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Daratumumab Plus VRd Yields Deep, Durable Responses in Patients with NDMM
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Key Takeaways
- Daratumumab combined with VRd significantly improved MRD-negativity, complete response, and progression-free survival in transplant-ineligible NDMM patients.
- The D-VRd regimen showed a 43% lower risk of disease progression or death compared to VRd alone.
The data supports quadruplet therapy’s potential in the first line for patients with newly diagnosed multiple myeloma (NDMM).
Adding daratumumab (Darzalex; Janssen Biotech, Inc.) plus bortezomib (Velcade; Millennium/Takeda and Janssen Pharmaceutical Companies), lenalidomide (Revlimid; Celgene Corporation) and dexamethasone (D-VRd) yielded deeper, more durable responses in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma (NDMM). The data from the phase 3 CEPHEUS trial (NCT03652064) were published in Nature Medicine.1,2
Blood cells | Image Credit: © Сергей Косилко - stock.adobe.com
Daratumumab is a monoclonal antibody that targets CD38, an overexpressed glycoprotein on cancerous cells that both enhances the growth of diseased cells and impairs the response to treatment. Initially approved in November 2015, daratumumab has 9 indications, including treatment of MM in the frontline setting as well as for newly diagnosed patients who are transplant eligible and ineligible. In the phase 3 CEPHEUS trial, daratumumab significantly improved clinical outcomes when combined with the triplet therapy VRd.2,3
In the trial, the researchers examined subcutaneous daratumumab plus VRd in 395 patients with transplant-ineligible NDMM or for whom transplant was not planned as the initial therapy. They were randomly assigned to receive either 8 cycles of D-VRd or VRd followed by daratumumab plus lenalidomide and dexamethasone (D-Rd) or Rd until progression. The primary end point was the overall minimal residual disease (MRD)-negativity rate at 10−5 by next-generation sequencing, with key secondary endpoints including complete response (CR) or better (≥CR) rate, progression-free survival (PFS), and sustained MRD-negativity rate at 10−5.2
At the 58.7-month median follow-up, patients in the D-VRd group achieved an MRD-negativity rate of 60.9% compared with 39.4% in the VRd group (odds ratio (OR), 2.37; 95% CI, 1.58–3.55; P < .0001]). The D-VRd group also demonstrated superior rates of ≥CR (81.2% versus 61.6%; P < .0001) and sustained MRD negativity (greater than or equal to 12 months; 48.7% versus 26.3%; P < .0001).2
PFS was not reached in the D-VRd group compared with 52.6 months in the VRd group (HR 0.57; 95% CI 0.41-0.79, P = .0005), and the estimated PFS rates at 54 months were 49.5% and 68.1%, respectively. The OS data were immature but favored the quadruplet D-VRd therapy (HR 0.85; 95% CI 0.58-1.24).2,4
Treatment with D-VRd resulted in a 43% lower risk of disease progression or death compared with VRd (HR, 0.57; 95% CI, 0.41–0.79; P = .0005). Additionally, the reported adverse events were consistent with the known safety profiles for daratumumab and VRd. Thrombocytopenia (28.4% versus 20%) and neutropenia (44.2% with D-VRd versus 29.7% with VRd) were the most frequent grade 3 or 4 treatment-emergent adverse events (TEAEs). In the D-VRd group, 61.9% of patients had peripheral neuropathies of any grade, whereas in the VRd group, 66.2% did. Of these, 31.5% and 36.9% had grade 2 peripheral neuropathy, while 11.2% and 10.8% had grade 3 or 4 peripheral neuropathy.2,4
The rates of treatment termination due to TEAEs were 7.6% and 15.9%, respectively, while 72.1% and 67.2% of patients in the D-VRd and VRd groups experienced serious TEAEs.2,4
The findings show the promising potential of D-VRd for patients with NDMM ineligible for transplant treatment and support its use as a new standard of care.
