoint: Part 1: Stringent complete response (sCR) after consolidation therapy assessed at 100 days after ASCT (or immediately after consolidation if >100 days); Part 2: PFS after second randomization
Secondary endpoints: Part 1: PFS, time to progression (TTP), proportion of post ASCT/consolidation MRD, proportion of post-induction sCR, PFS2, OS; Part 2: TTP from second randomization, ≥CR, MRD-negativity rates (in patients with ≥CR at a threshold of 10^-5 sensitivity by NGS), overall response rate (ORR), and OS from second randomization

Results - Part 1

Efficacy

Efficacy data from Part 1 of the study are presented in Table: Summary of Responses and MRD Status 100 Days after ASCT (CASSIOPEIA Part 1).
The proportion of patients with MRD-negative status at a 10^-5 sensitivity threshold following consolidation was larger in the D-VTd arm than in the VTd arm (346/543 [64%] vs 236/542 [44%]; P<0.0001) when assessed by multiparametric flow cytometry (MFC).

Summary of Responses and MRD Status 100 Days after ASCT (CASSIOPEIA Part 1)¹

	D-VTd (n=543)	VTd (n=542)	P Value^a
Overall response
Number with response	503	487	-
Percentage (95% CI)	92.6 (90.1-94.7)	89.9 (87-92.3)	0.11
Response, n (%)
sCR	157 (29)	110 (20)	0.0010
≥CR	211 (39%)	141 (26%)	<0.0001
≥VGPR	453 (83%)	423 (78%)	0.024
MRD-negative status (10^-5sensitivity)^b, n (%)
MRD-negative regardless of response	346 (64)	236 (44)	<0.0001
MRD-negative and ≥CR^c	183 (34)	108 (20)	<0.0001
MRD-negative and ≥VGPR^c	338 (62)	231 (43)	<0.0001
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone. ^aP values are given only for primary and secondary endpoints. ^bEuroFlow-based multiparametric flow cytometry. ^cPost hoc analysis.

Safety

Most common AEs during treatment in the safety populationin part 1 of the CASSIOPEIA Study have been reported by Moreau et al (2019)¹

Results - Part 2

The key baseline characteristics are summarized in Table: Key Baseline Disease Characteristics after Second Randomization in ITT Population (CASSIOPEIA Part 2).

Key Baseline Disease Characteristics after Second Randomization in ITT Population (CASSIOPEIA Part 2)²

Characteristics, n (%)	DARZALEX Monotherapy (n=442)	Observation (n=444)
Depth of response^a
MRD-negative, ≥VGPR	337 (76)	337 (76)
MRD-positive, ≥VGPR	68 (15)	69 (16)
MRD-positive^b, PR	37 (8)	38 (9)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; PR, partial response; ≥VGPR, very good partial response or better; VTd, bortezomib + thalidomide + dexamethasone. ^aAs determined by MRD measured by multiparametric flow cytometry at 10^-4 and post-consolidation response per investigator assessment used for stratification. ^bSix patients (3 who received previous D-VTd and 3 who received previous VTd) were MRD-negative with a response of PR at post-consolidation and were categorized as MRD-positive and PR due to the lack of specific stratum defined in the protocol for such patients.

Efficacy

After a median follow-up of 35.4 months (interquartile range [IQR], 30.2-39.9), median PFS from second randomization was not reached (NR) in the DARZALEX monotherapy arm vs 46.7 months in the observation arm (HR, 0.53; 95% CI, 0.42-0.68; P<0.0001).
- In the DARZALEX monotherapy arm, 108 PFS events were reported; in the observation arm, 173 PFS events were reported.
- The PFS benefit of the DARZALEX monotherapy arm vs the observation arm was observed in both the MRD-positive (HR, 0.46; 95% CI, 0.31-0.67) and MRD-negative (HR, 0.61; 95% CI, 0.44-0.83) prespecified subgroups.
MRD-negativity status (at 10^-5 sensitivity by NGS in patients with ≥CR) was achieved by 58.6% of patients in the DARZALEX monotherapy arm vs 47.1% in the observation arm (OR, 1.80; 95% CI, 1.33-2.43; P=0.0001).²^,⁵
MRD-negativity status (at 10^-5 sensitivity by NGS in patients with ≥CR) was achieved by 64.2% of patients in the D-VTd + DARZALEX monotherapy cohort vs 57.6% in the D-VTd + observation cohort (OR, 1.43; 95% CI, 0.93-2.19; P=0.1037) as a part of induction and consolidation treatment therapy.⁵
MRD-negativity status (at 10^-5 sensitivity by NGS in patients with ≥CR) was achieved by 52.6% of patients in the VTd + DARZALEX monotherapy cohort vs 35.8% in the VTd + observation cohort (OR, 2.26; 95% CI, 1.47-3.48; P=0.0002) as a part of induction and consolidation treatment therapy.⁵

Safety

Most common adverse events in safety population of part 2 of the CASSIOPEIA study have been reported by Moreau et al (2021).²

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

Avet-Loiseau et al (2019)³ evaluated MRD status and its association with PFS in Part 1 of the CASSIOPEIA study.

Study Design

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

Results

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

Evaluation of Baseline slimCRAB Subgroup and Association to Efficacy Outcomes in CASSIOPEIA Study Part 1

Touzeau et al (2020)⁴ performed a subgroup analysis from Part 1 of the CASSIOPEIA study based on baseline slimCRAB criteria.

Study Design

Patients in the CRAB subgroup had >1 feature of CRAB criteria.
Patients in the slim-only subgroup had >1 of the slim criteria and excluded patients with >1 conventional CRAB criterion based on baseline data collection.

Results

Baseline Characteristics

CRAB subgroup: n=1,004 (n=507) D-VTd vs (n=497) VTd
Slim subgroup: n=81 (n=36) D-VTd vs (n=45) VTd
ECOG PS score of >1: 22 % slim only arm vs 54% CRAB arm
ISS stage III disease: 4% slim only arm vs 16% CRAB arm
High-risk cytogenetics: 11% slim only arm vs 16% CRAB arm

Efficacy

MRD-negativity rates were similar for slim-only vs CRAB patients (46% vs 54%; OR, 0.70; 95% CI, 0.44-1.11; P=0.1261).
In the slim-only subgroup, MRD-negativity rates were significantly higher in the D-VTd arm vs VTd arm (67% vs 29%; OR, 7.83; 95% CI, 2.53-24.22; P<0.0001).
In addition, for the CRAB subgroup, the MRD-negativity rates were significantly higher in the D-VTd arm vs VTd arm (64% vs 45%; OR, 2.12; 95% CI, 1.65-2.73; P<0.0001).

MRD Analysis in CASSIOPEIA Study Part 1 and Part 2

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

Study Design/Methods

Sustained MRD-negativity rates were calculated using MRD responses observed at any time point during the study.
In the landmark analysis, sustained MRD-negativity was obtained only with reference to post-induction MRD.

Results

Efficacy

In Part 1, the ITT population (N=1,085) was analyzed, which included all first-randomization patients.
Following induction and consolidation, improvement in rates of ≥CR + MRD-negativity (MFC; 10^-5 sensitivity) was observed with D-VTd vs VTd.
≥CR + MRD-negativity rates (regardless of second randomization):
- Post-induction: D-VTd, 9.2%; VTd, 5.4% (OR, 1.79; P=0.0150)
- Post-consolidation: D-VTd, 33.7%; VTd, 19.9% (OR, 2.06; P<0.0001)
- ≥1 years sustained: D-VTd, 50.1%; VTd, 30.1% (OR, 2.37; P<0.0001)
- ≥2 years sustained: D-VTd, 35.5%; VTd, 18.8% (OR, 2.41; P<0.0001)
In Part 2, the maintenance ITT population (N=886) was analyzed, which included all re-randomized patients (DARZALEX, n=442; observation, n=444). Median follow-up was 35.4 months from second randomization.
During maintenance, ≥CR + MRD-negativity rates (NGS; 10^-5 sensitivity) with DARZALEX vs observation were as follows:
- MRD-negative: DARZALEX, 58.6%; observation, 47.1% (OR, 1.80; P=0.0001)
- ≥1 years sustained: DARZALEX, 42.3%; observation, 31.5% (OR, 1.71; P=0.0004)
- ≥2 years sustained: DARZALEX, 20.4%; observation, 17.6% (OR, 1.21; P=0.2855)
Rates of ≥CR + MRD-negativity at 10^-5 and 10^-6 sensitivities (NGS) during maintenance are presented in Table: Rates of ≥CR + MRD-Negativity at 10^-5 and 10^-6 Sensitivities (NGS) at Any Timepoint During Maintenance.

