Anti-CD38-Based Quadruplet Improves Outcomes in Transplant-Ineligible Myeloma

Daratumumab (Darzalex) plus the standard triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) significantly improved clinical outcomes versus VRd alone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma, results from the randomized phase III CEPHEUS trial showed.

Among nearly 400 patients, the minimal residual disease (MRD) negativity rate was 60.9% with D-VRd compared with 39.4% with VRd (OR 2.37, 95% CI 1.58-3.55, P<0.0001), reported Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in Nature Medicine.

The rate of sustained MRD negativity (≥12 months) was also significantly higher with D-VRd versus VRd (48.7% vs 26.3%; OR 2.63, 95% CI 1.73-4.00, P<0.0001), as was the rate of complete response (CR) or better (81.2% vs 61.6%; OR 2.73, 95% CI 1.71-4.34, P<0.0001).

In addition, progression-free survival (PFS) was not reached with D-VRd compared with 52.6 months with VRd (HR 0.57, 95% CI 0.41-0.79, P=0.0005). The estimated 54-month PFS rates were 68.1% versus 49.5%, respectively.

The daratumumab-based quadruplet has also been evaluated in the PERSEUS trial, which showed that D-VRd led to significant improvement in PFS compared with VRd alone in patients with newly diagnosed multiple myeloma eligible for stem cell transplant, and led to the regimen’s approval for that indication.

“Our results add further validity to the use of MRD negativity as an accelerated approval endpoint to predict PFS outcomes in NDMM [newly diagnosed multiple myeloma],” wrote Usmani and colleagues. “These data, together with the phase III PERSEUS study, demonstrate the consistent benefit of quadruplet daratumumab plus VRd therapy compared with triplet VRd therapy and support D-VRd quadruplet therapy as a new standard of care for NDMM, regardless of transplant eligibility.”

The open-label CEPHEUS trial enrolled 395 patients from December 2018 to October 2019 at 92 sites in 13 countries. Median age was 70 years, 28.1% had International Staging System stage III disease, and 13.2% had high cytogenetic risk. There were more women in the D-VRd group, and most patients in both groups were white.

The percentage of patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 was 11.7% in the D-VRd group and 7.1% for those in the VRd group, while 36% and 42.4%, respectively, had an ECOG performance status score of 0.

Overall survival (OS) data were immature, but demonstrated a trend in favor of D-VRd (HR 0.85, 95% CI 0.58-1.24).

Usmani and colleagues noted that much of the trial took place during the height of the COVID-19 pandemic, which impacted OS. They reported that 24 deaths in the study were caused by COVID-19 (21.6% of all deaths) — 15 of which occurred in the D-VRd group versus nine in the VRd group.

Sensitivity analyses of OS adjusted for the impact of COVID-19 deaths showed a more pronounced treatment effect for D-VRd versus VRd. Censoring any death caused by COVID-19 resulted in a hazard ratio of 0.69 (95% CI 0.45-1.05), while considering COVID-19 death as a competing risk resulted in an HR for non-COVID mortality of 0.67 (95% CI 0.44-1.03).

The most common grade 3 or 4 treatment-emergent adverse events (TEAEs) were neutropenia (44.2% with D-VRd vs 29.7% with VRd) and thrombocytopenia (28.4% vs 20%, respectively).

Peripheral neuropathies of any grade occurred in 61.9% of patients in the D-VRd group and 66.2% in the VRd group, with grade 2 peripheral neuropathy occurring in 31.5% and 36.9%, and grade 3 or 4 peripheral neuropathy in 11.2% and 10.8%, respectively.

Serious TEAEs occurred in 72.1% of patients in the D-VRd group and 67.2% in the VRd group, and the rates of treatment discontinuation caused by TEAEs were 7.6% and 15.9%, respectively.

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