An interim analysis of the international, phase III IMROZ study shows that the addition of isatuximab to bortezomib, lenalidomide, and dexamethasone (VRd) regimen led to a significant 40% lower risk of progression or death at a median follow-up of 5 years. The estimated progression-free survival (PFS) at 60 months was 63.2% in the isatuximab plus VRd group, as compared with 45.2% in the VRd group, a finding that highlights the profound PFS benefit with the isatuximab plus VRd regimen in patients with previously untreated multiple myeloma who were ineligible for transplantation. The findings are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Thierry Facon of the Centre Hospitalier Universitaire de Lille in Lille, France and colleagues on 3 June 2024 in The New England Journal of Medicine.
Furthermore, at the time of analysis of the primary endpoint of the phase III BENEFIT study, conducted by the Intergroupe Francophone of Myeloma (IFM), the isatuximab plus VRd regimen significantly improved the minimal residual disease (MRD) 10−5 negativity rate at 18 months from randomisation when compared to isatuximab plus Rd regimen. Isatuximab plus VRd significantly increased all other MRD endpoints from 12 months, including 10−6 MRD negativity rates, the proportion of patients with MRD negativity and at least achieved complete response, and the rate of complete response or better at 18 months. MRD benefit was consistent across subgroups. Data are still immature regarding survival analysis. The findings are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Xavier Leleu of the Hematology, CHU Poitiers in France and colleagues on 3 June 2024 in the Nature Medicine.
Treatment landscape and place for quadruplet regimens
Treatment with triplet therapies has historically improved outcomes in patients with newly diagnosed multiple myeloma, providing deep, durable disease control in most patients and delaying disease relapse. The SWOG S0777 study established VRd as a standard, first-line treatment for patients with multiple myeloma, regardless of their eligibility for transplantation, and is commonly used in clinical practice. Older patients with multiple myeloma benefit most when efficacious regimens are used early, given that some do not receive any subsequent lines of therapy after first-line treatment.
Isatuximab, an IgG1 monoclonal antibody, targets a specific epitope of human CD38, inducing myeloma-cell death by multiple mechanisms. Phase III studies have shown a benefit of isatuximab added to standard backbone regimens, with the combination of isatuximab, pomalidomide, dexamethasone in the ICARIA study and isatuximab, carfilzomib, dexamethasone in the IKEMA study for the treatment of patients with relapsed or refractory multiple myeloma.
Phase III studies showed improved outcomes with anti-CD38 quadruplet regimens including proteasome inhibitor–immunomodulatory drug backbones for patients with multiple myeloma who were eligible to undergo transplantation, thus positioning quadruplets as a new standard treatment. In patients who are ineligible for transplantation, the daratumumab, bortezomib, melphalan, prednisone quadruplet was approved based on the results of the ALCYONE study. Studies of daratumumab plus VRd (CEPHEUS) and daratumumab, carfilzomib, lenalidomide, and dexamethasone (GEM2017FIT) are ongoing.
IMROZ study
The authors wrote in the background that the results of a phase Ib study of isatuximab plus VRd showed excellent clinical activity and deep responses in patients who had no immediate intention to undergo transplantation. However, the efficacy of treatment with an anti-CD38 agent and VRd in the population of patients with newly diagnosed multiple myeloma who are ineligible to undergo transplantation has been unclear.
The study team report the findings from a prespecified interim analysis of IMROZ, an international, open-label, phase III study of the efficacy and safety of isatuximab plus VRd as compared with VRd in patients with multiple myeloma who were ineligible to undergo transplantation. The study investigators randomly assigned, in a 3:2 ratio, patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation to receive either isatuximab plus VRd or VRd alone. The primary efficacy endpoint was PFS. Key secondary endpoints included a complete response or better and MRD-negative status in patients with a complete response.
A total of 446 patients underwent randomisation. At a median follow-up of 59.7 months, the estimated PFS at 60 months was 63.2% in the isatuximab plus VRd group, as compared with 45.2% in the VRd group (hazard ratio for disease progression or death 0.60, 98.5% confidence interval [CI] 0.41 to 0.88; p < 0.001).
The percentage of patients with a complete response or better was significantly higher in the isatuximab plus VRd group than in the VRd group, 74.7% versus 64.1% (p = 0.01), as was the percentage of patients with MRD-negative status and a complete response, 55.5% versus 40.9% (p = 0.003).
No new safety signals were observed with the isatuximab plus VRd regimen. The incidence of serious adverse events during treatment and the incidence of adverse events leading to discontinuation were similar in the two groups.
