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. 2026 Jun 5;10(16):5594–5606. doi: 10.1182/bloodadvances.2026019937

Daratumumab in transplant-ineligible or -deferred newly diagnosed multiple myeloma: minimal residual disease in CEPHEUS

Sonja Zweegman 1,∗, Thierry Facon 2, Vania Hungria 3, Nizar J Bahlis 4, Christopher P Venner 5,6, Marc Braunstein 7, Ludek Pour 8, Josep Marti 9, Supratik Basu 10, Yael C Cohen 11, Morio Matsumoto 12, Kenshi Suzuki 13, Cyrille Hulin 14, Sebastian Grosicki 15, Wojciech Legiec 16, Meral Beksac 17, Angelo Maiolino 18,19, Hiroyuki Takamatsu 20, Aurore Perrot 21, Mehmet Turgut 22, Weiping Liu 23, Jianping Wang 24, Emilie van Brummelen 25, Maria Krevvata 24, Lorena Lopez-Masi 26, Jodi Carey 24, Fredrik Borgsten 26, Melissa Rowe 27, Robin Carson 24, Saad Z Usmani 28
PMCID: PMC13495367  PMID: 42234958

Key Points

  • •

    In CEPHEUS, D-VRd led to higher sustained MRD-negative CR or better rates vs VRd in transplant-ineligible/-deferred patients with NDMM.

  • •

    Deeper MRD responses with D-VRd translated into significantly improved PFS vs VRd.

Visual Abstract

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Abstract

In the phase 3 CEPHEUS study, D-VRd (daratumumab/bortezomib/lenalidomide/dexamethasone) increased overall minimal residual disease (MRD)-negativity rates vs VRd in patients who were transplant ineligible/deferred with newly diagnosed multiple myeloma (NDMM). We present an expanded MRD analysis of CEPHEUS. Patients who were transplant-ineligible or deferred transplant as initial therapy were randomized to D-VRd or VRd. Overall MRD negativity (next-generation sequencing) was defined as the proportion of patients achieving complete response or better and MRD-negative status assessed at 10−5 (primary end point) and 10−6 thresholds. In total, 395 patients were randomized (D-VRd, n = 197; VRd, n = 198). With 58.7-months median follow-up, overall MRD-negativity rates were significantly higher with D-VRd vs VRd (10−5: 60.9% vs 39.4%; odds ratio [OR], 2.37; 95% confidence interval [CI], 1.58-3.55; P < .0001; 10−6: 46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P = .0001). Sustained MRD negativity (≥12 months) was significantly higher with D-VRd vs VRd (10−5: 49.2% vs 27.3%; 10−6: 34.0% vs 16.2%; each P < .0001), with similar benefits at ≥24 and ≥36 months. MRD-negativity rates were higher at all prespecified time points and cumulatively with D-VRd. Among patients who achieved MRD negativity, progression-free survival (PFS) trended in favor of D-VRd vs VRd (10−5: hazard ratio, 0.61; 95% CI, 0.35-1.06; P = .0755; 10−6: 0.66; 95% CI, 0.31-1.41; P = .2811). Responses with D-VRd were deeper and more durable vs VRd, with increased overall, sustained, and landmark MRD-negativity rates, translating into improved overall PFS with D-VRd vs VRd (intent-to-treat), with potential to improve PFS even among patients with MRD negativity. D-VRd is therefore a new standard-of-care treatment for transplant-ineligible/transplant-deferred NDMM. This trial was registered at www.clinicaltrials.gov as NCT03652064.

Introduction

The achievement of minimal residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma (NDMM) is associated with improved survival outcomes.1, 2, 3, 4 The addition of daratumumab, a human immunoglobulin Gκ monoclonal antibody targeting CD38 with direct on-tumor5, 6, 7, 8 and immunomodulatory9, 10, 11 mechanisms of action, to frontline standard-of-care regimens has demonstrated high and sustained MRD-negativity rates, leading to prolonged progression-free survival (PFS) in patients with NDMM in 5 phase 3 clinical trials.12, 13, 14, 15, 16

In the phase 3 CEPHEUS study, frontline daratumumab plus bortezomib/lenalidomide/dexamethasone (D-VRd) followed by daratumumab plus lenalidomide/dexamethasone (D-Rd) vs VRd followed by Rd, demonstrated superior overall MRD negativity (10–5: 60.9% vs 39.4%, respectively), 12-month sustained MRD negativity (10–5: 48.7% vs 26.3%), and PFS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.41-0.79; P = .0005) in transplant-ineligible or -deferred NDMM.16 In the phase 3 MAIA study, frontline D-Rd for transplant-ineligible NDMM resulted in higher MRD-negativity rates (10–5: D-Rd, 31%; Rd, 10%),13 a 47% reduction in the risk of disease progression or death,13 and a 33% reduction in the risk of death17 vs Rd. In the phase 3 PERSEUS study of transplant-eligible NDMM, D-VRd induction/consolidation followed by D-R maintenance vs VRd followed by R, significantly improved PFS (HR, 0.42; 95% CI, 0.30-0.59; P < .0001), overall MRD-negativity rates (10–5: 75.2% vs 47.5%, respectively; 10–6: 65.1% vs 32.2%), and 12-month sustained MRD-negativity rates (10–5: 64.8% vs 29.7%; 10–6: 47.3% vs 18.6%).15,18 D-VRd has since received approval for treatment of adult patients with NDMM by the European Medicines Agency and US Food and Drug Administration, based on data from CEPHEUS and PERSEUS.19,20