Rates of ≥CR + MRD-Negativity at 10^-5 and 10^-6 Sensitivities (NGS) at Any Timepoint During Maintenance^a,⁶

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

Post-consolidation MRD-negativity rates among patients who achieved ≥CR were consistent across subgroups, including the ISS disease stage and high-risk cytogenetics subgroups. See Table: Subgroup Analysis of Maintenance ≥CR + MRD-Negativity (NGS; 10^-5 Sensitivity) Rates.

Subgroup Analysis of Maintenance ≥CR + MRD-Negativity (NGS; 10^-5 Sensitivity) Rates⁶

Subgroup	DARZALEX n/N (%)	Observation n/N (%)	OR (95% CI)
Age
<50 years	41/63 (65.1)	26/68 (38.2)	3.01 (1.48-6.14)
50-60 years	110/198 (55.6)	100/200 (50)	1.25 (0.84-1.85)
>60 years	108/181 (59.7)	83/176 (47.2)	1.66 (1.09-2.52)
Sex
Male	114/261 (55.2)	107/254 (42.1)	1.69 (1.19-2.4)
Female	115/181 (63.5)	102/190 (53.7)	1.50 (0.99-2.28)
Site
IFM	227/373 (60.9)	191/391 (48.8)	1.63 (1.22-2.17)
HOVON	32/69 (46.4)	18/53 (34)	1.68 (0.8-3.52)
ISS stage
I	111/189 (58.7)	86/171 (50.3)	1.41 (0.93-2.13)
II	102/181 (56.4)	93/214 (43.5)	1.68 (1.13-2.5)
III	46/72 (63.9)	30/59 (50.8)	1.71 (0.85-3.45)
Cytogenetic risk
High risk	41/57 (71.9)	33/70 (47.1)	2.87 (1.36-6.05)
Standard risk	217/383 (56.7)	176/374 (47.1)	1.47 (1.10-1.96)
Pre-maintenance baseline renal function (CrCl)
>90 mL/min	174/303 (57.4)	140/305 (45.9)	1.59 (1.15-2.19)
≤90 mL/min	85/139 (61.2)	69/139 (49.6)	1.60 (0.99-2.57)
Type of MM
IgG	130/253 (51.4)	113/270 (41.9)	1.47 (1.04-2.07)
Non-IgG	65/93 (69.9)	52/92 (56.5)	1.79 (0.97-3.27)
Pre-maintenance baseline ECOG PS score
0	145/252 (57.5)	130/260 (50)	1.36 (0.96-1.92)
≥1	114/190 (60)	79/184 (42.9)	1.99 (1.32-3.01)
Induction/ASCT/consolidation
VTd	112/213 (52.6)	77/215 (35.8)	1.99 (1.35-2.93)
D-VTd	147/229 (64.2)	132/229 (57.6)	1.32 (0.90-1.92)
Response
VGPR or better	255/405 (63)	209/406 (51.5)	1.60 (1.21-2.12)
PR	4/37 (10.8)	0/38	NE (NE-NE)
Abbreviations: ASCT, autologous stem cell transplant; CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HOVON, the Dutch-Belgian Cooperative Group for Hematology-Oncology; IFM, Intergroupe Francophone du Myelome; IgG, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; NE, not estimable; NGS, next-generation sequencing; OR, odds ratio; PR, partial response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.

Long-term Follow-up in CASSIOPEIA Study

Moreau et al (2024)⁷ reported long-term outcomes of the CASSIOPEIA study after a median follow-up duration of 80.1 months from the first randomization and at a median follow-up duration of 70.6 months from the second randomization.

Study Design

This planned analysis represents the study's conclusion with the final data cutoff of September 1, 2023. During the induction and consolidation phases, efficacy assessments were conducted on the ITT population cohort, encompassing all patients from the first randomization. In the maintenance phase, efficacy analyses were performed on the maintenance-specific ITT population, including patients randomized during the second randomization.

Results

Patient Disposition

Between September 22, 2015, and August 1, 2017, a total of 1085 patients were enrolled and randomized to receive D-VTd (n=543) and VTd (n=542).
Overall, 458 patients (84%) in the D-VTd group and 428 patients (79%) in the VTd group, who completed consolidation and achieved a partial response or better (≥PR), were re-randomized to either DARZALEX maintenance (n=442) or observation (n=444).
- At a clinical data cutoff of September 1, 2023, 339 patients (77%) had completed DARZALEX maintenance, and 317 patients (71%) had completed observation during the maintenance phase.
- A total of 61 patients (14%) in the DARZALEX maintenance group and 118 patients (27%) in the observation group had discontinued treatment due to disease progression during the maintenance phase.

Efficacy

The median duration of follow-up was 80.1 months from the first randomization and 70.6 months from the second randomization.
PFS on DARZALEX vs observation in MRD-negative subgroup is presented in Table: PFS in MRD-Positive/Negative Subgroups.
Data on patients with a ≥CR who achieved sustained MRD-negativity at any timepoint from post-induction onwards in the maintenance-specific ITT population are presented in Table: Proportion of Patients With a ≥CR and Sustained MRD-Negativity at Any Timepoint From Post-induction Onwards in the Maintenance-Specific ITT Population.
MRD-negativity rates measured by MFC were higher in the D-VTd group than in the VTd group both after induction therapy and after consolidation therapy. See Table: MRD-Negativity Rates at 10^-5 Sensitivity Threshold Following Induction and Consolidation in the ITT Population.

PFS in MRD-Positive/MRD-Negative Subgroups⁴⁹

Subgroup	DARZALEX		Observation		HR (95% CI)
Subgroup	n/N	Median PFS, Months	n/N	Median PFS, Months	HR (95% CI)
All patients in the maintenance-specific ITT population	186/442	NE	279/444	45.8	0.54 (0.45-0.65)
MRD
MRD-positive	66/105	46.5	95/107	24.2	0.44 (0.32-0.60)
MRD-negative	120/337	NE	184/337	61.1	0.55 (0.40-0.70)
Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; MRD, minimal residual disease; NE, not estimable; PFS, progression-free survival.

Proportion of Patients With a ≥CR and Sustained MRD-Negativity at Any Timepoint From Post-induction Onwards in the Maintenance-Specific ITT Population⁷

MRD- Negativity Sensitivity Threshold	D-VTd			OR (95% CI)	P Value	VTd		OR (95% CI)	P Value
MRD- Negativity Sensitivity Threshold	DARZALEX (n=229)		Obs (n=229)	OR (95% CI)	P Value	DARZALEX (n=213)	Obs (n=215)	OR (95% CI)	P Value
At any time point
10^-5, %	65.1	58.1		1.47 (0.95-2.26)	0.080	53.5	36.3	2.33 (1.51-3.60)	0.0001
10^-6, %	58.1	48.9		1.56 (1.04-2.34)	0.031	43.7	26.5	2.44 (1.56-3.81)	<0.0001
≥12 Months
10^-5, %	56.3	46.3		1.61 (1.08-2.41)	0.020	44.1	24.7	2.71 (1.73-4.23)	<0.0001
10^-6, %	47.6	36.2		1.68 (1.13-2.50)	0.0096	31.9	14.9	2.92 (1.77-4.82)	<0.0001
≥24 Months
10^-5, %	49.8	36.7		1.82 (1.23-2.71)	0.0028	36.2	16.7	3.15 (1.94-5.12)	<0.0001
10^-6, %	41	27.9		1.87 (1.25-2.81)	0.0023	24.9	10.2	3.11 (1.78-5.44)	<0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates at 10^-5 Sensitivity Threshold Following Induction and Consolidation in the ITT Population⁴⁹

	Post-Induction		Post-Consolidation
	D-VTd (n=543)	VTd (n=542)	D-VTd (n=543)	VTd (n=542)
MRD-negativity rate, %	9.2	5.4	33.7	20.3
P value	0.015		<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.

Safety

Summary of causes of death during and after the maintenance phase and SPMs by induction/consolidation treatment in the maintenance-specific safety population of the MAIA study have been reported by Moreau et al (2024)⁷.

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with NDMM

MAIA (MMY3008; clinicaltrials.gov identifier: NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).⁸ Kumar et al (2022)⁹ presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months), of the MAIA study in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT.

