The quadruplet‐based regimens Isatuximab + VRd (bortezomib, lenalidomide, and dexamethasone) and Daratumumab + VRd have become the new standards of care for patients with newly diagnosed multiple myeloma transplant‐ineligible (NDMM TI) over VRd based on IMROZ and CEPHEUS. 1 , 2 The BENEFIT 3 study compared Isatuximab + VRd to Isatuximab + Rd to examine the role of the proteasome inhibitor bortezomib in this combination.
Patients with high‐risk features (HRMM) benefit to a lesser extent from the discovery of new drugs for MM, with rapid loss of minimal residual disease (MRD) negativity rates and shorter survival times. 4 , 5 In the BENEFIT study (ClinicalTrials.gov identifier: NCT04751877), the definition of HRMM was initially based on the Intergroupe Francophone du Myélome (IFM) linear predictor (LP) cytogenetic score model, in the absence of an international consensus definition. 6 A recent international genomic consensus staging (GCS) (International Myeloma Society [IMS]/International Myeloma Working Group [IMWG]) has standardized the definition of HRMM based on a next‐generation sequencing (NGS)‐based definition plus serum beta‐2‐microglobulin level, to enable cross‐study comparisons. 7
We aimed to investigate the MRD rates 8 , 9 of Isa‐VRd compared to IsaRd in HRMM in the BENEFIT study overall, and also its safety profile using the recent GCS definition for HRMM.
BENEFIT is a Phase 3 trial sponsored by CHU (Centre Hospitalier Universitaire) Poitiers, France, in collaboration with the Intergroupe Francophone of Myeloma (IFM), that randomly assigned NDMM TI, aged 65–79 years, to Isa‐VRd or IsaRd until progression. MRD was centrally determined by NGS with a 10−6 sensitivity (Professor Avet Loiseau/Professor Corre, Toulouse Oncopole, France) and was performed at 12, 18, and 24 months, and yearly thereafter on bone marrow aspiration in patients who achieved at least a partial response (≥PR).10, 11, 12 In BENEFIT, no patient in PR only depth of response had obtained MRD‐negative status. We started to observe MRD‐negative status only in patients with VGPR or better response.
Three patients were studied using multiparametric flow cytometry (MFC) with a 10−5 sensitivity, and if MRD was 10−5 negative, they were always classified as 10−6 positive. The sustained MRD negativity rate at 10−5 was defined as the proportion of patients with MRD‐negative 10–5 results over 12 months (between Months 12 and 24), without any MRD‐positive results in between (Month 18).
Patients who were not identified as having HRMM at diagnosis and developed relapse within 18 months from diagnosis were classed as FHR. 7
HRMM was found in 72/270 (27%) patients using GCS, and 42/135 (31%) and 30/135 (22%) patients in the Isa‐VRd and IsaRd arms, respectively (Tables S1 and S2). The new GCS reclassified 49 (20%) NDMM TI patients into the HRMM category (Table S3) compared to the IFM LP score classification.
At the clinical cutoff date (February 17, 2025), a total of 78 (29%) patients dropped out of the study: 31 in the Isa‐VRd group and 47 in the IsaRd group, and 29 patients with HRMM and 49 patients with non‐HRMM (Figure S1). The 18‐month MRD negativity rate at 10−5 was similar between HRMM and non‐HRMM patients, 40% (n = 29/72, 29–53) and 39% (n = 77/198, 32–46), respectively, P = 0.84. It was higher for Isa‐VRd in HRMM, 50% (n = 21, 34–66), than for IsaRd, 27% (n = 8, 12–46) (OR 2.75 [1–7], P = 0.049), Figure 1A (Table S4). Similar superiority in terms of treatment with Isa‐VRd than IsaRd was observed in HRMM and non‐HRMM patients at 10−5 (P value for interaction, P = 0.74). Similar data were obtained in HRMM patients at 10−6, 45% for Isa‐VRD (n = 19, 30–61) and 27% for IsaRd (n = 8, 12–46) (OR 2.27 [0.8–6], P = 0.011), Figure 1A.
Figure 1.
