EHA 2025 Insights: Subgroup Analysis of Transplant-Ineligible Patients With NDMM in the CEPHEUS Trial

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The distinction between transplant-ineligible and transplant-deferred patients has become increasingly important in contemporary myeloma treatment planning. The CEPHEUS trial included truly transplant-ineligible patients (those with significant comorbidities, cardiac issues, respiratory problems, or chronic diseases) and patients who chose to defer transplant. Analysis of the truly transplant-ineligible subset revealed some benefit from quadruplet therapy (D-VRd) compared with standard triplet therapy, though with increased infection risks, particularly pneumonia. The MRD negativity rates at 10–5 showed improvement (45% vs 35%), demonstrating that even frail patients can benefit from treatment intensification. This finding supports the use of quadruplet therapy across a broad patient population, regardless of transplant candidacy.

For community oncologists treating 2 to 3 patients with myeloma monthly, the transition from familiar VRd to quadruplet regimens requires practical guidance and flexibility. Experts recommend starting with partial regimens if needed, beginning with VRd components and adding daratumumab at day 8 or day 15 of the first cycle to allow for disease control and performance status improvement. Dose reductions are acceptable and preferable to delayed treatment, with the principle that “dose-attenuated quadruplet therapy is better than full-dose triplet therapy.” The availability of subcutaneous daratumumab (5-minute injection) significantly improves practicality compared with the historical 8-hour intravenous (IV) infusion, making quadruplet therapy more accessible in community settings where resource limitations might otherwise preclude its use.

The management of infection risk in patients receiving CD38-targeted therapy requires careful consideration of prophylaxis strategies, though expert consensus on IV immunoglobulin (IVIG) use remains variable. Most experts recommend antiviral prophylaxis universally for patients receiving CD38 antibodies, whereas IVIG use is typically reserved for patients with recurrent infections or documented hypogammaglobulinemia. The highest infection risk occurs during the first treatment cycle, coinciding with peak immunosuppression from active myeloma. Experts emphasize that patients are most immunocompromised at diagnosis, and effective treatment improves immune function over time despite therapy-related risks. Functional assessment of IG levels is preferred over absolute numbers, as many patients have elevated but nonfunctional IGs at diagnosis. This approach balances infection prevention with avoiding unnecessary interventions in patients who can tolerate CD38-targeted therapy without additional support.