Study Design/Methods

Primary endpoint: PFS
Secondary endpoints: ≥CR, duration of response (DOR), very good partial response or better (≥VGPR), MRD-negativity rate (10^-5 sensitivity) via NGS, ORR, overall survival (OS), PFS2, sCR, time to next (second-line) treatment, time to response (TTR), TTP, and safety

Results

Efficacy

The median duration of follow-up was 64.5 months overall, and 73.6 months for OS.
At a median follow-up of 64.5 months, MRD-negativity rate, and rates of sustained MRD-negativity lasting ≥12 months and ≥18 months were higher in the D-Rd vs Rd treatment. See Table: Summary of MRD-Negativity Rate and Sustained MRD-Negativity Rates in the ITT Population (MAIA).
At a median follow-up of 73.6 months, the OS was improved in patients who were MRD-negative (D-Rd, 88.9%; Rd, 78%) vs patients who were MRD-positive (D-Rd, 55.9%; Rd, 50.4%) in both treatment arms; however, more patients in the D-Rd arm achieved MRD-negativity.

Summary of MRD-Negativity Rate and Sustained MRD-Negativity Rates in the ITT Population (MAIA)⁹

Parameter	D-Rd (n=368)^a	Rd (n=369)^a	P Value^a
MRD-negative, n (%)	118 (32.1)	41 (11.1)	<0.0001
Sustained MRD-negative, n (%)
Lasting ≥12 months	69 (18.8)	15 (4.1)	<0.0001
Lasting ≥18 months	62 (16.8)	12 (3.3)	<0.0001
Abbreviations: CR, complete response; D-Rd, daratumumab + lenalidomide + dexamethasone; ITT, intent to treat; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; VGPR, very good partial response.^aData are based on a median follow-up of 64.5 months.

Safety

Summary of any-grade (≥30%) and grade 3/4 (≥20%) treatment-emergent adverse events (TEAEs) in the safety population of the MAIA study have been reported by Kumar et al (2022).⁹

Predictive and Prognostic Role of MRD-Negativity and Durability in MAIA Study

San-Miguel et al (2022)¹⁰ evaluated the predictive and prognostic role of MRD-negativity and durability in patients with NDMM ineligible for transplant in the MAIA study.

Results

Patient Characteristics

The baseline characteristics of the ITT and MRD-negative populations are presented in the Table: Demographics and Baseline Characteristics by MRD Durability (MAIA).
MRD assessments were performed in any patients achieving ≥CR. MRD assessments were conducted at 12, 18, 24, and 30 months (after 1st dose) in those patients with a ≥CR.
Follow-up median duration was 36.4 months (range, 0-49.9).

Demographics and Baseline Characteristics by MRD Durability (MAIA)⁵⁰

Characteristic	D-Rd				Rd
	ITT (n=368)	MRD-Negative Patients			ITT (n=369)	MRD-Negative Patients
	ITT (n=368)	At Any Time (n=106)	≥12 Months (n=40)	Not ≥12 Months (n=66)	ITT (n=369)	At Any Time (n=34)	≥12 Months (n=9)	Not ≥12 Months (n=25)
Age, years
Median (range)	73 (50-90)	72 (65-87)	71 (66-85)	73.5 (65-87)	74 (45-89)	72.5 (66-87)	71 (69-78)	73 (66-87)
Distribution
<75	208 (56.5)	68 (64.2)	31 (77.5)	37 (56.1)	208 (56.4)	20 (58.8)	6 (66.7)	14 (56)
≥75	160 (43.5)	38 (35.8)	9 (22.5)	29 (43.9)	161 (43.6)	14 (41.2)	3 (33.3)	11 (44)
ISS disease stage^a, n (%)
I	98 (26.6)	24 (22.6)	10 (25)	14 (21.2)	103 (27.9)	11 (32.4)	5 (55.6)	6 (24)
II	163 (44.3)	55 (51.9)	19 (47.5)	36 (54.5)	156 (42.3)	15 (44.1)	3 (33.3)	12 (48)
III	107 (29.1)	27 (25.5)	11 (27.5)	16 (24.2)	110 (29.8)	8 (23.5)	1 (11.1)	7 (28)
Cytogenetic profile^b, n (%)
Patients evaluated	319	96	34	62	323	27	8	19
Standard-risk cytogenetic abnormality	271 (85)	85 (88.5)	29 (85.3)	56 (90.3)	279 (86.4)	26 (96.3)	8 (100)	18 (94.7)
High-risk cytogenetic abnormality^c	48 (15)	11 (11.5)	5 (14.7)	6 (9.7)	44 (13.6)	1 (3.7)	0 (0)	1 (5.3)
del(17p)	25 (7.8)	6 (6.3)	2 (5.9)	4 (6.5)	29 (9)	0 (0)	0 (0)	0 (0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; Rd, lenalidomide + dexamethasone. ^aISS staging is derived based on the combination of serum β2-microglobulin and albumin. ^bCytogenetic risk status was determined by fluorescence in situ hybridization or karyotype testing. ^cHigh risk is defined as having a positive test for any of the del17p, t(14;16), or t(4;14) molecular abnormalities.

Efficacy

In the ITT population and among patients with ≥CR, patients receiving the D-Rd regimen achieved higher rates of MRD-negativity and durability compared with Rd. Please see Table: Rates of Sustained MRD-Negativity Status in Transplant-ineligible NDMM (MAIA).
In the ITT population, MRD-negative patients had improved PFS compared with MRD-positive patients (HR, 0.15; 95% CI, 0.09-0.26; P<0.0001).
Durable MRD-negativity lasting ≥6 months or ≥12 months improved PFS compared with MRD-negative patients who did not maintain MRD-negativity for ≥6 months or ≥12 months.
Estimated 36-month rates of time to subsequent anticancer therapy were mostly higher for patients who achieved MRD-negativity at any time vs MRD-positive patients, and for patients with sustained MRD-negativity lasting ≥6 months or ≥12 months compared with those who did not have durable MRD-negativity. Please see Table: Estimated Rates of Patients without Subsequent Therapy at 36 Months in the ITT Population (MAIA).
Estimated 36-month PFS2 rate (ITT; D-Rd, n=368; Rd, n=369):
- MRD-negative (10^-5 sensitivity) at ≥1 time point: D-Rd, 95% (n=106); Rd, 83.9% (n=34)
- MRD-positive: D-Rd, 65.5% (n=262); Rd, 61.5% (n=335)

Rates of Sustained MRD-Negativity Status in Transplant-ineligible NDMM (MAIA)¹⁰

MRD-Negativity (10^-5Sensitivity)	(N=737)
MRD-Negativity (10^-5Sensitivity)	D-Rd	Rd	P value^a
ITT, n	368	369
MRD-negative status, n (%)	106 (28.8)	34 (9.2)	<0.0001
≥6 months sustained	55 (14.9)	16 (4.3)	<0.0001
≥12 months sustained	40 (10.9)	9 (2.4)	<0.0001
≥CR, n	182	100
MRD-negative status, n (%)	106 (58.2)	34 (34)	0.0001
≥6 months sustained	55 (30.2)	16 (16)	0.0097
≥12 months sustained	40 (22)	9 (9)	0.0053
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide + dexamethasone. ^aP value was calculated using Fisher’s exact test.

Estimated Rates of Patients Without Subsequent Therapy at 36 months in the ITT Population (MAIA)¹⁰

Estimated 36-Month Time to Subsequent Anticancer Therapy Rate, n (%)	D-Rd (n=368)	Rd (n=369)
MRD-negative (10^-5sensitivity) at ≥1 time point	106 (96.9)	34 (90.5)
MRD-positive	262 (65.4)	335 (48.7)
Achieved and remained MRD-negative (10^-5sensitivity) for ≥6 months	55 (96.1)	16 (100)
MRD-negativity not ≥6 months	51 (98)	18 (78.7)
Achieved and remained MRD-negative (10^-5sensitivity) for ≥12 months	40 (94.6)	9 (100)
MRD-negativity not ≥12 months	66 (98.5)	25 (85.2)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; Rd, lenalidomide + dexamethasone.

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone in Patients with NDMM

ALCYONE (MMY3007; clinicaltrials.gov identifier: NCT02195479) is a phase 3, multicenter, randomized, open-label, active-controlled study which evaluated the safety and efficacy of D-VMP compared with VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.¹¹ Mateos et al (2022)¹² presented an updated analysis of the ALCYONE study that evaluated the efficacy and safety of D-VMP vs VMP in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT.