(A) Minimal residual disease negativity rates at 18 months according to treatments’ arms and HRMM status. (B) Sustained minimal residual disease negativity rates in treatments’ arms. (C) Sustained minimal residual disease negativity rates according to treatments’ arms and HRMM status. All analysis done in ITT (Intention to Treat). IMS, International Myeloma Society; IMWG, International Myeloma Working Group; MRD, minimal residual disease; NGS, next‐generation sequencing; and sMRD, sustained minimal residual disease.
With a median follow‐up of 33.4 months [95% CI, 33−34], the overall sMRD (sMRD, sustained negative MRD ≥ 12 months) negativity rate at 10−5 was higher for Isa‐VRd, 34% (n = 46/135, 95% CI, 26–43), than for IsaRd, 16% (n = 22/135, 11–24) (OR 2.73 [95% CI, 1.5–4.8, P = 0.0007]) (Figure 1B). A similar observation was made at 10−6: 21% (n = 28, 14–29) and 7% (n = 10, 4–13) (OR 3.19 [1.5–6.9, P = 0.003]) (Figure 1B). On studying sMRD in the Isa‐VRd and IsaRd arms in HRMM, the sMRD negativity rate at 10−5 was higher, although non‐significant, 31% (n = 13, 18–47) and 13% (n = 4, 4–31), respectively, OR 2.91 (0.8–10, P = 0.09), Figure 1C (details in Table S5, similar to the 10−6 threshold, Figure 1C).
Among the 24 patients who progressed in the first 18 months from the initiation of treatment (FHR criteria), 11 (4% of the cohort) were not considered to have HRMM initially: 5 in the Isa‐VRd arm and 6 in the IsaRd arms. There were no differences in both arms regarding patients' and disease characteristics (data not shown). Interestingly, 1 patient and 3 patients presented with t(11;14) in both arms, and 2 and 4 patients presented with isolated 1q+ gain/amplification, respectively. None of these patients ever reached MRD‐negative status (10−5 threshold).
The most common adverse events (AEs) (occurring in ≥10% of patients in both groups) were not different in HRMM compared to non‐HRMM (Table 1), and the median relative dose intensity was maintained in the two arms in HRMM similar to non‐HRMM groups, including for bortezomib (Table S6). There were 169 Grade ≥2 AEs, resulting in discontinuation of Bortezomib in the Isa‐VRd arm (temporarily or permanently) and involving 78 patients (57 (56%) in non‐HRMM and 21 (64%) in HRMM) (Table S7). A total of 23 solid tumor second primary malignancies were observed in 19 (7%) patients, with no difference observed in both arms and according to risk (Table S8). The repartition of the events per patient‐years is summarized in Table S9, with no difference observed in both arms and according to HRMM.
Table 1.
Most common adverse events of any grade (worst grade by patient) in the safety population. a
| Non‐HRMM (n = 213) | HRMM* (n = 72) | |||
|---|---|---|---|---|
| Event, no. of patients (%) | IsaRd (n = 105) | Isa‐VRd (n = 93) | IsaRd (n = 30) | Isa‐VRd (n = 42) |
| ≥Grade 3 hematologic adverse events | ||||
| Neutropenia | 53 (50) | 42 (45) | 15 (50) | 15 (36) |
| Lymphopenia | 28 (27) | 35 (38) | 10 (33) | 14 (33) |
| Anemia | 6 (6) | 7 (8) | 1 (3) | 5 (12) |
| Thrombocytopenia | 7 (7) | 7 (8) | 2 (7) | 9 (21) |
| ≥Grade 2 nonhematologic adverse events | ||||
| Diarrhea | 32 (30) | 33 (35) | 6 (20) | 14 (33) |
| Constipation | 15 (14) | 21 (23) | 2 (7) | 6 (14) |
| Nausea | 7 (7) | 6 (6) | 2 (7) | 0 |
| Infections and infestations | 68 (65) | 57 (61) | 17 (57) | 29 (69) |
| Infection of the respiratory system | 29 (28) | 37 (40) | 8 (26) | 14 (34) |
| Covid‐19 | 29 (28) | 27 (29) | 8 (27) | 10 (24) |
| Rash | 8 (8) | 9 (10) | 1 (3) | 4 (10) |
| Erythema | 2 (2) | 3 (3) | 3 (10) | 4 (10) |
| Asthenia | 15 (14) | 20 (22) | 4 (13) | 6 (14) |
