Isa-KrD for Transplant-Eligible and -Ineligible High-Risk Newly Diagnosed Multiple Myeloma

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In an interim analysis of a German phase II trial (MMG-CONCEPT) reported in the Journal of Clinical Oncology, Leypoldt et al found that Isa-KrD (isatuximab, carfilzomib, lenalidomide, and dexamethasone) produced high rates of measurable residual disease (MRD) negativity newly diagnosed patients with high-risk multiple myeloma—both in those with transplant-eligible and transplant-ineligible disease.

Study Details

The interim analysis of the investigator-initiated multicenter trial included 125 patients with high-risk disease, defined as International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations. A total of 99 patients were transplant-eligible and 26 were transplant-noneligible. All patients received Isa-KRd induction/consolidation and Isa-KR maintenance. Transplant-eligible patients received high-dose melphalan; transplant-noneligible patients received two additional Isa-KRd cycles postinduction. Median age was 58 years in the transplant-eligible group and 74 years in the transplant-noneligible group. A total of 72 patients in the transplant-eligible group underwent autologous stem cell transplantation. The primary endpoint was MRD negativity at < 10-5 at end of consolidation in the intention-to-treat population. The null hypothesis was a MRD negativity rate of ≤ 50% in the transplant-eligible group and ≤ 30% in the transplant-noneligible group.

Key Findings

MRD negativity after consolidation was achieved in 63 patients (67.7%) in the transplant-eligible group (P < .004 vs null hypothesis) and 13 patients (54.2%) in the transplant-noneligible group (P = .012 vs null hypothesis). MRD negativity was achieved at any time point in 81 patients (81.8%) in the transplant-eligible group and 18 (69.2%) in the transplant-noneligible group. MRD negativity was sustained at ≥ 6 and ≥ 12 months in 72.7% and 62.6% of patients in the transplant-eligible group and 53.8% and 46.2% of those in the transplant-noneligible group, respectively.

Complete response/stringent complete response was achieved in 78.2% of patients in the transplant-eligible group and very good partial response was achieved in 18.2%, with an overall objective response rate of 94.9%; among transplant-noneligible patients, respective proportions were 57.7%, 30.8%, and 88.5%. Responses deepened over time.

At a median follow-up of 44 months in the transplant-eligible group and 33 months in the transplant-noneligible group, median progression-free survival was not reached in either group. In the transplant-eligible group, rates at 1, 2, and 3 years were 86.4%, 78.3%, and 68.9%; in the transplant-noneligible group, rates were 75.1%, 62.6%, and 58.4%. Median overall survival was not reached in either group, with rates at 1 and 2 years of 92.0% and 83.9% and 83.5% and 71.0%.

Among all patients, the most common grade ≥ 3 adverse events were neutropenia (37%; 39% and 28% in the transplant-eligible and transplant-noneligible groups, respectively), thrombocytopenia (25%; 27% and 16%), and leukopenia (21%; 25% and 4%); the most common nonhematologic grade ≥ 3 toxicity was (primarily respiratory) infection (28%; 28% and 28%). Grade ≥ 3 cardiac toxicity occurred in 1.2% of transplant-eligible patients and 20% of transplant-noneligible patients. Treatment-related adverse events led to discontinuation in three patients in each group.

The investigators concluded, “Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat high-risk newly diagnosed multiple myeloma population, regardless of transplant status, translating into a median progression-free survival that was not yet reached after 44/33 months.”

Katja C. Weisel, MD, of University Medical Center Hamburg-Eppendorf, Hamburg, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Amgen, Bristol Myers Squibb/Celgene, and Sanofi. For full disclosures of the study authors, visit

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