The authors commented that PFS benefit with isatuximab plus VRd was maintained through the subsequent line of therapy and the time to next treatment. The results for patients with high-risk cytogenetic features in this analysis did not show PFS benefit with isatuximab plus VRd. Further analyses and longer follow-up are warranted based on the observed benefits with isatuximab-based combinations in patients with high-risk cytogenetic features in the contexts of first-line treatment and relapsed disease.
They concluded that isatuximab plus VRd was more effective than VRd as initial treatment in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ineligible to undergo transplantation. IMROZ results complement those from a phase Ib study involving patients with no immediate intention to undergo transplantation and those from the phase III GMMG-HD7 study involving patients who were eligible to undergo transplantation, showing the benefit of isatuximab plus VRd across the disease continuum.
The IMROZ study was supported by Sanofi. Enrollment at the University of Texas M.D. Anderson Cancer Center was supported by a Cancer Center Support Grant.
BENEFIT study
The authors wrote in the background that CD38-targeting immunotherapy, daratumumab is approved in combination with Rd in patients with newly diagnosed multiple myeloma that are transplant-ineligible and is considered the best standard-of-care to date based on a median PFS of 62 months. In the MAIA study conducted among patients with newly diagnosed multiple myeloma that are transplant-ineligible, the complete response MRD negativity 10−5 rate was at best 31% in the daratumumab plus Rd group, with a 6-month sustained MRD negativity rate at 10−5 of 14.9%. However, novel quadruplet-based strategies are needed to further deepen responses, particularly to improve the MRD negativity rate, and to prevent relapses often responsible for early deaths in this elderly population.
The unprecedented results of MAIA in patients with newly diagnosed multiple myeloma that are transplant-ineligible favoured the development of two studies for registration of the quadruplet combination of CD38-targeting immunotherapies plus VRd, using daratumumab (CEPHEUS) or isatuximab (IMROZ) in comparison with VRd using twice-weekly bortezomib.
The phase III BENEFIT/IFM2020-05 study was conducted to demonstrate the efficacy and safety profile of the quadruplet combination CD38-targeting immunotherapy isatuximab plus weekly VRd compared with the triplet combination of isatuximab plus Rd in a population of patients with newly diagnosed multiple myeloma that are transplant-ineligible. The authors reported the findings from the primary analysis of BENEFIT/IFM2020-05.
This IFM phase III study randomised 270 patients with newly diagnosed multiple myeloma that were transplant-ineligible, aged 65–79 years, to isatuximab plus VRd or isatuximab plus Rd groups. The primary endpoint was MRD negativity rate at 10−5 by next-generation sequencing at 18 months from randomisation. Key secondary endpoints included response rates, MRD assessment rates, survival and safety.
The 18-month MRD negativity rates at 10−5 were reported in 35 patients (26%, 95% CI 19–34) in isatuximab plus Rd versus 71 (53%, 95% CI 44–61) in isatuximab plus Rd group with odds ratio for MRD negativity of 3.16 (95% CI 1.89–5.28, p < 0.0001). MRD benefit was consistent across subgroups at 10−5 and 10−6, and was already observed at 12-month.
The proportion of patients with complete response or better at 18 months was higher with isatuximab plus VRd (58% versus 33%; p < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; p = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times due to immature data. However, the authors commented that given the MRD 10−5 and 10−6 negativity rates observed with isatuximab plus VRd in BENEFIT, these high MRD rates will potentially translate into prolonged survival times compared with those observed in MAIA. MRD is in general considered a surrogate marker for survival endpoints in newly diagnosed multiple myeloma, including in transplant-ineligible populations.
The authors concluded that isatuximab plus VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10−5, the study primary endpoint, compared with isatuximab plus Rd. The results of BENEFIT study, along with those of IMROZ, confirm that the quadruplet-based isatuximab combined with VRd regimen is a new standard-of-care for the patients with newly diagnosed multiple myeloma that are transplant-ineligible.
BENEFIT study was sponsored by the CHU Poitiers, France. This study was funded by Sanofi. Sanofi provided drug supply for isatuximab. The monitoring was in part performed by TempoPHARMA co. Data management was done by Euraxi Pharma. The Hydrashift test was provided by Sebia.
References
- Facon T, Dimopoulos M-A, Leleu XP, et al. for the IMROZ Study Group. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. NEJM; Published online 3 June 2024. DOI: 10.1056/NEJMoa2400712
- Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nature Medicine; Published online 3 June 2024. DOI: https://doi.org/10.1038/s41591-024-03050-2