Battle of the Proteasome Inhibitors: Which One Endured?

The frontline therapy for most patients with newly diagnosed multiple myeloma (MM) consists of a three-drug induction regimen followed by high-dose melphalan with autologous stem cell rescue and subsequent maintenance therapy, with the goal of providing long-term disease control. The frontline three-drug regimens include proteasome inhibitor–based regimens (bortezomib, lenalidomide, and dexamethasone given either in a 21-day [RVd]¹  or 28-day [VRd] cycle,²  or bortezomib, cyclophosphamide, and dexamethasone [CyBorD or VCd]³ ) or a daratumumab-based regimen (daratumumab, lenalidomide, dexamethasone [DRd])⁴  for transplant-ineligible patients. Based on randomized phase III clinical trial data in the relapsed MM setting, there has been debate around whether bortezomib is the “optimal” proteasome inhibitor for newly diagnosed MM, and some single-arm studies have touted “better” response rates and progression-free survival (PFS). However, the only way to solve this dilemma would be a head-to-head showdown, like the “Rumble in the Jungle” or the “Thrilla in Manila.” And so, we now have the results of the ENDURANCE trial — the largest, randomized phase III trial attempted in the U.S. cooperative group setting (n=1,087).

The ENDURANCE trial compared the VRd regimen, established as standard-of-care induction based on the SWOG-0777 study,²  with carfilzomib, lenalidomide, and dexamethasone (KRd) as induction for eight cycles on each arm, followed by a second randomization to two years of lenalidomide maintenance versus continuous lenalidomide maintenance. The study had two co-primary endpoints — PFS postinduction phase and overall survival in the maintenance phase. Of note, the study included mostly standard-risk patients, as the high-risk patients were being enrolled on the sister trial SWOG-1211,⁵  which focused on newly diagnosed high-risk MM. The recently published data reports on the first co-primary endpoint of postinduction PFS, demonstrating no difference between VRd and KRd induction arms in terms of median PFS (34.4 months vs. 34.6 months, respectively; HR, 1.04; 95% CI, 0.83-1.31; p=0.74). The overall response was similar as well, although the KRd arm did have a higher proportion of patients with very good partial remission or better (74% vs. 65%; p=0.0015). The prespecified subgroup analyses did not reveal any differences in PFS between the two arms of the study. In terms of safety, there were no major surprises: Although the overall grade 3 or higher adverse events were similar in the two arms, the VRd arm seems to have higher grade 3 or greater neuropathy rates, whereas the KRd arm had higher grade 3 or greater cardiac and renal adverse events.