In the EVIDENCE meta-analysis of 5130 patients with NDMM from 8 clinical trials, global odds ratios (ORs) reported a strong association between 12-month MRD negativity and PFS and overall survival (OS) among transplant-eligible (PFS, 2.45 [95% CI, 1.40-3.51]; OS, 3.78 [95% CI, 0.78-6.78]) and transplant-ineligible patients (PFS, 6.15 [95% CI, 4.27-8.03]; OS, 4.08 [95% CI, 2.44-5.72]).21 Similarly, in a pooled analysis of MM trials reported by the i2TEAMM group, both 9- and 12-month MRD-negative complete response (CR; at the 10–5 sensitivity threshold) was strongly correlated with PFS and OS in transplant-eligible, -ineligible, and relapsed/refractory MM.22 As patient survival has increased over the last few decades,23 prognostic markers such MRD are crucial as clinical trials subsequently require greater time to reach survival end points. In light of this, the use of MRD testing in patients achieving a CR or better as an early end point in myeloma clinical trials recently received unanimous support from the Oncologic Drugs Advisory Committee to assist the accelerated approval of new treatments.24

The phase 3 CEPHEUS study is, to our knowledge, the first daratumumab-based clinical trial to use overall MRD negativity in patients achieving CR or better as a primary end point. The International Myeloma Working Group (IMWG) considers the “MRD-negative CR” criterion as the most sensitive response assessment,25 hence all MRD results presented for the CEPHEUS study are among patients who achieved CR or better. Here, we present an expanded, comprehensive MRD analysis of the CEPHEUS study.

Methods

Study design

Complete study design of this randomized, open-label, multicenter phase 3 study (ClinicalTrials.gov identifier: NCT03652064) have been published previously.16 Briefly, patients with NDMM who were transplant-ineligible or had deferred transplant were enrolled between 11 December 2018, and 7 October 2019, from 92 sites across 13 countries. All patients provided written informed consent. The study protocol and amendments were approved by an independent review or independent ethics committee at each participating site, and the study was conducted in accordance with the Declaration of Helsinki, current International Council for Harmonisation Good Clinical Practice guidelines, and any country- or site-specific regulations.

Patients

Full eligibility criteria have been published previously.16 Eligible patients were aged <80 years, had a frailty index score of <2, had NDMM (IMWG criteria),26 an Eastern Cooperative Oncology Group performance status score of 0 to 2, and were transplant ineligible or had deferred transplant. Patients aged ≥65 years could be considered transplant ineligible due to age alone; however, patients aged between 65 and <70 years could also be considered transplant-deferred (according to the investigator). Patients aged >18 to 65 years were considered either transplant ineligible if presenting with underlying medical conditions or comorbidities that would likely have a negative impact upon transplant tolerability, or as transplant-deferred if they did not plan to receive a transplant as initial therapy.

Study treatment

Patients were randomized 1:1 to receive VRd, with or without subcutaneous daratumumab, stratified by International Staging System (ISS) disease stage (I, II, or III) and age/transplant eligibility (<70 years ineligible, <70 years and transplant-deferred, or ≥70 years). Randomization was balanced using permuted blocks.

All patients received 8, 21-day cycles of VRd, consisting of subcutaneous bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle), oral lenalidomide (25 mg on days 1-14 of each cycle), and oral dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle; for patients aged >75 years or underweight [body mass index, <18.5 kg/m2], 20 mg on days 1, 4, 8, and 11). For cycle 9 and onward, bortezomib was discontinued per protocol, and patients received 28-day cycles of Rd only, consisting of oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; in patients aged >75 years or underweight, 20 mg weekly) until disease progression or unacceptable toxicity. Patients randomized to the D-VRd group also received a fixed-dose of subcutaneous daratumumab (1800 mg coformulated with recombinant human hyaluronidase PH20 [2000 U/mL of solution]; ENHANZE drug delivery technology, Halozyme) weekly during cycles 1 and 2, every 3 weeks during cycles 3 through 8, and every 4 weeks in cycle 9 and onward, until disease progression or unacceptable toxicity.

