EHA 2025 Insights: CEPHEUS Trial Updates on Daratumumab-Based Regimens for Transplant-Ineligible Patients With High-Risk Cytogenetics in NDMM

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The widespread adoption of quadruplet regimens in multiple myeloma treatment reflects their superior efficacy and manageable toxicity profile compared with historical triplet approaches. Expert consensus indicates that the addition of CD38 monoclonal antibodies to standard backbones significantly improves outcomes with minimal additional toxicity burden. The discussion emphasizes that quadruplet therapy is not necessarily continued throughout maintenance, making initial tolerability less concerning as most patients can tolerate 1 to 2 cycles to establish disease response. For the rare patients who cannot tolerate full quadruplet therapy, experts recommend isatuximab plus lenalidomide-dexamethasone over traditional proteasome inhibitor–based triplets, highlighting the transformative impact of CD38-targeted therapy in the treatment landscape.

The CEPHEUS trial evaluated quadruplet therapy in transplant-ineligible patients, revealing important insights about treatment benefits across different risk groups. The study enrolled 395 patients with equal randomization between D-VRd and VRd, focusing particularly on cytogenetic risk stratification. Traditional high-risk cytogenetics (deletion 17p, t[4;14], t[14;16]) represented only 50 patients (25 per arm), showing modest benefit from quadruplet therapy. When expanded to include 1q21 amplification, the high-risk group increased to 180 patients but surprisingly showed no additional benefit from daratumumab addition. The primary benefit appeared concentrated in standard-risk patients, contrasting with transplant-eligible trial results where high-risk patients derived substantial benefit from treatment intensification.

The CEPHEUS trial results highlight the complexity of treating transplant-ineligible patients with multiple myeloma, particularly regarding risk stratification and treatment selection. Although quadruplet therapy showed overall benefit, the lack of improvement in expanded high-risk cytogenetics patients raises questions about optimal treatment approaches for this population. Experts emphasize that transplant-ineligible patients represent a heterogeneous group including frail patients and those who defer transplant, requiring individualized treatment strategies. The trial’s findings suggest that standard-risk transplant-ineligible patients derive the most benefit from quadruplet intensification, whereas high-risk patients may require alternative approaches or more intensive regimens to achieve optimal outcomes in the absence of transplant consolidation.