What New Trial Data Reveal About Daratumumab Sensitivity in Newly Diagnosed Multiple Myeloma

Multiple myeloma (MM) remains largely incurable despite decades of therapeutic innovation, with most patients eventually relapsing after initial treatment.¹ Daratumumab (Darzalex; Janssen Biotech, Inc), a CD38-directed monoclonal antibody, has transformed the frontline treatment landscape, yet responses to monotherapy vary considerably, especially in older adults ineligible for autologous stem cell transplantation. Findings from a pivotal phase 2 trial (NCT04151667) recently published in Blood shed critical light on the biological determinants of daratumumab sensitivity in this population.²

Trial Design and Key Outcomes

The trial enrolled patients aged 65 and older with newly diagnosed MM who were ineligible for high-dose chemotherapy. All patients received daratumumab monotherapy for 2 cycles. Those achieving at least a partial response continued on monotherapy, whereas nonresponders had lenalidomide (Revlimid; Bristol Myers Squibb) or bortezomib (Velcade; Takeda Pharmaceuticals America, Inc) added, guided by ex vivo drug-sensitivity assays. The overall response rate was 97%, and 37% of patients remained on monotherapy without escalation, demonstrating that a meaningful subset can achieve durable disease control with a single agent and reduced toxicity burden.²

CD38 Expression and Plasma Cell Phenotype

Daratumumab binds CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells, triggering cytotoxicity through antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and direct apoptosis.³ The study data showed that patients who were able to sustain monotherapy had a baseline CD38 expression approximately 1.7-fold higher than those requiring combination therapy, with CD38 present on a larger proportion of tumor cells.² Monotherapy responders displayed canonical plasma cell gene expression programs, including enrichment for translation and interferon response pathways. In contrast, patients requiring combination therapy harbored tumors with B-cell memory, TNF signaling, and KRAS signaling signatures, reflecting a less differentiated, more immune-evasive biology inherently less susceptible to CD38-directed killing. Loss of CD38 expression via antigen downregulation or biallelic gene deletion has been independently identified as a key resistance mechanism, occurring in approximately 20% of patients who relapse after anti-CD38 therapy.⁴

Clonal Dynamics and Emerging Resistance

Using single-cell RNA sequencing, the investigators tracked clonal evolution longitudinally and found that, after only 2 treatment cycles, tumor cells in responding patients had already begun to acquire resistance transcriptomic signatures matching those observed at baseline in combination-therapy patients.² This indicates that resistant subclones preexist as minor populations and are rapidly selected under CD38-directed pressure, rather than being induced by treatment. These findings are consistent with emerging genomic evidence that resistance to anti-CD38 antibodies can arise through multiple concurrent mechanisms.⁴

Implications for Pharmacy Practice

Daratumumab is now a cornerstone of frontline MM therapy across transplant-eligible and -ineligible patients, and its use continues to expand. This is supported by data from a 2025 meta-analysis showing significant improvements in progression-free survival, overall survival, and minimal residual disease negativity compared with standard regimens.⁵ Pharmacists in oncology settings should recognize that CD38 expression quantification, plasma cell transcriptomic profiling, and immune tumor microenvironment (iTME) characterization may increasingly inform treatment selection. Understanding resistance timelines also enables more targeted patient counseling and monitoring. Importantly, the trial’s low adverse event rates highlight the potential to spare older, frail patients from unnecessary combination-regimen toxicities when monotherapy suffices.⁶

Conclusion

Findings from the response-adapted daratumumab trial provide a prospective clinical framework for identifying patients with newly diagnosed MM who are most likely to benefit from single-agent therapy. CD38 antigen density, plasma cell differentiation status, and an activated iTME emerge as key predictors of sensitivity, while dedifferentiated tumor biology and immunosuppressive microenvironments signal the need for combination approaches. These insights advance precision oncology in MM and underscore the value of biomarker-driven, pharmacist-informed medication management.²

References

1. Dyer MR, Zheleznyak A, Teubner EN, et al. Ablation of CD38 in multiple myeloma cells leads to an aggressive phenotype in a mouse xenograft model. Blood Adv. 2026;10(2):343-355. doi:10.1182/bloodadvances.2025017296

2. Meads MB, Zhao X, Noyes D, et al. Target antigen and plasma cell phenotype are critical factors for sensitivity to response-adapted daratumumab therapy. Blood. 2026;147(5):497-512. doi:10.1182/blood.2025029921

3. Rajkumar SV. Daratumumab in multiple myeloma. Lancet. 2016;387(10027):1490-1492. doi:10.1016/S0140-6736(15)01226-X

4. Diamond B, Baugh L, Poorebrahim M, et al. Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma. Blood. 2025;146(13):1575-1585. doi:10.1182/blood.2025026452

5. Wang C, Xu Z, Jiang M, Chen Y, Lan Y. Daratumumab in transplant-ineligible newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials. Cancers (Basel). 2025;17(20):3349. doi:10.3390/cancers17203349

6. Seckinger A, Delgado JA, Moser S, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31(3):396-410. doi:10.1016/j.ccell.2017.02.002