End points and MRD assessments

The primary end point was overall MRD-negativity rate, defined as the proportion of patients who achieved CR or better and had MRD-negative status (at or below the 10–5 sensitivity threshold) after randomization and before progressive disease or subsequent antimyeloma therapy. All MRD-negativity results reported here are for patients achieving CR or better; patients whose response was not evaluable, who did not achieve CR, or who had an indeterminate result were considered MRD positive. Additional MRD analyses reported here include MRD-negativity rates at specific time points and over time (cumulative), and PFS by overall and sustained MRD status. Sustained MRD-negativity rates are defined as the proportion of patients who achieved MRD-negative status at any time during the study with ≥2 bone marrow aspirate examinations that were a specific number of months apart (with an allotted window of ±1 month for ≥12 months, and ±3 months for 24 and 36 months), without MRD-positive status in between.

MRD was assessed using bone marrow aspirates by next-generation sequencing (clonoSEQ assay, version 2.0; Adaptive Biotechnologies)27,28 at baseline; at the time of suspected CR; and at 12, 18, 24, 30, and 36 months after the first dose (±1 month), and yearly thereafter (±3 months) in patients who achieved CR and remained on study. Both 10–5 and 10–6 sensitivity thresholds are reported. Using a portion of baseline bone marrow aspirate, cytogenetic abnormalities were also assessed by fluorescence in situ hybridization. High cytogenetic risk was defined as the presence of ≥1 of t(4;14), t(14;16), and/or del(17p). Tumor response and disease progression were assessed per IMWG criteria,26 using a validated centralized computer algorithm, and all disease assessments, including MRD, were performed centrally with the exception of local bone marrow results for confirmation of CR and stringent CR. The SEBIA Hydrashift 2/4 daratumumab immunofixation electrophoresis interference test was used centrally to confirm CR/stringent CR in the cases of suspected daratumumab interference.

Statistical analyses

Full statistical methods have been published previously.16 The primary end point of overall MRD-negativity rate was calculated for each treatment group based on the intent-to-treat (ITT) analysis set, consisting of all randomized patients assigned to either D-VRd or VRd. This study was powered to test the assumption that the addition of daratumumab to VRd would lead to a 15% absolute increase in overall MRD-negativity rate (50% vs 35%, for D-VRd and VRd, respectively). A stratified Cochran Mantel-Haenszel estimate of OR with 95% CIs and P values from the Fisher exact test were used to test the difference between the 2 treatment groups for overall MRD negativity; a Chi-squared estimate of common ORs with 95% CIs and P value from the Fisher exact test were used for sustained MRD negativity. Correlation of MRD-negativity status and PFS and exploratory MRD analyses were not part of the hierarchical hypothesis testing and are presented with nominal P values. For prespecified subgroup analyses, a Mantel-Haenszel estimate of the common OR for unstratified tables was used. The Kaplan-Meier method was used to estimate PFS distributions, with treatment effect measured by HRs and CIs from a Cox proportional hazards model with treatment as the sole explanatory variable, stratified by ISS staging (I, II, III), and age/transplant eligibility (aged <70 years and ineligible, aged <70 years and transplant deferred, or aged ≥70 years).

Results

Patients

In total, 395 patients were enrolled and randomized to D-VRd (n = 197) or VRd (n = 198; supplemental Table 1). Patient disposition has been published previously, and baseline characteristics were well balanced between groups.16 Among all patients, median age was 70 (range, 31-80) years, 50.1% were male, 80.5% were White, 28.1% had ISS stage III disease, and 13.2% had high-risk cytogenetics.

A total of 392 patients received ≥1 dose of the study treatment (D-VRd, n = 197; VRd, n = 195). Median duration of study treatment was ∼2 years longer in the D-VRd vs VRd group (56.3 vs 34.3 months, respectively); at the time of final clinical cutoff (7 May 2024), 51.8% and 34.4% of patients in the D-VRd and VRd group, respectively, remained on study treatment. Four (2.1%) patients in the VRd arm and no patient in the D-VRd arm underwent autologous stem cell transplant as subsequent antimyeloma therapy, after discontinuation of study treatment.

MRD calibration and sampling compliance

The proportion of patients with CR or better and evaluable bone marrow aspirates for MRD testing was 99.6% (D-VRd, 99.4%; VRd, 100%). The rate of successful calibration was high at 93.6% overall (D-VRd, 93.1%; VRd, 94.3%; supplemental Table 2). Calibration failure of the baseline bone marrow collected occurred in 8 of 11 cases in the D-VRd arm and 7 of 7 cases in the VRd arm, primarily attributed to the inability to identify the sequence of the malignant clone due to low clonal expansion. In a few cases in which the clone was identified, the sequence was not unique enough to be tracked. Overall, the proportion of patients with a CR or better who had an MRD test result available was generally high throughout the study across all prespecified time points, ranging between 91.3% and 95.7%, with the exception of the month 12 time point (85.5%) in which some samples were not collected due to COVID-19–related protocol deviations.