Study Design/Methods

Primary endpoint: PFS
Secondary endpoints: ≥CR rate, ≥VGPR rate, MRD-negativity (10^-5 sensitivity), ORR, and median OS

Results

Efficacy

The rates of MRD-negativity and sustained MRD-negativity lasting both for ≥12 and ≥18 months were higher in the D-VMP vs VMP arm. See Table: Summary of MRD-Negativity Rates and Sustained MRD-Negativity Rates in ITT Population (ALCYONE).
The OS was improved in patients who were MRD-negative (D-VMP, 71.8%; VMP, 54.3%) vs patients who were MRD-positive (D-VMP, 49%; VMP, 38.6%) in both treatment arms; however, more patients in the D-VMP arm were MRD-negative.

Summary of MRD-Negativity Rates and Sustained MRD-Negativity Rates in ITT Population (ALCYONE)¹²

Parameter	D-VMP (n=350)	VMP (n=356)	P Value
MRD-negative, n (%)	99 (28.3)	25 (7)	<0.0001
Sustained MRD-negativity, n (%)
Lasting ≥12 months	49 (14)	10 (2.8)	<0.0001
Lasting ≥18 months	31 (8.9)	6 (1.7)	<0.0001
Abbreviations: D-VMP, daratumumab + bortezomib + melphalan + prednisone; ITT, intent to treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone

Safety

Summary of any grade (≥15%) and grade 3/4 (≥5%) TEAEs in the safety population of the ALCYONE study have been reported by Mateos et al (2022).¹²

Predictive and Prognostic Role of MRD-Negativity and Durability in ALCYONE Study

San-Miguel et al (2022)¹⁰ evaluated the predictive and prognostic role of MRD-negativity and durability in patients with NDMM ineligible for transplant in the ALCYONE study.

Results

Patient Characteristics

The baseline characteristics of the ITT and MRD-negative populations are presented in the Table: Demographics and Baseline Characteristics by MRD Durability (ALCYONE).
Follow-up median duration was 36.4 months (range, 0-49.9).

Demographics and Baseline Characteristics by MRD Durability (ALCYONE)⁵⁰

Characteristic	D-VMP				VMP
	ITT (n=350)	MRD-Negative Patients			ITT (n=356)	MRD-Negative Patients
	ITT (n=350)	At Any Time (n=94)	≥12 Months (n=49)	Not ≥12 Months (n=45)	ITT (n=356)	At Any Time (n=25)	≥12 Months (n=10)	Not ≥12 Months (n=15)
Age, years
Median (range)	71 (40-93)	71 (40-93)	71 (40-87)	71 (56-93)	71 (50-91)	73 (52-82)	72 (52-82)	74 (67-82)
Distribution
<75	246 (70.3)	68 (72.3)	36 (73.5)	32 (71.1)	249 (69.9)	15 (60)	6 (60)	9 (60)
≥75	104 (29.7)	26 (27.7)	13 (26.5)	13 (28.9)	107 (30.1)	10 (40)	4 (40)	6 (40)
ISS disease stage^a
I	69 (19.7)	16 (17)	9 (18.4)	7 (15.6)	67 (18.8)	5 (20)	2 (20)	3 (20)
II	139 (39.7)	39 (41.5)	23 (46.9)	16 (35.6)	160 (44.9)	10 (40)	5 (50)	5 (33.3)
III	142 (40.6)	39 (41.5)	17 (34.7)	22 (48.9)	129 (36.2)	10 (40)	3 (30)	7 (46.7)
Cytogenetic profile^b
Patients evaluated	314	88	46	42	302	23	9	14
Standard-risk cytogenetic abnormality	261 (83.1)	74 (84.1)	40 (87)	34 (81)	257 (85.1)	19 (82.6)	7 (77.8)	12 (85.7)
High-risk cytogenetic abnormality^c	53 (16.9)	14 (15.9)	6 (13)	8 (19)	45 (14.9)	4 (17.4)	2 (22.2)	2 (14.3)
del(17p)	29 (9.2)	8 (9.1)	4 (8.7)	4 (9.5)	27 (8.9)	3 (13)	1 (11.1)	2 (14.3)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone. All data are n (%) unless otherwise indicated. ^aISS staging is derived based on the combination of serum β2-microglobulin and albumin. ^bCytogenetic risk status was determined by fluorescence in situ hybridization or karyotype testing. ^cHigh risk is defined as having a positive test for any of the del17p, t(14;16), or t(4;14) molecular abnormalities.

Efficacy

In the ITT population and among patients with ≥CR, patients receiving the D-VMP regimen achieved higher rates of MRD-negativity and durability compared with VMP. Please see Table: Rates of Sustained MRD-Negativity Status in Transplant-ineligible NDMM (ALCYONE).
In the ITT population, MRD-negative patients had improved PFS compared with MRD-positive patients.
Durable MRD-negativity lasting ≥6 months or ≥12 months improved PFS compared with MRD-negative patients who did not maintain MRD-negativity for ≥6 months or ≥12 months.
Estimated 36-month rates of time to subsequent anticancer therapy were mostly higher for patients who achieved MRD-negativity at any time vs MRD-positive patients, and for patients with sustained MRD-negativity lasting ≥6 months or ≥12 months compared with those who did not have durable MRD-negativity. Please see Table: Estimated Rates of Patients Without Subsequent Therapy at 36 Months in the ITT Population (ALCYONE).
Estimated 36-month PFS2 rate (ITT; D-VMP, n=350; VMP, n=356)⁵⁰ :
- MRD-negative (10^-5 sensitivity) at ≥1 time point: D-VMP, 87% (n=94); VMP, 92% (n=25)
- MRD-positive: D-VMP, 67.9% (n=256); VMP, 51.9% (n=331)

Rates of Sustained MRD-Negativity Status in Transplant-ineligible NDMM (ALCYONE)¹⁰

MRD-Negativity (10^-5Sensitivity)	(N=706)
MRD-Negativity (10^-5Sensitivity)	D-VMP	VMP	P Value^a
ITT, n	350	356
MRD-negative status, n (%)	94 (26.9)	25 (7)	<0.0001
≥6 months sustained	55 (15.7)	16 (4.5)	<0.0001
≥12 months sustained	49 (14)	10 (2.8)	<0.0001
≥CR	160	90
MRD-negative status, n (%)	94 (58.8)	25 (27.8)	<0.0001
≥6 months sustained	55 (34.4)	16 (17.8)	0.0055
≥12 months sustained	49 (30.6)	10 (11.1)	0.0006
Abbreviations: CR, complete response; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; VMP, bortezomib + melphalan + prednisone. ^aP value was calculated using Fisher’s exact test.

Estimated Rates of Patients Without Subsequent Therapy at 36 Months in the ITT Population (ALCYONE)¹⁰

Estimated 36-Month Time to Subsequent Anticancer Therapy Rate, n (%)	D-VMP (n=350)	VMP (n=356)
MRD-negative (10^-5sensitivity) at ≥1 time point	94 (88.7)	25 (75.3)
MRD-positive	256 (54.9)	331 (33.2)
Achieved and remained MRD-negative (10^-5sensitivity) for ≥6 months	55 (96.3)	16 (93.8)
MRD-negativity not ≥6 months	39 (77.2)	9 (38.9)
Achieved and remained MRD-negative (10^-5sensitivity) for ≥12 months	49 (95.8)	10 (100)
MRD-negativity not ≥12 months	45 (80.5)	15 (57.8)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.

DARZALEX in Combination with Bortezomib, Lenalidomide, and Dexamethasone in Patients with NDMM

GRIFFIN (MMY2004; clinicaltrials.gov identifier: NCT02874742) is an ongoing, 2-part, randomized, active-controlled, phase 2 US study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.¹³ Voorhees et al (2021)¹⁴ reported the final analysis of the safety run-in cohort (part 1) of the GRIFFIN study. Voorhees et al (2020)¹³ reported the primary analysis and updated analysis of the randomized portion (part 2) of this study. Laubach et al (2021)⁵¹ presented updated efficacy and safety results after 2 years of maintenance therapy in this study. Sborov et al (2022)⁵² presented the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end of study treatment.

Study Design/Methods

Primary endpoints: sCR (by end of post-ASCT consolidation)
Secondary endpoints: MRD (10^-5 sensitivity via NGS), CR, ORR, ≥VGPR

Part 1: Safety Run-in Phase Final Analysis

Voorhees et al (2021)¹⁴ reported the final analysis of the safety run-in cohort (N=16) of the GRIFFIN study.

Results

Efficacy

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.
MRD-negativity rates at 10^-5 sensitivity threshold and 10^-6 sensitivity threshold, respectively:
- 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 of 10^-5 sensitivity was sustained for ≥12 months in 8 (50%) patients.

Part 2: Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)¹⁵ 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.

