There are an increasing number of treatment options for patients newly diagnosed with multiple myeloma (MM), including medication-based therapies as well as stem cell transplantation (SCT). Medication-based regimens frequently include proteasome inhibitors, monoclonal antibodies (mAbs), immunomodulatory drugs, and corticosteroids.1 Bortezomib, lenalidomide, and dexamethasone (VRd) is a frequently used regimen in patients with newly diagnosed MM. Two of the key landmark studies evaluating this VRd regimen in MM are the SWOG S0777 and IFM 2009 trials. SWOG S077 found a median PFS of 43 months, median overall survival (OS) of 75 months, and rate of overall response of 82%.2 Patients receiving VRd also had relatively high rates of grade 3 or higher adverse events (75%) and discontinuation of induction treatments because of adverse events (23%).
The IFM 2009 study compared VRd with high-dose melphalan and SCT.3 This study reported a median PFS of 36 months, complete response rate of 48%, and rate of OS at 4 years of 82%. The VRd group did have lower rates of grade 3 or 4 neutropenia (92% vs 47%), grade 3 or 4 gastrointestinal disorders (28% vs 7%), and infections (20% vs 9%) when compared to the SCT group, respectively.
Although the VRd data is relatively positive, there is an opportunity to improve on the peripheral neuropathy associated with bortezomib along with the relapse rates and PFS seen in SWOG S0777 and IFM 2009.2,3 Carfilzomib is also a proteasome inhibitor that is potent, selective, and exhibits irreversible binding (PI) which is in contrast to bortezomib, which is a reversible inhibitor (PI).4,5 Bortezomib can be administered both via the intravenous (IV) and subcutaneous (SC) routes.5 In contrast, carfilzomib is only administered intravenously, but does appear to have less peripheral neuropathy.4,5
Like bortezomib, carfilzomib can also be used with lenalidomide and dexamethasone (KRd) in the treatment of both initial and relapsed MM. As the clinical studies evaluating KRd in MM continue to increase, there is growing interest in how KRd compares with VRd based on efficacy and safety. To further evaluate the differences between KRd and VRd, a group of authors led by Kumar et al compared the outcomes of patients newly diagnosed with MM who were not considered for immediate autologous SCT (ASCT) and started on either regimen.1
The ENDURANCE study was a multicenter, open-label, phase 3, randomized controlled trial in the United States of patients 18 years or older that were newly diagnosed with MM who were either ineligible for ASCT or ASCT was not part of their initial treatment plan. Patients were randomized in a 1:1 ratio to receive either VRd (IV or SC bortezomib) or KRd induction therapy for 36 weeks. Those patients who completed induction therapy were subsequently randomized again to either 2 years of maintenance therapy with lenalidomide or indefinite maintenance. Eligible patients did not have evidence of high-risk MM and also had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2. Primary endpoints included progression-free survival (PFS) in the induction phase and OS in the maintenance phase.
There was no statistical difference in median PFS between the KRd group (34.6 months, 95% CI, 28.8-37.8) and the VRd group (34.4 months, 95% CI, 30.1-not estimable [NE]) with a hazard ratio (HR) of 1.04 (95% CI, 0.83-1.31, P =.74). Additionally, the median time to progression was similar between the KRd (36.3 months, 95% CI, 31.7-42.8) and VRd groups (44.6 months, 95% CI, 32.2-NE) with a HR of 0.97 (95% CI, 0.75-1.21, P =.79). The follow-up maintenance phase was still ongoing at the time of this publication, therefore the median OS had not been reached in either group. However when Kaplan-Meier estimates were used for OS at 3 years, there was no difference between the VRd and KRd groups (84% vs 86%, HR 0.98, P =.92).