Overall MRD negativity

At a median follow-up of 58.7 months, the overall MRD-negativity rate was significantly higher with D-VRd vs VRd at 10–5 (60.9% vs 39.4%, respectively, exceeding the protocol assumption of 50% vs 35%; OR, 2.37; 95% CI, 1.58-3.55; P < .0001) and 10–6 (46.2% vs 27.3%; OR, 2.24; 95% CI, 1.48-3.40; P = .0001), as previously published.16 Prespecified subgroup analyses of overall MRD negativity demonstrated consistently higher overall MRD-negativity rates with D-VRd vs VRd across most patient subgroups, both at 10–5, as previously reported,16 and at 10–6 (Figure 1).

Figure 1.

Figure 1.

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Prespecified subgroup analysis of overall MRD-negativea CR or better rate. Assessed at the 10–5 (A) and 10–6 (B) sensitivity thresholds. aMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR or better in the ITT population. Patients who were not evaluable, did not achieve CR or better, or had indeterminate results were considered MRD positive. bMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR of >1 indicates an advantage for D-VRd. cHigh risk was defined as the presence of del(17p), t(4;14), and/or t(14;16), as assessed by fluorescence in situ hybridization testing. Panel A was reproduced from Usmani et al.16 ECOG, Eastern Cooperative Oncology Group.

The treatment effect with D-VRd was less pronounced in the small subgroup of patients with high cytogenetic risk (D-VRd, n = 25; VRd, n = 27); however, notably, overall MRD-negativity rates (10–5) were unexpectedly high among patients with high cytogenetic risk treated with VRd, with rates much higher than the VRd ITT population (55.6% vs 39.4%, respectively). Furthermore, patients with high cytogenetic risk who received D-VRd had a shorter median duration of treatment vs patients who received VRd (27 vs 35.5 cycles, respectively), primarily due to early treatment discontinuation, thus leading to a higher proportion of missing postbaseline MRD values in the high cytogenetic risk D-VRd group (n = 6 [24.0%]) than the VRd group (n = 4 [14.8%]; supplemental Table 3). Double the number of patients in the high cytogenetic risk D-VRd group (n = 6 [24.0%]) discontinued treatment before their first postbaseline MRD sample compared with the VRd group (n = 3 [11.1%]), meaning fewer patients in the high cytogenetic risk D-VRd group had the opportunity to be tested for MRD negativity (reasons for treatment discontinuation provided in supplemental Table 3). Regardless, among those patients with high cytogenetic risk who did achieve MRD negativity at the 10–5 threshold (D-VRd, 12/25 [48.0%]; VRd, 15/27 [55.6%]), a trend in favor of PFS benefit was observed with D-VRd vs VRd (HR, 0.33; 95% CI, 0.07-1.57; P = .1419; Figure 2).

Figure 2.

Figure 2.

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PFS by MRD-negativea CR or better (10–5) in patients with high cytogenetic risk.baMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR or better. Patients who were not evaluable or had indeterminate results were considered MRD positive. bHigh risk was defined as the presence of del(17p), t(4;14), and/or t(14;16), as assessed by fluorescence in situ hybridization testing.

MRD negativity over time

The attainment of MRD negativity (10–5) was more rapid with D-VRd compared with VRd (Figure 3A). Overall MRD-negativity rates (10–5) continued to increase over time with D-VRd until the time of this final analysis, whereas a plateau was observed in the VRd group starting from 18 months. Rates of cumulative MRD negativity (10–‍5 and 10–6) were consistently higher in the D-VRd group compared with the VRd group (Figure 3B). Similarly, landmark rates of MRD negativity (10–5 and 10–6) were higher with D-VRd vs VRd across all prespecified time points (supplemental Figure 1). Sustained MRD negativity was significantly higher and almost doubled with D-VRd vs VRd for ≥12 months at 10–5 (49.2% vs 27.3%; OR, 2.56; 95% CI, 1.69-3.89; P < .0001) and at 10–6 (34.0% vs 16.2%; OR, 2.66; 95% CI, 1.65-4.30; P < .0001), with similar benefits observed for ≥24 and ≥36 months (Figure 4).

Figure 3.

Figure 3.

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Cumulative MRD-negativea CR or better rate. Presented both over time (10–5) (A) and at prespecified time pointsb (10–5 and 10–6) (B). aMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR or better in the ITT population. Patients who were not evaluable, did not achieve CR or better, or had indeterminate results were considered MRD positive. bA window of ±3 months at each time point was applied to complete the bone marrow aspiration. Panel A was reproduced from Usmani et al.16

Figure 4.

Figure 4.