Results

Efficacy

The median duration of follow-up was 49.6 months (IQR, 47.452.1).
The MRD-negativity rates at the 10^-5 and 10^-6 sensitivity thresholds at the end of maintenance are summarized in Table: Final Analysis of MRD-Negativity Rates at the End of Maintenance.

Final Analysis of MRD-Negativity Rates at the End of Maintenance¹⁵^,⁵³

Parameter	D-VRd	VRd	P Value
MRD-negative
ITT population, n	104	103	-
10^-5sensitivity, n (%)	67 (64)	31 (30)	<0.0001^a
OR (95% CI)	4.23 (2.35-7.62)
10^-6 sensitivity, n (%)	37 (36)	16 (16)	0.0013^a
OR (95% CI)	2.95 (1.52-5.75)
In patients achieving ≥CR, n	83	59	-
10^-5 sensitivity, n (%)	64 (77)	28 (47)	0.0004^a
10^-6 sensitivity, n (%)	35 (42)	14 (24)	0.031^a
Durable MRD-negativity
Lasting ≥12 months, n	104	103	-
10^-5 sensitivity, n (%)	46 (44)	14 (14)	<0.0001^a
OR (95% CI)	5 (2.5-9.99)
10^-6 sensitivity, n (%)	10 (10)	4 (4)	0.16^a
OR (95% CI)	2.48 (0.76-8.07)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone. ^aP value was calculated using the Fisher’s exact test. Note: The predefined per protocol final analysis was performed 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.

By the end of the 2-year maintenance therapy, 14% (n/N=15/104) and 10% (n/N=10/103) of patients 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 sensitivity). The 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).

Summary of MRD-Negativity Rates Over Time (ITT Population)^a,¹⁵^,⁵³

Timepoint, %	D-VRd		VRd
Timepoint, %	MRD-Negativity (10^-5Sensitivity)	MRD-Negativity (10^-6 Sensitivity)	MRD-Negativity (10^-5 Sensitivity)	MRD-Negativity (10^-6 Sensitivity)
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, intent-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 were performed at the first evidence of suspected CR or sCR after induction (but before stem cell collection), consolidation, and 12 and 24 months of maintenance, regardless of response.

No patient in either treatment arm with sustained MRD-negativity 10^-5 sensitivity lasting ≥12 months became MRD-Positive later.
The median time to MRD-negativity in the D-VRd vs VRd arm at the 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 NR (HR, 1.93; 95% CI, 1.05-3.54; P=0.031).

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with RRMM

POLLUX (MMY3003; clinicaltrials.gov identifier: NCT02076009) is a phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the safety and efficacy of Rd and D-Rd in patients with RRMM (N=569).¹⁷ Kaufman et al (2019)⁵⁴ presented the updated safety and efficacy of the POLLUX study after a median follow-up of 54.8 months. Dimopoulos et al (2023)¹⁷ reported the updated efficacy and safety results of the POLLUX study at a median follow-up of 79.7 months. Results of this update are summarized below.

Study Design/Methods

Primary endpoint: PFS
Key secondary endpoints: ORR, ≥VGPR, ≥CR, OS, TTR, and MRD-negativity

Results

Patient Characteristics

Overall, 569 patients were included (D-Rd, n=286; Rd, n=283).
The median duration of follow-up was 79.7 (range, 0-86.5) months.

Efficacy

In the D-Rd vs Rd arm, the MRD-negativity rate (10^-5 sensitivity) was 33.2% vs 6.7% (P<0.0001). MRD-negativity was associated with improved OS in both the treatment arms.

Safety

No new safety signals were identified with the updated follow-up. Most common (>15% of patients) and grade 3/4 (>5% of patients) TEAEs in the safety population of the POLLUX study have been reported by Dimopoulos et al (2023).¹⁷

DARZALEX in Combination with Bortezomib and Dexamethasone in Patients with RRMM

CASTOR (MMY3004; clinicaltrials.gov identifier: NCT02136134) is an open-label, randomized, multicenter, active-controlled, phase 3 study which evaluated the safety and efficacy of Vd alone compared to D-Vd in patients with RRMM (N=498). Sonneveld et al (2022)¹⁹ reported updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months. Results of this update are summarized below.

Study Design/Methods

Primary endpoint: PFS
Secondary endpoints: time to disease progression, overall response, DOR, TTR, ≥VGPR, OS, and MRD

Results

Efficacy

The median duration of follow-up was 72.6 (range, 0-79.8) months.
MRD-negativity rate at a 10^-5 sensitivity threshold was 15.1% with D-Vd vs 1.6% with Vd (P <0.0001).

Safety

Updated most common (>15% of patients) and grade 3/4 TEAEs (>5% of patients) in the safety population of the CASTOR study have been reported by Sonneveld et al (2022).¹⁹

DARZALEX in Combination with Carfilzomib and Dexamethasone in Patients with RRMM

CANDOR (clinicaltrials.gov identifier: NCT03158688) is a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM. Usmani et al (2023)²¹ reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months.

Study Design/Methods

Primary endpoint: PFS
Key secondary endpoints: ORR, MRD (10^-5 sensitivity), and OS

Results

Efficacy

In the D-Kd vs Kd arm, median follow-up duration was 50.6 (range, 0-57) months vs 50.1 (range, 0-58) months.
Survival and MRD-negativity rates are summarized in Table: Overall Survival and MRD-Negativity (10^-5 Sensitivity) Rates (CANDOR).

Overall Survival and MRD-Negativity (10^-5 Sensitivity) Rates (CANDOR)²¹

Parameter	D-Kd, % (95% CI) (n=312)	Kd, % (95% CI) (n=154)
MRD-negativity rate at 12 months	n=57	n=8
MRD-negativity rate at 12 months	18.3 (14.1-23)	5.2 (2.3-10)
OR (95% CI)	4.403 (2.007-9.656)
MRD-negative CR rate at 12 months	n=40	n=3
MRD-negative CR rate at 12 months	12.8 (9.3-17)	1.9 (0.4-5.6)
OR (95% CI)	7.819 (2.364-25.858)
MRD-negativity rate at any time	n=87	n=14
MRD-negativity rate at any time	27.9 (23-33.2)	9.1 (5.1-14.8)
OR (95% CI)	4.222 (2.277-7.829)
MRD-negative CR rate at any time	n=68	n=12
MRD-negative CR rate at any time	21.8 (17.3-26.8)	7.8 (4.1-13.2)
OR (95% CI)	3.551 (1.833-6.877)
Abbreviations: CI, confidence interval; CR, complete response; D-Kd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; OR, odds ratio.

Safety

TEAEs in the safety population of the CANDOR study have been reported by Usmani et al (2023).²¹

MRD-Negative CR and Best Overall MRD-negative Results of CANDOR

Landgren et al (2020)²² presented results from a post-hoc analyses of the best overall MRD-negative status at any time point and MRD-negative CR at various cutoffs from the CANDOR study.

For each analysis, MRD-negativity rates were higher in the D-Kd arm. MRD data are presented in Table: Summary of MRD-negativity Rates in Key Secondary and Exploratory Analyses.
At the 12-month landmark, MRD-negative CR rates for D-Kd vs Kd were consistent across subgroups. See Table: MRD-negative CR rates at 12-month Landmark by Subgroup.
The D-Kd arm observed higher CR rates vs Kd arm (26.9% vs 9.7%) and relatively deeper MRD responses at 12 months. For depth of response results, see Table: Level of Residual Disease in CR Patients at 12-month Landmark.
With median follow-up of 6 months from the 12-month landmark, no patient with an MRD-negative CR response progressed.

Summary of MRD-Negative Rates in Key Secondary and Exploratory Analyses²²

Rate Type, %	D-Kd	Kd	OR (95% CI)	P Value (1-Sided)^a
Best overall MRD-negative rate at any time	22.8	5.8	5.15	<0.0001
12-month MRD-negative rate	17.6	3.9	5.8 (2.4-14)	<0.0001
Best overall MRD-negative CR rate at any time	13.8	3.2	4.95	<0.0001
12-month MRD-negative CR rate^b	12.5	1.3	11.3 (2.7-47.5)	<0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; OR, odds ratio. ^aP values were calculated using the stratified Cochran-Mantel-Haenszel test for “All randomized patients”, and the Fisher’s exact test for subgroups.^bPrespecified secondary endpoint.