| Pain | 15 (14) | 11 (12) | 4 (13) | 7 (17) |
| Muscle spasms | 9 (9) | 2 (2) | 1 (3) | 5 (12) |
| Peripheral edema | 9 (9) | 13 (14) | 3 (10) | 4 (10) |
| Pyrexia | 5 (5) | 2 (2) | 4 (13) | 6 (14) |
| Weight loss | 8 (8) | 11 (12) | 6 (20) | 1 (2) |
| Dyspnea | 8 (8) | 2 (2) | 2 (7) | 1 (2) |
| Cough | 4 (4) | 4 (4) | 2 (7) | 2 (5) |
| Insomnia | 4 (4) | 6 (6) | 2 (7) | 0 |
| Nervous system disorders | 24 (23) | 36 (39) | 8 (27) | 19 (45) |
| Peripheral neuropathy | 11 (10) | 29 (31) | 3 (10) | 9 (21) |
| Eye disorders | 10 (10) | 10 (11) | 4 (13) | 5 (12) |
| Hepatobiliary disorders | 11 (10) | 7 (8) | 4 (13) | 2 (5) |
| Renal and urinary disorders | 16 (15) | 15 (16) | 0 | 7 (17) |
| Cardiac disorders | 11 (10) | 9 (10) | 1 (3) | 5 (12) |
| Vascular disorders | 20 (19) | 15 (16) | 2 (7) | 9 (21) |
| Hypokalemia | 11 (10) | 10 (11) | 1 (3) | 6 (14) |
Note: Listed adverse events of ≥ Grade 3 for hematologic adverse events and ≥ Grade 2 for nonhematologic adverse events that were reported in at least 10% of patients according to treatment arms and cytogenetic risk groups are shown. Isa‐VRd denotes isatuximab plus bortezomib/lenalidomide/dexamethasone. IsaRd denotes isatuximab/lenalidomide/dexamethasone. *HRMM definition according to the international genomic consensus staging. 7 For fourteen patients (Isa‐VRd n = 6 and IsaRd n = 7), cytogenetic analysis was not carried out, and these patients were classified as non‐HRMM in the ITT analysis.
Abbreviations: %, percentages; HRMM, high‐risk; no., number.
The safety population included all patients who received at least one dose of study treatment.
At the time of analysis of the primary endpoint of the BENEFIT study, the addition of bortezomib to the IsaRd regimen (Isa‐VRd) significantly improved the MRD 10−5 negativity rate at 18 months from randomization in the most effective control arm for NDMM TI non‐frail patients. 3 The Isa‐VRd arm demonstrated a higher sMRD ≥ 12‐month negativity rate compared to the IsaRd arm in BENEFIT, similar to IMROZ and CEPHEUS. 1 , 2
Patients with HRMM encompass a heterogeneous group involving various definitions and a common experience of shorter survival times, as they benefit to a lesser extent from discoveries of drugs and regimens in terms of treatment. 4 , 5 , 13 , 14 The quadruplet‐based regimens Isa‐VRd (IMROZ) and DVRd (CEPHEUS) showed improved survival times in HRMM according to older definitions. 1 , 2 We observed a greater benefit overall of Isa‐VRd on MRD negativity rates at all assessed time points in GCS‐based HRMM patients, although it did not reach significance in some subgroups with a limited number of patients. This suggests the need to conduct HRMM‐dedicated clinical trials in this TI population.
The survival remains immature in BENEFIT, with a median follow‐up of 33.4 months (95% CI, 33–34). However, we expect that Isa‐VRd will show differences in terms of survival compared to IsaRd with a longer follow‐up duration, given the differences in the rate of relapse and the MRD rate in both arms.14, 15, 16
We report a decrease in the MRD 10−5 negativity rates in the Isa‐VRd arm in BENEFIT from 53% at 18 months to 44% at 24 months. This decrease was similar in the HRMM group, 50%–40%, and the non‐HRMM group, 54%–45%. Bortezomib was administered twice monthly from cycles 13 to 18 and was stopped at 18 months in BENEFIT. Overall, the data suggest the importance of bortezomib to induce MRD negative status and question the role of a proteasome inhibition addition as a maintenance drug alongside the prolonged IsaR regimen to maintain the MRD negative status. Similar data were shown with carfilzomib.