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Sustained MRD-negative CR or better rate (10–5 and 10–6).aChi-squared estimate of the common OR is used. An OR of >1 indicates an advantage for D-VRd. bMantel-Haenszel estimate of the common OR for stratified tables is used. The stratification factors are ISS staging (I, II, III) and age/transplant eligibility (aged <70 years ineligible, aged <70 years and refusal to transplant, or aged ≥70 years) as randomized. An OR of >1 indicates an advantage for D-VRd. cP value from the Fisher exact test. dProportion of patients who achieved CR or better and achieved MRD-negative status at 2 bone marrow assessments that are 12 months apart with an allotted window of ±1 month, without any MRD-positive status in between. eProportion of patients who achieved CR or better and achieved MRD-negative status at 2 bone marrow assessments that are 24 months apart with an allotted window of ±3 months, without any MRD-positive status in between. fProportion of patients who achieved CR or better and achieved MRD-negative status at any time during the study at 2 bone marrow assessments that are 36 months apart with an allotted window of ±3 months, without any MRD-positive status in between.

Among patients with ≥1 negative MRD test (D-VRd, n = 122; VRd, n = 81), fewer patients in the D-VRd group experienced a loss of MRD negativity (10–5) before disease progression compared with those in the VRd group (18/122 [14.8%] vs 27/81 [33.3%], respectively). In patients who lost their MRD-negative status and became MRD positive before disease progression, a lower proportion of patients who received D-VRd subsequently experienced disease progression per IMWG criteria vs those who received VRd alone (7/18 [38.9%] vs 17/27 [63.0%], respectively). Notably, among patients with high cytogenetic risk with ≥1 negative MRD test (D-VRd, n = 12; VRd, n = 15), no patient (0/12 [0%]) in the D-VRd group experienced a loss of MRD negativity, whereas 4 patients (4/15 [26.7%]) in the VRd group experienced loss of MRD negativity with subsequent disease progression.

PFS by MRD status

As previously reported, in the ITT population, deep MRD-negative responses subsequently translated into superior PFS for D-VRd vs VRd (HR, 0.57; 95% CI, 0.41-0.79; P = .0005).16 In an analysis of PFS by overall MRD-negativity status (10–5 and 10–6), a greater PFS benefit was observed in patients who achieved MRD-negative status, regardless of study treatment, compared with patients with an MRD-positive status (Figure 5). However, at 10–5 and 10–6 sensitivity thresholds (Figure 5A and B, respectively), a favorable treatment effect was seen with D-VRd compared with VRd, regardless of MRD-negativity status. At 10–5, the treatment effect trended in favor of D-VRd in MRD-negative (HR, 0.61; 95% CI, 0.35-1.06; P = .0755) and MRD-positive patients (HR, 0.82; 95% CI, 0.54-1.24; P = .3402; Figure 5A). In patients who achieved MRD negativity at the more stringent threshold of 10–6, median PFS was not reached in either treatment group; however, the treatment effect of PFS trended in favor of D-VRd over VRd (HR, 0.66; 95% CI, 0.31-1.41; P = .2811; Figure 5B), with a 54-month estimated PFS rate of 86.2% vs 79.0%, respectively. In patients with MRD-positive (10–6) status, median PFS was improved in the D-VRd group, and the treatment effect trended in favor of D-VRd vs VRd (60.3 vs 38.7 months, respectively; HR, 0.74; 95% CI, 0.51-1.06; P = .1022). In an 18-month landmark analysis, similar favorable trends were observed at 10–5 and 10–6 thresholds with D-VRd compared with VRd, regardless of whether patients were MRD negative (10–5: HR, 0.54; 95% CI, 0.29-1.00; P = .0486; 10–6: HR, 0.65; 95% CI, 0.29-1.48; P = .3040) or positive (10–5: HR, 0.67; 95% CI, 0.37-1.21; P = .1786; 10–6: HR, 0.60; 95% CI, 0.36-0.99; P = .0445; Figure 6).

Figure 5.

Figure 5.

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PFS by MRD-negativea CR or better status. Assessed at the 10–5 (A) and 10–6 (B) sensitivity thresholds. aMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR or better in the ITT population. Patients who were not evaluable or had indeterminate results were considered MRD positive.

Figure 6.

Figure 6.

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PFS landmark analysis at 18 months by MRD-negativea CR or better status. Assessed at the 10–5 (A) and 10–6 (B) sensitivity thresholds. aMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR or better in the ITT population. Patients who were not evaluable or had indeterminate results were considered MRD positive.

In an analysis of PFS by sustained MRD negativity (≥12 months), as mentioned previously, a greater number of patients achieved sustained MRD negativity (10–5) with D-VRd (D-VRd, 49.2%; VRd, 27.3%); subsequently translating into a more favorable trend in PFS vs that with VRd (HR, 0.50; 95% CI, 0.22-1.13; P = .0898; Figure 7A). In patients who did not achieve sustained MRD negativity (10–5), the PFS HR for D-VRd vs VRd was 0.90 (95% CI, 0.63-1.28; P = .5634). In patients who achieved sustained MRD negativity at 10–6, the PFS HR for D-VRd vs VRd was 0.92 (95% CI, 0.30-2.87; P = .8867); notably, however, among patients who did not achieve sustained MRD (10–6), a favorable trend in PFS benefit was observed with D-VRd (HR, 0.73; 95% CI, 0.52-1.02; P = .0666; Figure 7B).