MRD-negative CR rates at 12-month Landmark by Subgroup²²

Group	D-Kd		Kd		OR (95% CI)
Group	n/N	MRD-Negative CR, %	n/N	MRD-Negative CR, %	OR (95% CI)
Prior lines of therapy per IXRS
1	1/67	1.5	22/133	16.5	13.1 (1.7, 99.3)
≥2	1/87	1.1	17/179	9.5	9 (1.2, 69)
Age at baseline, years
≤75	1/136	0.7	37/287	12.9	20 (2.7, 147.2)
>75	1/18	5.6	2/25	8	1.5 (0.1, 17.7)
Baseline CrCl, mL/min
≥15-49	0/27	0	4/38	10.5	NE
≥50-79	1/50	2	14/97	14.4	8.3 (1.1, 64.8)
≥80	1/77	1	21/176	11.9	10.3 (1.4, 78)
Prior lenalidomide exposure
Yes	0/74	0	14/123	11.4	NE
No	2/80	2.5	25/189	13.2	5.9 (1.4, 25.7)
Refractory to lenalidomide
Yes	0/55	0	13/99	13.1	NE
No	2/99	2	26/213	12.2	6.7 (1.6, 29)
Prior bortezomib or ixazomib exposure
Yes	2/137	1.5	34/289	11.8	9.0 (2.1, 38)
No	0/17	0	5/23	21.7	NE
Refractory to bortezomib or ixazomib
Yes	1/55	1.8	7/100	7	4.1 (0.5, 33.9)
No	1/99	1	32/212	15.1	17.4 (2.3, 129.4)
Prior IMiD exposure
Yes	0/110	0	24/206	11.7	NE
No	2/44	4.5	15/106	14.2	3.5 (0.8, 15.8)
Refractory to IMiD
Yes	0/65	0	16/130	12.3	NE
No	2/89	2.2	23/182	12.6	6.3 (1.4, 27.3)
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-Kd, DARZALEX + carfilzomib + dexamethasone; IMiD, immunomodulatory imide drugs; IXRS, interactive voice/web response system; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NE, not evaluated; OR, odds ratio.

Level of Residual Disease in Patients with CR at 12-month Landmark²²

Patients With CR, n (%)	D-Kd (n=84)	Kd (n=15)
<10^-6sensitivity	19 (22.6)	0 (0)
10^-5 to 10^-6sensitivity	20 (23.8)	2 (13.3)
10^-4 to 10^-5sensitivity	14 (16.7)	2 (13.3)
10^-4sensitivity	31 (36.9)	11 (73.3)
Abbreviations: CR, complete response; D-Kd, DARZALEX + carfilzomib + dexamethasone; Kd, carfilzomib + dexamethasone; MRD, minimal residual disease; NGS, next-generation sequencing. ^aDepth of response measured by NGS MRD level.

DARZALEX FASPRO in Combination with Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; clinicaltrials.gov identifier: NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in DVRd group or R in VRd group in patients with NDMM eligible for ASCT. Sonneveld et al (2023)²³ reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT.

Study Design/Methods

A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) arm.
- Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).
Dosing:
- Induction and consolidation: Total duration of induction and consolidation treatment was 6 cycles. Each cycle was 28 days.
  - DVRd:
    - DARZALEX FASPRO- 1800 mg once every week (QW) at cycles 1-2 and once every 2 weeks (Q2W) at cycles 3-4
    - SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
    - Orally (PO)/IV lenalidomide- 25 mg on days 1-21 of each cycle
    - PO/IV dexamethasone- 40 mg on days 1-4 and days 9-12 of each cycle
  - VRd:
    - SC bortezomib- 1.3 mg/m² on days 1, 4, 8, and 11 of each cycle
    - PO lenalidomide- 25 mg daily on days 1-21 of each cycle
    - PO/IV dexamethasone- 40 mg on days 1-4 and days 9-12 of each cycle
- Maintenance: Total duration of maintenance (≥24 months) was cycle 7 until progressive disease. Each cycle was 28 days.
  - DVRd:
    - DARZALEX FASPRO- 1800 mg SC once every 4 weeks (Q4W)
    - PO lenalidomide- 10 mg until PD or unacceptable toxicity
    - Patients who achieved sustained MRD for 12 months after ≥24 months of maintenance discontinued DARZALEX FASPRO, but continued PO lenalidomide until PD or unacceptable toxicity. Once they experienced loss of MRD-negativity or CR, they restarted on DARZALEX FASPRO.
    - Patients who did not achieved sustained MRD for 12 months after ≥24 months of maintenance continued DARZALEX FASPRO and PO lenalidomide
  - VRd:
    - PO lenalidomide-10 mg daily until PD or unacceptable toxicity
Primary endpoint: PFS.
Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.
Other secondary endpoints: ORR, ≥VGPR, sCR, duration of MRD-negativity.

Results

Patient Characteristics

A total of 709 patients were randomized into the D-VRd (n=355) and VRd (n=354) groups.
A total of 698 patients (D-VRd, n=351; VRd, n=347) received ≥1 dose of treatment.
As of the clinical data cutoff date of August 1, 2023, 322 (91.7%) vs 300 (86.5%) patients in the D-VRd vs VRd group, who started the induction phase continued into the maintenance phase, respectively.
- A total of 207/322 patients in the D-VRd group who were receiving maintenance treatment discontinued DARZALEX FASPRO per protocol after receiving ≥24 months of maintenance treatment and achieving ≥CR and sustained MRD-negativity for ≥12 months.
A total of 315 (89.7%) vs 302 (87%) patients in the D-VRd vs VRd group received ASCT, respectively.
The median duration of follow-up was 47.5 months (range, 0-54.4).

Efficacy

A summary of response rates and MRD status in the ITT population is presented in Table: Summary of MRD Status in the ITT Population.
Analyses of overall ≥CR rates and overall MRD-negativity rates (at 10^-5 sensitivity) in prespecified subgroups appeared to favor D-VRd over VRd across clinically relevant subgroups.

Summary of MRD Status in the ITT Population^a,²³

Parameter	D-VRd (n=355)	VRd (n=354)	P Value^b
MRD-negativity^c, n (%)
10^-5 sensitivity	267 (75.2)	168 (47.5)	<0.0001
10^-6 sensitivity	231 (65.1)	114 (32.2)	-
Sustained MRD-negativity (10^-5sensitivity) for ≥12 months, n (%)	230 (64.8)	105 (29.7)	-
Abbreviations: CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IMWG, International Myeloma Working Group; ITT, intention-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; VRd, bortezomib + lenalidomide + dexamethasone. ^aResponse rates and MRD-negativity rates at any time during the study. The responses were assessed based on the IMWG response criteria. ^bP values were calculated with the use of the stratified Cochran-Mantel-Haenszel chi-squared test. ^CThe MRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity and ≥CR. Sustained MRD-negativity for 12 months was defined as 2 consecutive MRD-negative results 12 months apart, without any MRD-positive results in between. The MRD status was assessed using bone marrow samples and evaluated using an NGS assay (clonoSEQ assay, version 2; Adaptive Biotechnologies) in accordance with the IMWG guidelines for assessing MRD.

Safety

Most common AEs during treatment in the safety population of the PERSEUS study have been reported by Sonneveld et al (2023).²³

Significance of CTC as a Biomarker in Transplant-Eligible NDMM Patients - Results From the PERSEUS Study

Bertamini et al (2024)²⁴ presented (at the 66^th ASH Annual Meeting) results from the PERSEUS study that highlighted the significance of CTC as a biomarker in transplant-eligible NDMM patients.

Results

Patient Characteristics

The CTC testing was performed at screening in 451 patients from the PERSEUS study (D-VRd, 231/355 [65.1%] vs VRd, 220/354 [62.1%] patients). The baseline patient characteristics were balanced between the treatment groups and are summarized in Table: Baseline Characteristics in Patients From the PERSEUS Study - CTC Subgroup.

Baseline Characteristics in Patients From the PERSEUS Study - CTC Subgroup²⁴

Characteristic	D-VRd (n=231)	VRd (n=220)	P Value
CTC detected, n/N (%)	183/231 (79.2)	187/220 (85)	0.73
CTC, median (IQR), %	0.0104 (0.0009-0.0738)	0.0088 (0.0012-0.0746)	0.88
Median age (IQR), years	60 (53.5-65)	59 (52.8-65)	0.71
Female sex, n (%)	84 (36.4)	95 (43.2)	0.14
ISS disease stage, %
I	53.2	50.9	0.76
II	31.6	35	0.76
III	15.2	14.1	0.76
High LDH, n (%)	63 (27.3)	42 (19.1)	0.04
Cytogenetic high-risk^a, n (%)	51 (22.1)	49 (22.3)	0.86
Abbreviations: CTC, circulating tumor cell; D-VRd, DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone; IQR, interquartile range; ISS, International Staging System; LDH, lactate dehydrogenase; VRd, bortezomib, lenalidomide, and dexamethasone.^aHigh-risk cytogenetics was defined by the presence of t(4;14) and/or t(14;16) and/or del17p by fluorescence in situ hybridization.

