On December 11, 2021 Sanofi reported that Sarclisa (isatuximab) trial is first Phase 3 study to meet primary endpoint of minimal residual disease negativity in transplant-eligible patients with newly diagnosed multiple myeloma (Press release, Sanofi, DEC 11, 2021, View Source [SID1234596806])
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Sarclisa combination therapy is first to demonstrate superiority to standard of care lenalidomide, bortezomib and dexamethasone (RVd) in a Phase 3 trial
50.1% of patients achieved undetectable levels of disease after 18 weeks of induction treatment with Sarclisa-RVd
GMMG will share the results as an oral presentation, and as part of the press program, at ASH (Free ASH Whitepaper) 2021
December 11, 2021
The Phase 3 HD7 trial, conducted by the German-Speaking Myeloma Multicenter Group (GMMG), met the primary endpoint, the rate of minimal residual disease (MRD) negativity after induction therapy and before transplant in patients with newly diagnosed multiple myeloma (MM) treated with Sarclisa (isatuximab) in combination with lenalidomide, bortezomib and dexamethasone (RVd). This is the first Phase 3 trial to evaluate MRD negativity at the end of induction as a primary endpoint, and to demonstrate statistically significant improvement in rates of MRD negativity in this patient population by adding an anti-CD38 monoclonal antibody to RVd. MRD negativity is an important clinical endpoint associated with better patient outcomes, which is meaningful for MM where most patients relapse.1
"It is unprecedented for half of patients to achieve MRD negativity this early in treatment with this regimen," said Hartmut Goldschmidt, M.D., President of GMMG, Professor of Medicine at the Heidelberg University Hospital (UKHD), Germany and principal investigator of the study. "We know that achieving deeper responses earlier in treatment may translate to longer periods of progression free survival and are excited about these results."
After an induction phase of 18 weeks, the rate of MRD negativity for patients receiving Sarclisa combination therapy (n=331) was 50.1% versus 35.6% for those who received RVd (n=329) (odds ratio [OR]=1.83; 95% confidence interval [CI]: 1.34-2.51; p<0.001). The safety and tolerability of Sarclisa observed in this trial was consistent with the observed safety profile of Sarclisa in other clinical trials, with no new safety signals observed. Rates of all adverse events observed were 63.6% for the Sarclisa combination versus 61.3% for RVd and serious adverse effects and discontinuations were similar in both study arms (34.8% versus 36.3%, respectively). However, the number of deaths were higher in the RVd arm (1.2% versus 2.4%) during the induction period. The trial is ongoing, following the second randomization to evaluate progression free survival (PFS) for Sarclisa and lenalidomide combination as maintenance therapy.
"The results of this trial reinforce our belief in Sarclisa’s potential to become the anti-CD38 of choice," said Peter C. Adamson, Global Development Head, Oncology at Sanofi. "To observe such a high proportion of patients who have MRD negative disease following a relatively brief induction period is highly encouraging. We look forward to our continued collaborative efforts with GMMG to deliver a potential treatment option to transplant-eligible patients with newly diagnosed multiple myeloma."
MRD negativity is defined as the absence of myeloma cells in the bone marrow after treatment, as measured by diagnostic techniques that must have a sensitivity of at least 1 in 100,000 cells.2 This assessment is the most sensitive tool to measure the depth of response to treatment in patients with MM.3
This GMMG initiated clinical trial was conducted in close collaboration with Sanofi based on jointly defined research. Sanofi provided financial support to GMMG for this study.
The use of Sarclisa in combination with RVd is investigational and has not been evaluated by any regulatory authority.
About the trial
The pivotal, randomized, open-label, multicenter, Phase 3 GMMG-HD7 trial is a two-part study that enrolled 662 patients with newly diagnosed, transplant-eligible MM across 67 sites in Germany. In the first part of the study, all participants were equally randomized to receive three 42-day cycles of RVd in both arms of the trial, while Sarclisa was added to only one trial arm. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks of cycle one, then every other week for the rest of the induction period.
MRD negativity was assessed by next-generation flow cytometry (cut off 1×10-5) after induction. An odds ratio was used to measure this endpoint to determine the association between adding Sarclisa to standard of care and participants achieving MRD negativity.
The primary endpoints are MRD negativity after induction treatment for the first part of the study, and PFS following the second randomization after transplant for part two of the study, in which Sarclisa is added to lenalidomide maintenance. Secondary endpoints include rates of complete response after induction, overall survival after maintenance therapy and safety.
About Sarclisa
Sarclisa is a monoclonal antibody that targets a specific epitope on the CD38 receptor on MM cells. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.
Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase 3 IKEMA study, Sarclisa is also approved in combination with carfilzomib and dexamethasone in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).
Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies and solid tumors. The safety and efficacy of these additional uses have not been reviewed by any regulatory authority worldwide.
For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.
About multiple myeloma
MM is the second most common hematologic malignancy,4 with more than 130,000 new diagnoses of MM worldwide yearly.5 Despite available treatments, MM remains an incurable malignancy and is associated with significant patient burden. Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.
About the German-Speaking Myeloma Multicenter Group (GMMG)
GMMG is the largest study group focusing on MM in Germany, with headquarters based in Heidelberg. Within the last 20 years, the GMMG study group has performed numerous trials including five randomized, multicenter Phase 3 clinical trials with 4,000 patients enrolled from about 90 participating and co-treating centers throughout Germany. The overall goal of GMMG is to generate improved therapies for myeloma patients through the development and testing of novel and personalized, genome- and signaling-driven treatment strategies.