Figure 7.

Figure 7.

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PFS by sustained (≥12 months) MRD-negativea CR or better. Assessed at the 10–5 (A) and 10–6 (B) sensitivity thresholds. aProportion of patients who achieved CR or better and achieved MRD-negative status at any time during the study at 2 bone marrow assessments that are 12 months apart with an allotted window of ±1 month, without any examination showing MRD-positive status in between.

Discussion

Achieving MRD negativity is closely associated with prolonged survival,1, 2, 3 with deeper and sustained MRD negativity at 10–6 strongly correlating with superior survival outcomes in patients with MM.4 Therefore, attaining MRD negativity, specifically sustained MRD-negativity at 10–6, is a crucial goal of MM therapies. Results of this expanded MRD analysis of CEPHEUS demonstrate that the addition of daratumumab to VRd leads to higher and deeper rates of overall and sustained CR or better MRD negativity vs VRd alone, translating into superior PFS outcomes in transplant-ineligible or transplant-deferred NDMM. At the time of this analysis, of patients who achieved MRD negativity (10–6) with D-VRd, 86.2% were alive and progression free at 54 months, and of patients who achieved 12-months sustained MRD negativity (10–6), 93.8% were alive and progression free at 48 months.

Patients who received D-VRd achieved significantly higher overall MRD-negativity rates at 10–5 (60.9% vs 39.4%; P < .0001) and 10–6 (46.2% vs 27.3%; P = .0001) vs patients who received VRd, which led to consistently higher rates of sustained MRD negativity over time at 12, 24, and 36 months. Patients who received D-VRd also demonstrated faster attainment of MRD negativity, with MRD-negativity rates that continued to increase over 3 years. This is in contrast to the slower, plateaued rates seen with VRd. In addition, among patients who achieved MRD negativity at 10–5, a PFS treatment benefit with D-VRd was observed, whereas at 10–6, PFS outcomes were similar between D-VRd and VRd groups, albeit nearly double the number of D-VRd patients achieved MRD negativity at 10–6. This suggests that in CEPHEUS, achievement of MRD negativity is increased with the addition of daratumumab to the treatment paradigm, thus raising the proportion of patients expected to achieve long-term disease control. A favorable trend in PFS was also seen with D-VRd in MRD-positive patients vs VRd alone, suggesting the value of ongoing daratumumab in controlling readily detectable disease. It is also important to note that MRD is dynamic. In CEPHEUS, among patients with ≥1 negative MRD test, fewer patients experienced MRD-negativity loss with D-VRd, including patients with high-risk cytogenetics. Furthermore, among those who lost their MRD-negative status, patients who received D-VRd were less likely to experience disease relapse compared with those who received only VRd, likely reflecting the ongoing suppressive effect of the D-R approach in slowing the progression of expanding clones. Collectively, data support the early use of daratumumab to achieve rapid and deep responses, and continued use over time for sustained benefit, especially in patients with nonsustained MRD negativity.

Although cross-trial comparisons should be interpreted with caution, CEPHEUS is the fifth phase 3 clinical trial to demonstrate favorable outcomes after the addition of daratumumab to standard-of-care regimens across the NDMM spectrum.12, 13, 14, 15, 16 Overall, MRD-negativity rates in ALCYONE12 and MAIA29 were lower than that observed in CEPHEUS (10–5: D-VMP [daratumumab plus bortezomib, melphalan, and prednisone], 28%; D-Rd, 32.1%; D-VRd, 60.9%, respectively), which demonstrates the benefits of a D-VRd quadruplet in patients who were transplant-ineligible or transplant-deferred and are able to tolerate D-VRd. However, although head-to-head comparative trials are lacking, these varying MRD rates may have been due to differences in study eligibility and patient characteristics (transplant ineligible in ALCYONE and MAIA,30 with a median age of 71 [range, 40-93] and 73 [range, 45-90] years, respectively, vs transplant-ineligible/-deferred patients in CEPHEUS with a median age of 70 [range, 31-80] years). Regardless, results support the benefit of treating patients who are transplant ineligible with daratumumab as a triplet or quadruplet regimen.

The benefit of D-VRd has also been reported in transplant-eligible NDMM in the phase 3 PERSEUS study.15 In the PERSEUS primary analysis (median follow-up, 47.5 months), D-VRd vs VRd alone led to higher overall (10–5: 75.2% vs 47.5%, respectively; 10–6: 65.1% vs 32.2%) and sustained (≥12 months) MRD-negativity rates (10–5: 64.8% vs 29.7%; 10–6: 47.3% vs 18.6%).15,18 As expected, MRD-negativity rates were higher in the PERSEUS transplant-eligible population vs the CEPHEUS transplant-ineligible/-deferred population; however, data from CEPHEUS and PERSEUS collectively show the consistent benefit of quadruplet D-VRd therapy, compared with triplet VRd therapy alone, across the NDMM spectrum. This evidence supports D-VRd quadruplet therapy as a new standard-of-care NDMM treatment.

