Dr Braunstein on the FDA Approval of Subcutaneous Daratumumab With VRd For Newly Diagnosed Multiple Myeloma

“[Data from CEPHEUS] showed that at the median follow up, the MRD negativity rate was superior with the daratumumab plus VRd vs VRd alone, with an MRD negativity rate of in 52.3% vs 34.8% in the control group, and that was significant. The data between the transplant-eligible and -ineligible groups both support the efficacy of anti-CD38 quadruplet regimens in newly diagnosed myeloma.”

Marc J. Braunstein, MD, PhD, associate professor in the Department of Medicine and codirector of the Hematology-Oncology System at the New York University (NYU) Grossman Long Island School of Medicine, discussed the clinical implications of the FDA approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).

Braunstein contextualized this regulatory decision within the broader evolution of frontline myeloma therapy, noting that contemporary treatment paradigms increasingly converge across transplant-eligible and -ineligible populations. Although eligibility for ASCT remains an important stratification factor in clinical guidelines, accumulating evidence supports the use of anti-CD38–based quadruplet regimens across both settings.

The approval was supported by findings from the phase 3 CEPHEUS trial (NCT03652064), which evaluated daratumumab and hyaluronidase plus VRd (n = 197) compared with VRd alone (n = 198) in patients who were transplant ineligible or who elected to defer upfront ASCT. The study met its primary end point of minimal residual disease (MRD) negativity at a sensitivity threshold of 10⁻⁵, demonstrating a significantly higher MRD negativity rate with the daratumumab-based quadruplet. In the prespecified analysis cited in the regulatory decision, MRD negativity was achieved in 52.3% of patients treated with daratumumab plus VRd versus 34.8% of those receiving VRd alone (P = .0005). The combination was also associated with a statistically significant improvement in progression-free survival (PFS), with a HR of 0.60 (95% CI, 0.41-0.88; P = .0078).

Braunstein emphasized that these findings are concordant with data from transplant-eligible populations, such as the phase 3 PERSEUS trial (NCT03710603), which demonstrated improved PFS with daratumumab-based quadruplet therapy. Together, these studies reinforce the biologic and clinical rationale for incorporating CD38-targeted antibodies into frontline regimens regardless of transplant intent.

He also noted that CEPHEUS was conducted during COVID-19, which contributed to higher observed rates of infectious complications, including COVID-19 and pneumonia. Despite this context, the overall safety profile was considered manageable and consistent with prior experience using daratumumab-containing regimens.

Braunstein highlighted that current National Comprehensive Cancer Network Guidelines now recommend anti-CD38–based quadruplet regimens as category 1 options for many patients with newly diagnosed multiple myeloma, including those who are transplant ineligible but not frail, generally under 80 years of age. In clinical practice, he uses these regimens in a selected manner, favoring patients with adequate physiologic reserve who are likely to tolerate quadruplet therapy and achieve deeper responses, including MRD negativity.

Overall, Braunstein concluded that the CEPHEUS data support the expanding role of daratumumab-based quadruplets as a foundational approach in newly diagnosed multiple myeloma, further aligning treatment strategies across transplant eligibility categories.