Dr Richardson on Optimal Treatment Strategies for 1q–Amplified Multiple Myeloma

“We have the ability to be even more tailored in our [treatment of patients with multiple myeloma] given the success of these respective quadruplet approaches.”

Paul G. Richardson, MD, clinician program leader and director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute; as well as the RJ Corman Professor of Medicine at Harvard Medical School, discussed the activity of anti-CD38–based quadruplet regimens in patients with high-risk multiple myeloma.

In the subset of patients with multiple myeloma who exhibit 1q amplification—a cytogenetic abnormality associated with high-risk disease—there is emerging evidence to suggest a differential therapeutic response to monoclonal antibodies targeting CD38, Richardson began. This genomic alteration, which occurs in approximately 30% to 40% of newly diagnosed patients, may render tumor cells susceptible to isatuximab-irfc (Sarclisa)–based therapies, he stated.

Although both daratumumab (Darzalex)- and isatuximab-based regimens have demonstrated efficacy in patients with high-risk cytogenetic profiles, preclinical findings have suggested that isatuximab may offer enhanced therapeutic benefit in the context of 1q amplification, Richardson explained. This appears to be driven, at least in part, by the overexpression of CD55 on malignant plasma cells within this subgroup, he said. CD55 is known to confer resistance to complement-mediated cytotoxicity, a key mechanism of action for anti-CD38 monoclonal antibodies, he noted. Interestingly, isatuximab appears to maintain potent activity in the presence of CD55 expression, suggesting a potential mechanistic advantage in overcoming complement resistance in 1q-amplified disease, he emphasized.

Although these insights are primarily based on preclinical data, retrospective clinical observations hint at a consistent and possibly superior performance of isatuximab in high-risk populations, including those with 1q abnormalities, according to Richardson. This may inform clinical decision-making, especially when tailoring regimens for specific patient profiles, he added. For instance, in older or frail patients with high-risk cytogenetics like 1q amplification, who may not tolerate the cardiovascular risks associated with carfilzomib (Kyprolis), an isatuximab-based regimen featuring lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone may represent a more appropriate and safer alternative, he reported. Conversely, in younger and more fit patients, a carfilzomib-based approach may still be preferred when feasible, he continued. The growing armamentarium of quadruplet regimens—including those incorporating daratumumab or isatuximab—provides hematologists with the flexibility to personalize therapy based on both disease biology and patient characteristics, he concluded.