Although very dense in IMROZ/CEPHEUS, 1 , 2 twice‐weekly bortezomib was administered for 6 months, while in BENEFIT, it was administered weekly for 18 months. 3 The sMRD ≥ 12‐month negativity rates were similar at 24 months in both studies, suggesting that the number of injections rather than the dose of bortezomib might play a role. This information is important, as weekly bortezomib will be the preferred option in NDMM TI in the real world. Future studies will need to validate whether there is an optimal schedule in HRMM.
We observed a lower MRD negativity rate for NDMM TI with t(11;14) MM up to 24 months (data not shown), despite the non‐high‐risk disease profile of this subgroup. These data suggest that t(11;14) MM may respond more slowly in TI patients, may not reach MRD‐negative status, or may need specific treatment approaches.17, 18, 19, 20
In summary, the results from the BENEFIT study confirm the meaningful benefit of the quadruplet‐based Isa‐VRd regimen compared to IsaRd in all NDMM TI patients based on ≥12‐month sMRD. Importantly, the benefit of the Isa‐VRd regimen is observed in HRMM patients compared to IsaRd. These data point to Isa‐VRd as a new SOC for patients with NDMM TI aged 65–79 over the current triplet‐based SOC DRd, particularly for HRMM in NDMM TI.
AUTHOR CONTRIBUTIONS
Jill Corre: Writing—review and editing; Validation; Investigation. Jerome Lambert: Formal analysis; Supervision; Writing—review and editing; Writing—original draft; Conceptualization; Methodology; Validation. Arthur Bobin: Conceptualization; Writing—original draft; Writing—review and editing; Investigation. Salomon Manier: Conceptualization; Investigation; Writing—original draft; Writing—review and editing; Validation. Aurore Perrot: Conceptualization; Investigation; Writing—review and editing; Validation. Lionel Karlin: Conceptualization; Investigation; Validation; Writing—review and editing. Murielle Roussel: Investigation; Validation; Writing—review and editing. Noemie Bigot: Formal analysis; Investigation; Writing—review and editing. Omar Benbrahim: Investigation; Validation; Writing—review and editing. Olivier Allangba: Investigation; Validation; Writing—review and editing. Philippe Rey: Investigation; Validation; Writing—review and editing. Véronique Dorvaux: Investigation; Validation; Writing—review and editing. Marguerite Vignon: Investigation; Validation; Writing—review and editing. Virginie Roland: Investigation; Validation; Writing—review and editing. Réda Garidi: Investigation; Validation; Writing—review and editing. Jean‐Noel Bastie: Investigation; Validation; Writing—review and editing. Marie‐Lorraine Chretien: Investigation; Validation; Writing—review and editing. Sophie Godet: Investigation; Validation; Writing—review and editing. Lydia Montes: Investigation; Validation; Writing—review and editing. Brieuc Cherel: Investigation; Validation; Writing—review and editing. Anne Vekhoff: Investigation; Validation; Writing—review and editing. Thomas Chalopin: Investigation; Validation; Writing—review and editing. Borhane Slama: Investigation; Validation; Writing—review and editing. Kamel Laribi: Investigation; Validation; Writing—review and editing. Claire Dingremont: Investigation; Validation; Writing—review and editing. Christophe Roul: Investigation; Validation; Writing—review and editing. Valentine Richez‐Olivier: Investigation; Validation; Writing—review and editing. Clara Mariette: Investigation; Validation; Writing—review and editing. Sophie Rigaudeau: Investigation; Validation; Writing—review and editing. Claire Calmettes: Investigation; Validation; Writing—review and editing. Mamoun Dib: Investigation; Validation; Writing—review and editing. Mourad Tiab: Investigation; Validation; Writing—review and editing. Laure Vincent: Investigation; Validation; Writing—review and editing. Jacques Delaunay: Investigation; Validation; Writing—review and editing. Sabrina Maheo: Investigation; Validation; Writing—review and editing. Anais Schavgoulidze: Investigation; Validation; Writing—review and editing. Laurent Frenzel: Investigation; Validation; Writing—review and editing. Pascal Godmer: Investigation; Validation; Writing—review and editing. Ronan Le Calloch: Investigation; Validation; Writing—review and editing. Emilie Chalayer: Investigation; Validation; Writing—review and editing. Helene Gardeney: Investigation; Validation; Writing—review and editing. Margaret Macro: Investigation; Validation; Writing—review and editing. Bruno Royer: Investigation; Validation; Writing—review and editing. Stephanie Harel: Investigation; Validation; Writing—review and editing. Olivier Decaux: Investigation; Validation; Writing—review and editing. Bertrand Arnulf: Investigation; Validation; Writing—review and editing. Karim Belhadj: Investigation; Validation; Writing—review and editing. Aurelie Gontier: Conceptualization; Methodology; Validation; Writing—review and editing; Project administration; Data curation; Supervision; Resources. Cyrille Touzeau: Investigation; Conceptualization; Validation; Writing—review and editing. Mohamad Mohty: Investigation; Conceptualization; Validation; Writing—review and editing. Philippe Moreau: Conceptualization; Investigation; Validation; Writing—review and editing. Thierry Facon: Conceptualization; Investigation; Validation; Writing—review and editing. Cyrille Hulin: Conceptualization; Investigation; Validation; Writing—review and editing. Xavier Leleu: Conceptualization; Investigation; Funding acquisition; Writing—original draft; Methodology; Validation; Visualization; Writing—review and editing; Formal analysis; Project administration; Supervision; Resources; Data curation.
CONFLICT OF INTEREST STATEMENT
X.L.: consultancy, honoraria, and travel fees from Sanofi, Janssen‐Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GlaxoSmithKline, and Bristol Myers Squibb. C.H.: consultancy and honoraria fees from Janssen‐Cilag. A.B.: consultancy and honoraria from Sanofi and Janssen‐Cilag. A.P.: consultancy, honoraria, and travel fees from AbbVie, Amgen, Bristol Myers Squibb, Janssen, GlaxoSmithKline, Menarini Stemline, Pfizer, Sanofi, and Takeda. L.K.: consultancy, honoraria, and travel fees from Sanofi, Janssen‐Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GlaxoSmithKline, and Bristol Myers Squibb. T.C.: consultancy and honoraria from Sanofi and Janssen‐Cilag. C.T.: consultancy, honoraria, and travel fees from Sanofi, Janssen‐Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GlaxoSmithKline, and Bristol Myers Squibb. M.M.: consultancy, honoraria, and travel fees from Sanofi, Janssen‐Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GlaxoSmithKline, and Bristol Myers Squibb. P.M.: consultancy and honoraria from Janssen‐Cilag, Amgen, Novartis, Takeda, Pfizer, AbbVie, GlaxoSmithKline, Bristol Myers Squibb, and Sanofi. J.C.: consultancy, honoraria, and travel fees from Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive, and research support from Sanofi and Bristol Myers Squibb.
FUNDING
This study was sponsored by the CHU Poitiers, France. This study was funded by Sanofi.
Supporting information
Supporting Information.
ACKNOWLEDGMENTS
Sanofi supplied Isatuximab.
Benefit ClinicalTrials.gov number, NCT04751877.
The authors wish to thank the patients who volunteered to participate in this trial, their families, and the staff members at the trial sites who cared for them (Supplementary Appendix).
We thank the IFM team, C. Louni, G. Belot, M. O. Petillon, MD, S. Rollet, G. Massart, E. Guillaume, and L. Gibel.
We thank the BENEFIT study project managers of the protocol, Aurelie Gontier and Veronique Ferrand Rigallaud, from CHU Poitiers. We would like to thank the members of the sponsor project team, S. Noel, C. Abonneau, M. Stefanini, R. Habbachi, and A. Soman.
The monitoring was in part performed by TempoPHARMA Co. (Vélizy‐Villacoublay).
Data Management was carried out by Euraxi Pharma (Joué Les Tours).
The Hydrashift test was provided by Sebia (Lisses).
We also thank the members of the independent data and safety monitoring committee, Pr Jean‐Paul Fermand, chair, Pr Nathalie Meuleman (Belgium), and Pr Stephanie Ragot (methodologist). Pr Jean‐Paul Fermand was replaced in 2024 by Pr Thierry Lamy‐de‐la‐Chapelle as chair of the study.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.