Dr Banerjee on the Ongoing Debate Over Proteasome Inhibitor Selection in Newly Diagnosed Myeloma

“When it comes to quadruplet therapy in myeloma, [ultimately the current advice is to] pick…whatever quadruplet [regimen] you get insurance approval for that works for your patient, just roll with it. [In the meantime,] these trials will keep rolling on."

Rahul Banerjee, MD, FACP, assistant professor, Clinical Research Division, Fred Hutchinson Cancer Center; assistant professor, Division of Hematology and Oncology, University of Washington, discusses considerations for choosing a proteasome inhibitor when building triplet or quadruplet regimens for patients with newly diagnosed multiple myeloma, based on findings from the phase 3 COBRA trial (NCT03729804).

The COBRA trial compared carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) against bortezomib (Velcade) plus lenalidomide and dexamethasone (VRd) in newly diagnosed multiple myeloma. Data presented at the 2025 ASH Annual Meeting revealed that KRd reduced the risk of progression or death by 43% compared with VRd (HR, 0.57; 95% CI, 0.37-0.88; P = .0095). The median progression-free survival (PFS) was not reached in the KRd group versus 48.8 months in the VRd arm.

During an OncLive and coMMit workshop held during ASH 2025, Banerjee and colleagues discussed these results as a group to determine if the findings should alter standard practice and proteasome inhibitor selection. Banerjee noted a significant imbalance in PI exposure between the 2 arms: the KRd group received carfilzomib for approximately 2 years, while the VRd group received bortezomib for approximately 6 months. This discrepancy may explain the perceived outperformance of carfilzomib over bortezomib. He noted that while the phase 2 MASTER trial (NCT03224507) successfully evaluated quadruplet induction with daratumumab (Darzalex), carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), the subsequent phase 2 MASTER-2 trial (NCT05231629) utilized Dara-VRd due to the ubiquity and convenience of subcutaneous bortezomib.

Banerjee concluded that the COBRA data did not fundamentally change the ongoing debate between these two agents. Instead, treatment selection remains highly individualized; carfilzomib is often favored for patients with ultra-high-risk disease or pre-existing neuropathy, while bortezomib may be a better choice for patients with significant cardiac issues. Ultimately, clinicians are encouraged to select the therapy most likely to receive insurance approval and suit the patient's clinical needs.