Shifting Standards of Care: Insights from CEPHEUS on Anti-CD38 Therapy
An expert discusses how frontline management of transplant-ineligible multiple myeloma has progressed from melphalan-based regimens to modern anti-CD38–based combinations, now including emerging quadruplet strategies. He highlights data showing improved responses and progression-free survival (PFS) even in frail populations, while emphasizing the need to balance efficacy with treatment burden, especially for older adults with comorbidities.
The management of transplant-ineligible multiple myeloma has evolved significantly over the years, moving from melphalan-based regimens to more modern combinations involving immunomodulatory agents and monoclonal antibodies. A major advancement was the incorporation of anti-CD38 therapies, particularly in combination with lenalidomide and dexamethasone, which showed promising outcomes with durable responses even in older populations. This shift has led to a reexamination of what constitutes optimal frontline therapy, especially for patients who are not candidates for transplant due to age or comorbidities. Adding further complexity, newer strategies are now testing quadruplet regimens that introduce a proteasome inhibitor to the existing triplet backbone.
One recent study examined the benefit of a quadruplet regimen in the nontransplant population, comparing it with traditional triplet therapy. The results suggested improved response rates, minimal residual disease negativity, and PFS with the addition of a proteasome inhibitor. Subgroup analyses indicated that standard-risk patients derived the most significant benefit, whereas high-risk groups still showed a need for better treatment strategies. Although the trial data demonstrated efficacy across various patient characteristics, concerns were raised regarding study design. Specifically, the inclusion of patients who were transplant deferred rather than truly ineligible may have influenced outcomes, as these individuals could tolerate more aggressive treatment than the intended frail population.
Further analysis separated truly transplant-ineligible individuals from those who simply deferred transplant. These patients were typically older and more representative of the real-world population. Encouragingly, the benefits of the quadruplet regimen remained consistent in this subset, with significantly improved PFS compared with triplet therapy alone. These findings support the use of anti-CD38–based quadruplet regimens even in less robust patient groups, although practical considerations such as treatment burden and patient tolerance still play a role when selecting the most appropriate therapy. Ongoing research continues to refine these strategies.
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