Efficacy

D-VRd vs VRd significantly improved patient outcomes across both high and low CTC levels (P<0.0001).²⁴
- D-VRd vs VRd improved MRD-negativity rates (with ≥CR; 10^–5 and 10^–6 sensitivities) and sustained MRD-negativity rates (with ≥CR; 10^-5 and 10^–6 sensitivities; ≥12 months) in patients with both high and low CTC levels, and the results are presented in Table: Summary of Overall MRD-Negativity (With ≥CR) Rates.²⁴

Summary of Overall MRD-Negativity (With ≥CR) Rates²⁴

Patients, %	CTC Low Level^a			CTC High Level^b
Patients, %	D-VRd (n=195)	VRd (n=187)	P Value	D-VRd (n=36)	VRd (n=33)	P Value
Overall MRD-negativity (with ≥CR)^c
10^-5 sensitivity	74	58	<0.001^d	69	33	<0.01^d
10^-6 sensitivity	66	39	<0.001^d	47	21	<0.01^d
Sustained MRD-negativity (with ≥CR; ≥12 months)^e
10^-5 sensitivity	64	36	<0.0001^f	50	15	<0.01^f
10^-6 sensitivity	42	21	<0.0001^f	39	6	<0.01^f
Abbreviations: CI, confidence interval; CR, complete response; CTC, circulating tumor cell; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; VRd, bortezomib + lenalidomide + dexamethasone. ^aCTC-low is defined by CTC <0.175%. ^bCTC-high is defined by CTC ≥0.175%. ^cProportion of patients who achieved both MRD-negativity and ≥CR in the randomized ITT population.^dP value from a Chi-square test.^eTwo consecutive MRD-negative results ≥12 months apart with no MRD-positive results in between.^fP value from a Fisher’s test.

DARZALEX FASPRO in Combination with Pomalidomide and Dexamethasone in Patients with RRMM

APOLLO (MMY3013; clinicaltrials.gov identifier: NCT03180736) is an ongoing phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of D-Pd vs Pd in patients with RRMM who received ≥1 prior treatment with both lenalidomide and a PI. Dimopoulos et al (2021)²⁵ reported the primary analysis of this study.

Study Design/Methods

Primary endpoint: PFS
Key secondary endpoints: ORR, MRD-negativity rate (10^-5 sensitivity via NGS), ≥VGPR, ≥CR, and OS

Results

Patient Characteristics

The ITT population consisted of 151 patients in the D-Pd arm and 153 patients in the Pd arm.

Efficacy

After 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).

Safety

Most common adverse events in the safety population of the APOLLO study has been reported by Dimopoulos et al (2021).²⁵

DARZALEX FASPRO in Combination with 4 Standard-of-Care Regimens

PLEIADES (MMY2040; clinicaltrials.gov identifier: NCT03412565) is an ongoing, 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. Chari et al (2021)²⁶ presented the results of safety and efficacy analysis of D-VRd, D-VMP, and D-Rd in the PLEIADES study. Moreau et al (2020)²⁷ presented updated safety and efficacy results of the D-Kd, D-Rd, and D-VMP arms in the PLEIADES study.

Study Design/Methods

D-VRd for patients with transplant-eligible NDMM (n=67).
D-VMP for patients with transplant-ineligible NDMM (n=67).
D-Rd for patients with RRMM with ≥1 LOT (n=65)
D-Kd in patients with RRMM with 1PL (n=60)
Primary endpoints: ORR for the D-VMP and D-Rd cohorts; ≥VGPR after the 4 induction cycles for the D-VRd cohort
Key secondary endpoints: ≥CR, DOR, MRD-negativity rate and ≥VGPR for the D-VMP, D-Rd cohorts; ORR for the D-VRd cohort

Results - D-VRd, D-VMP, and D-Rd

Efficacy

The pre-specified primary analysis with a median follow-up was 3.9 months, 6.9 months, and 7.1 months for D-VRd, D-VMP, and D-Rd cohorts, respectively.
At a subsequent clinical cut-off, the median duration of follow-up was 14.3 months, and 14.7 months for D-VMP, and D-Rd cohorts respectively.
Primary endpoints were met for all 3 cohorts and response rates were similar to DARZALEX studies in GRIFFIN¹³, ALCYONE¹¹, and POLLUX¹⁶.
MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10^-5.
- 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.

Safety

Safety summary in the D-VRd, D-VMP, and D-Rd cohorts, and most common grade 3/4 TEAEs (≥5% in any cohorts) of the PLEIADES study have been reported by Chari et al (2021).²⁶

Moreau et al (2020)²⁷ presented updated safety and efficacy results of the D-Kd, D-Rd, and D-VMP arms in the PLEIADES study.

Results - D-Kd, D-Rd, and D-VMP

Efficacy

Median duration of follow-up was 9.2 months (primary analysis), 25.7 months, and 25.2 months for D-Kd, D-Rd, and D-VMP cohorts, respectively.
Response rates were similar to DARZALEX studies in CANDOR²⁰, POLLUX⁵⁴, and ALCYONE⁵⁵
MRD-negativity rates were evaluated via 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.

Safety

Summary of TEAEs occurring in the D-Kd, D-Rd, and D-VMP cohorts of the PLEIADES study have been reported by Moreau et al (2020).²⁷

DARZALEX FASPRO in Combination with Lenalidomide

AURIGA (MMY3021; clinicaltrials.gov identifier: NCT03901963) is an ongoing, open-label, active-controlled, multicenter, randomized, phase 3 study evaluating the conversion rate to MRDnegativity after maintenance treatment with DR vs lenalidomide alone in patients with NDMM who are MRD-positive after ASCT.²⁸^-³⁰

Badros et al (2024)²⁸^,²⁹ reported primary results from the phase 3 AURIGA study.

Study Design/Methods

The trial enrolled 200 patients from the United States and Canada.²⁸
Patients underwent 1:1 randomization to receive D-R (n=99) or R alone (n=101) across 28-day cycles.²⁸^,³⁰
- D-R: DARZALEX FASPRO 1800 mg SC QW in cycles 1-2, Q2W in cycles 3-6, Q4W in cycles 7+.
- R: Lenalidomide 10 mg PO once a dayon days 1-28.
The treatment regimen continued until unacceptable toxicity, disease progression, consent withdrawal, or for a maximum of 36 cycles.²⁸
Primary endpoint: MRD-negativity conversion rate from baseline by 12 months.²⁸
- MRD was assessed at 12, 18, 24, and 36 months.
- If lenalidomide is well tolerated, the dose may be increased to 15 mg daily after cycle 3, at the investigator’s discretion.
Secondary endpoints: Safety, PFS, overall MRD-negativity conversion rate, sustained MRD-negativity rate (≥6 months), response rates including CR/sCR as assessed by International Myeloma Working Group 2016 criteria, duration of ≥CR, OS, HRQoL changes based on patient reported outcomes.²⁸

Results

Patient Characteristics

A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.²⁸
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.²⁸
The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the ITT Population.²⁸
The median follow-up was 32.3 months.²⁸
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.²⁸
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.²⁸

Baseline Demographics and Disease Characteristics of the ITT Population²⁸

	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)
Other^a	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 stage^b, 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 diagnosis^d, n (%)
Standard risk	63 (68.5)	66 (74.2)
High risk^e	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 diagnosis^f, n (%)
Standard risk	52 (55.9)	53 (59.6)
High risk^g	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.²⁸^,²⁹
- 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^-5sensitivity) rates at ≥12 months (17.2% vs 5%) than the R arm.
Subgroup analyses of MRD-negativity (10^-5sensitivity) 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.²⁸

Summary of MRD Status in the ITT Population²⁸^,²⁹

Parameter	D-R (n=99)	R (n=101)	OR^a (95% CI)	P-Value^b
Overall MRD-negativity conversion rate^c, 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 months^d	35 (35.4)	14 (13.9)	3.40 (1.69-6.83)	0.0005
≥12 months^d	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 Population²⁸

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 risk^a	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 risk^b	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).

CEPHEUS (MMY3019; clinicaltrials.gov identifier: 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).³²^-³⁴ Usmani et al (2025)³⁴ reported results from the phase 3 CEPHEUS study.