In MM, new IMWG guidelines present MRD-negative CR as a more stringent response for patients with CR or better.25 This was also reflected in 2 recent meta-analyses that were presented and discussed at the Oncology Drug Advisory Committee meeting in April 2024, which contributed to the endorsement of MRD-negative CR as an accelerated approval end point for MM clinical trials.21,22,24

In light of this, all MRD results presented for CEPHEUS are among patients with CR or better. This strict definition should be considered when making cross-trial comparisons. In the recent IMROZ trial among transplant-ineligible patients (n = 446; median age, 72 [range, 55-80] years) randomized to IV isatuximab with VRd (Isa-VRd, n = 265) or VRd alone (n = 181), MRD negativity was primarily defined as the achievement of MRD negativity and very good partial response or better.31 When applying a strict, IMWG definition of MRD negativity (10–5) with CR or better, MRD negativity remained higher with Isa-VRd vs VRd (55.5% vs 40.9%, respectively), with overall MRD-negativity rates comparable with those in the VRd arm in CEPHEUS (39.4%); however, rates were numerically higher with D-VRd (60.9%) than Isa-VRd.

In this analysis, overall MRD-negativity rates consistently favored D-VRd across most prespecified subgroups. Patients with high-risk cytogenetic abnormalities, however, often have poor prognoses and unmet clinical need.32 In this analysis, the treatment effect with D-VRd was less pronounced in the small subgroup of patients with high-risk cytogenetics. This may be due to the unexpectedly high MRD-negativity rates experienced by patients at high risk in the VRd group, which cannot currently be explained and is not reflected in the ITT population, but likely affected the subgroup analysis. The low number of patients at high risk (D-VRd, n = 25; VRd, n = 27) also makes interpretation difficult due to the impact of few events in either high-risk treatment group. Additionally, patients with high cytogenetic risk in the D-VRd group had shorter treatment durations compared with VRd due to early treatment discontinuations, unlike the ITT population in which median duration of treatment was ∼2 years longer with D-VRd. Due to these early discontinuations, a greater proportion of patients at high risk in the D-VRd group had missing postbaseline MRD tests than those in the high-risk VRd subgroup (24.0% vs 14.8%, respectively), thus reducing their opportunity to achieve MRD negativity and likely affecting observed MRD and PFS outcomes. This may explain the differing findings in CEPHEUS compared with other daratumumab-based studies, in which daratumumab-containing regimens demonstrated an MRD benefit for patients with high cytogenetic risk.15,33,34 Of note, in the primary analysis of CEPHEUS, there was a reduction in the risk of disease progression or death with D-VRd over VRd in patients with high cytogenetic risk (HR, 0.88; 95% CI, 0.42-1.84),16 and, as presented here, this reduction was greater in patients with high cytogenetic risk who achieved MRD negativity with D-VRd vs VRd (HR, 0.33; 95% CI, 0.07-1.57). Additional trials enriched with patients at high risk are warranted to further investigate quadruplets in this population.

MRD negativity is widely recognized as a strong predictor of favorable long-term outcomes in MM,1, 2, 3, 4 a view supported by the recent unanimous Oncology Drug Advisory Committee vote supporting its use as a primary end point for accelerated approval.24 Although previous studies suggest MRD-negative patients generally experience similar positive long-term outcomes regardless of therapy setting and, at times, regardless of transplant status,4 findings from CEPHEUS provide a novel perspective. As reported here, a trend toward improved PFS among MRD-negative patients who received D-VRd vs VRd was observed, with Kaplan-Meier curves separating over time. This may reflect the role of continued daratumumab-based therapy in maintaining MRD negativity and delaying relapse, supported by higher sustained MRD-negativity rates with D-VRd.

In conclusion, this expanded MRD analysis of the CEPHEUS study demonstrates that the addition of daratumumab to VRd results in higher and deeper rates of overall and sustained CR or better MRD-negative responses in transplant-ineligible or transplant-deferred NDMM. Furthermore, deep and durable responses translated into favorable long-term outcomes, with a rapid increase in MRD-negativity rates seen over time and a PFS improvement with D-VRd vs VRd in both overall and sustained MRD-negative and MRD-positive patients. Moreover, although follow-up is ongoing, a reduction in the risk of death has also been observed with D-VRd vs VRd (HR, 0.85; 95% CI, 0.58-1.24).16 Overall, CEPHEUS was, to our knowledge, the first daratumumab-based phase 3 clinical trial in MM to use MRD as a primary end point. Given the plethora of evidence supporting the importance of MRD negativity for optimal long-term outcomes, the beneficial outcomes reported here are clinically relevant. Data further support D-VRd as a standard-of-care treatment for patients with NDMM who are transplant-ineligible or for whom transplant is deferred.

