Hangzhou, China — The last 20 years have brought many more therapeutics for multiple myeloma (MM).
A recent review in the Annals of Hematology pointed out the standard first-line therapy for MM “consists of a three-drug induction regimen based on immunomodulatory drugs and proteasome inhibitors, combined with autologous stem cell transplantation. However, MM remains incurable; therefore, therapies for relapsed/refractory MM (RRMM) are emerging and evolving rapidly.”1
Chinese authors sought to summarize and review the results of RRMM trials over the past 5 years. The goal was to provide “a holistic overview and insights for practitioners in related fields, and to provide additional ideas for clinical trialists.”
The study indicated that daratumumab and isatuximab continue to significantly advance as treatment options. “Additionally, novel antibody drugs, such as elotuzumab and selinexor, as well as bispecific antibodies, teclistamab and talquetamab, are currently undergoing clinical research with promising outcomes,” according to the authors. “However, chimeric antigen receptor-T cell therapy targeting B-cell maturation antigen remains the optimal approach for MM treatment.”
Another recent trial, GMMG-CONCEPT, investigated isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM). The study, reported in the Journal of Clinical Oncology, was focused exclusively on high-risk disease for whom prospective trials are limited. Researchers said they aimed “to induce minimal residual disease (MRD) negativity.”2
The academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory 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 (HRCAs).
The international study provided patients with Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan, while TNE patients received two additional Isa-KRd cycles postinduction. The prespecified interim analysis (IA) reported the primary end point, MRD negativity (<10−5, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS).
The results indicated that, among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common high-risk cytogenetic abnormality (HRCA), (TE, 44.4%; TNE, 42.3%); about one-third of evaluable TE/TNE patients presented two or more HRCAs, respectively.
The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. The researchers advised that 81 of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%), with MRD negativity sustained for more than a year in 62.6% of patients. “With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm,” the authors added.
The researchers concluded that Isa-KRd “effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.”
Noting that clinical outcomes in multiple myeloma (MM) have greatly improved over the past decade with the implementation of novel agents and continuous treatment approaches, the authors suggested, “Adding anti-CD38 monoclonal antibodies to backbone regimens has led to unprecedented outcomes for transplant-eligible (TE) and transplant-noneligible (TNE) patients. However, outcomes remain dismal for patients with MM who have high-risk disease. As was recently reported, patients with higher Second Revision of the International Staging System (R2-ISS) stages III and IV show a median progression-free survival (PFS) of only 30 and 20 months, respectively.”
- Chen Q, Zhang M, Zheng S, Tong Y, Tan Y. Therapeutic progress in relapsed/refractory multiple myeloma. Ann Hematol. 2024 Apr 13. doi: 10.1007/s00277-024-05730-y. Epub ahead of print. PMID: 38609727.
- Leypoldt LB, Tichy D, Besemer B, Hänel M, et. Al. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2024 Jan 1;42(1):26-37. doi: 10.1200/JCO.23.01696. Epub 2023 Sep 27. PMID: 37753960; PMCID: PMC10730063.