Study Design/Methods

The trial has enrolled 395 patients from 13 different countries including the United States.³³
Primary endpoint: Overall MRD-negativity (≥CR) rate at 10^-5 sensitivity threshold.³²^,³³
Key secondary endpoints: PFS, ORR, ≥VGPR, ≥CR, PFS2, OS, and sustained MRD-negativity (10^-5) rate at ≥12 months.³²^,³³

Results

Patient Characteristics

A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.³⁴
The baseline demographics and clinical characteristics of the intention-to-treat (ITT) population are presented in Table: Baseline Demographics and Clinical Characteristics of the ITT Population.
The median follow-up was 58.7 months (range, 0.1-64.7).³⁴

Baseline Demographics and Clinical Characteristics of the ITT Population^a,³⁴

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)
Male^b, n (%)	87 (44.2)	111 (56.1)
Race^b, 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 PS^c, n (%)
0	71 (36)	84 (42.4)
1	103 (52.3)	100 (50.5)
2	23 (11.7)	14 (7.1)
Frailty score^d, 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)
Other^e	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 stage^f, n (%)
I	68 (34.5)	68 (34.3)
II	73 (37.1)	75 (37.9)
III	56 (28.4)	55 (27.8)
Cytogenetic risk profile^g, n (%)
Standard risk	149 (75.6)	149 (75.3)
High risk	25 (12.7)	27 (13.6)
Indeterminate^h	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%).³⁴
- 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%).³⁴
- 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 Population³⁴

Parameter	D-VRd (n=197)	VRd (n=198)	OR (95% CI)	P Value
Overall MRD-negativity^a, %
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
Response^b, 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 Rates³⁴

Subgroup	D-VRd	VRd	OR (95% CI)
Subgroup	Number of Patients With MRD-Negativity/ Total Number of Patients (%)		OR (95% CI)
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)³⁵ presented (at the 66^th ASH Annual Meeting) 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.³⁵

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^-6sensitivities) vs VRd alone at all prespecified timepoints.³⁵
- D-VRd almost doubled sustained MRD-negativity (≥) CR rates at 12, 24, and 36 months.³⁵
- Among patients who achieved both MRD-negativity (10^-6sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.³⁵
D-VRd vs VRd showed PFS benefit regardless of the MRD-negativity status (10^-6sensitivity).³⁵
- 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 Analysis³⁵

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 months^b	49.2	27.3	2.56 (NR)	<0.0001
≥24 months^c	42.1	22.7	2.47 (NR)	<0.0001
≥36 months^d	29.9	15.2	2.37 (NR)	0.0005
Sustained MRD-negativity (10^-6sensitivity; ≥CR)^a, %
≥12 months^b	34	16.2	NR	NR
≥24 months^c	27.9	13.6	NR	NR
≥36 months^d	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 Subgroups³⁵

Subgroups, n/N (%)	D-VRd	VRd	OR (95% CI)	D-VRd	VRd	OR (95% CI)
Subgroups, n/N (%)	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.

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 12 February 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	Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38.
2	Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.
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5	Moreau P, Hulin C, Perrot A, et al. Supplement to: Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.
6	Avet-Loiseau H, Sonneveld P, Moreau P, et al. Daratumumab (DARA) with bortezomib, thalidomide, and dexamethasone (VTd) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) negativity in CASSIOPEIA part 1 and part 2. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.
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17	Dimopoulos M, Oriol A, Nahi H, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1590-1599.
18	Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
19	Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1600-1609.
20	Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.
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23	Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4)(4):301-313.
24	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.
25	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.
26	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.
27	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.
28	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. 2024;In press.
29	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.
30	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 February 12]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03901963 NLM Identifier: NCT03901963.
31	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. 2024;In press.
32	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.
33	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 February 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT03652064 NML Identifier: NCT03652064.
34	Usmani SZ, Facon T, Hungria V. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study. doi.org/10.1038/s41591-024-03485-7. Nat Med. 2025.
35	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.
36	Moreau P, Facon T, Usmani S, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): clinical assessment of key subgroups of the phase 3 MAIA study. Poster presented at: The German Society for Hematology and Medical Oncology (DGHO) Annual Conference; October 13-16, 2023; Hamburg, Germany.
37	Rodriguez C, Kaufman J, Laubach J, et al. Daratumumab + lenalidomide, bortezomib, and dexamethasone in transplant-eligible newly diagnosed multiple myeloma: a post hoc analysis of sustained minimal residual disease negativity from GRIFFIN. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL/Virtual Meeting.
38	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.
39	Chari A, Kaufman JL, Laubach J, et al. Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 2024;14(1).
40	Spencer A, Moreau P, Mateos MV, et al. Daratumumab in combination with bortezomib plus dexamethasone (D-Vd) or lenalidomide plus dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): subgroup analysis of the phase 3 CASTOR and POLLUX studies in patients with early or late relapse after initial therapy. presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL/Virtual Meeting.
41	Spencer A, Moreau P, Mateos MV, et al. Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX. Blood Adv. 2024;8(2):388-398.
42	Spencer A, Moreau P, Mateos MV, et al. Supplement to: Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX. Blood Advances. 2024;8(2):388-389.
43	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.
44	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.
45	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.
46	Rodriguez-Otero P, Voorhees PM, Boccadoro M, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone in transplant-eligible patients with multiple myeloma: a pooled analysis of patients aged ≥65 years from both PERSEUS and GRIFFIN studies. Poster presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil.
47	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.
48	Moreau P, Facon T, Usmani SZ, et al. Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study. [published online ahead of print January 15, 2025]. doi:10.1038/s41375-024-02506-1. Leukemia. 2025.
49	Moreau P, Hulin C, Perrot A, et al. Supplement to: Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. [published online ahead of print June 14, 2024]. Lancet Oncol. 2024. doi:10.1016/s1470-2045(24)00282-1.
50	San-Miguel J, Avet-Loiseau H, Paiva B, et al. Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE. Blood. 2021;139(4):492-501.
51	Laubach J, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual Meeting.
52	Sborov D, Laubach J, Kaufman JL, et al. Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Oral Presentation presented at: 19th International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA.
53	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.
54	Kaufman JL, Usmani S, Miguel J, et al. Four-year follow-up of the phase 3 POLLUX study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in relapsed or refractory multiple myeloma (RRMM). Poster presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.
55	Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141.

Medical inquiries

DARZALEX® (daratumumab)

Medical Information

DARZALEX + DARZALEX FASPRO - Minimal Residual Disease in Clinical Trials

SUMMARY

DARZALEX

DARZALEX FASPRO

PRODUCT LABELING

CLINICAL DATA

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone in Previously Untreated MM

Study Design/Methods

Results - Part 1

Efficacy

Safety

Most common AEs during treatment in the safety populationin part 1 of the CASSIOPEIA Study have been reported by Moreau et al (2019)1

Results - Part 2

The key baseline characteristics are summarized in Table: Key Baseline Disease Characteristics after Second Randomization in ITT Population (CASSIOPEIA Part 2).

Efficacy

Safety

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

Study Design

Results

Evaluation of Baseline slimCRAB Subgroup and Association to Efficacy Outcomes in CASSIOPEIA Study Part 1

Study Design

Results

Baseline Characteristics

Efficacy

MRD Analysis in CASSIOPEIA Study Part 1 and Part 2

Study Design/Methods

Results

Efficacy

Long-term Follow-up in CASSIOPEIA Study

Study Design

Results

Patient Disposition

Efficacy

Safety

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with NDMM

Study Design/Methods

Results

Efficacy

Safety

Predictive and Prognostic Role of MRD-Negativity and Durability in MAIA Study

Results

Patient Characteristics

Efficacy

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone in Patients with NDMM

Study Design/Methods

Results

Efficacy

Safety

Predictive and Prognostic Role of MRD-Negativity and Durability in ALCYONE Study

Results

Patient Characteristics

Efficacy

DARZALEX in Combination with Bortezomib, Lenalidomide, and Dexamethasone in Patients with NDMM

Study Design/Methods

Part 1: Safety Run-in Phase Final Analysis

Results

Efficacy

Part 2: Final Efficacy and Safety Analysis of Maintenance Therapy

Results

Efficacy

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with RRMM

Study Design/Methods

Results

Patient Characteristics

Efficacy

Safety

DARZALEX in Combination with Bortezomib and Dexamethasone in Patients with RRMM

Study Design/Methods

Results

Efficacy

Safety

DARZALEX in Combination with Carfilzomib and Dexamethasone in Patients with RRMM

Study Design/Methods

Results

Efficacy

Safety

MRD-Negative CR and Best Overall MRD-negative Results of CANDOR

Most common AEs during treatment in the safety populationin part 1 of the CASSIOPEIA Study have been reported by Moreau et al (2019)¹