Conflict-of-interest disclosure: S.Z. received research funding from Janssen and Takeda; and participated on advisory boards (fees to institute) of Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. V.H. received honoraria for lectures/advisory board participation from AbbVie, Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, Regeneron, Sanofi, and Takeda. N.J.B. consulted for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm, Kite Pharma, Novartis, Pfizer, Roche, Sanofi, and Takeda; received research funding from Janssen and Pfizer; received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm, Kyte, Novartis, Pfizer, Roche, Sanofi, and Takeda; and served on a board of directors or advisory committees for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm Therapeutics, Kite Pharma, Novartis, Pfizer, Roche, Sanofi, and Takeda. C.P.V. received honoraria from Janssen, Bristol Myers Squibb, GSK, Sanofi, Pfizer, AbbVie, and FORUS Therapeutics. M.B. participated in speakers bureaus for Bristol Myers Squibb, Janssen, Takeda, and Sanofi. J.M. served as a consultant for Bristol Myers Squibb, Medison Pharma, Pfizer, and Roche. Y.C.C. served as a consultant, received research funding and honoraria, and served on a board of directors or advisory committees for Bristol Myers Squibb, Janssen, Takeda, Sanofi, and GSK. M.M. received honoraria from Janssen, Ono Pharmaceutical, Takeda, Sanofi K.K. Nippon Kayaku, and SymBio Pharmaceutical; and received research funding Janssen, Bristol Myers Squibb K.K., GSK, and Pfizer Inc. K.S. received lecture fees from Takeda, Ono Pharmaceutical, Novartis, Sanofi, Bristol Myers Squibb, and Janssen; and has received advisory fees from SRL Medisearch Inc. M.B. served as a consultant for Bristol Myers Squibb, Takeda, Janssen, Menarini, Amgen, and GSK; and participated in speakers bureaus for Bristol Myers Squibb, Janssen, Takeda, and Sanofi. A.M. served on an advisory board and as a consultant for Johnson & Johnson, Sanofi, Pfizer, and Bristol Myers Squibb. H.T. received honoraria from Janssen, Ono Pharmaceutical, Sanofi, and Bristol Myers Squibb. A.P. served on an advisory board for, and received honoraria from, Johnson & Johnson, Bristol Myers Squibb, Amgen, Pfizer, Sanofi, GSK, AbbVie, and Menarini. W.L., J.W., E.v.B., M.K., L.L.-M., J.C., F.B., M.R., and R.C. are employees of Johnson & Johnson. S.Z.U. received research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seagen, SkylineDX, and Takeda; and has consulted for AbbVie, Amgen, Bristol Myers Squibb, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seagen, SecuraBio, SkylineDX, Takeda, and Teneobio. The remaining authors declare no competing financial interests.

Acknowledgments

The authors thank the patients who volunteered to participate in this trial, their families/caregivers, and the staff members at the trial sites who cared for them; the members of the independent data and safety monitoring committee; and the independent review committee members.

This study was sponsored by Johnson & Johnson. Medical writing and editorial support were provided by Holly Clarke, of Lumanity Communications Inc, and were funded by Johnson & Johnson.

Authorship

Contribution: S.Z., T.F., M. Beksac, W. Liu, J.W., M.K., J.C., M.R., and S.Z.U. contributed to the study design; S.Z., T.F., V.H., N.J.B., C.P.V., M. Braunstein, J.M., S.B., Y.C.C., M.M., K.S., M. Beksac, A.M., H.T., A.P., M.K., J.C., M.R., and S.Z.U. contributed to data collection; S.Z., T.F., V.H., C.P.V., M. Braunstein, S.B., Y.C.C., M.M., K.S., M. Beksac, A.M., H.T., W. Liu, J.W., J.C., M.R., and S.Z.U. contributed to data analysis; S.Z., T.F., V.H., N.J.B., C.P.V., M. Braunstein, S.B., Y.C.C., K.S., M. Beksac, A.M., H.T., A.P., W. Liu, J.W., M.K., J.C., M.R., and S.Z.U. contributed to data interpretation; and all authors participated in drafting and revising the manuscript and approved the final version for submission, and had full access to all study data and shared final responsibility for the decision to submit for publication.

Footnotes

The data sharing policy of Johnson & Johnson is available at https://innovativemedicine.jnj.com/our-innovation/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access project site at http://yoda.yale.edu.

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Tables and Figure
BLOODA_ADV-2026-019937-mmc1.pdf (234.9KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Tables and Figure
BLOODA_ADV-2026-019937-mmc1.pdf (234.9KB, pdf)

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