Emerging Concepts in the Treatment of Multiple Myeloma - Episode 13
The phase III ENDEAVOR trial enrolled 929 patients with relapsed multiple myeloma who had received one to three prior lines of therapy for a head-to-head comparison between proteasome inhibitors, bortezomib and carfilzomib. The carfilzomib dose was escalated to 56 mg/m2, which is higher than the dose on the package insert, and was infused over 30 minutes rather than 10 minutes, potentially improving tolerability.
The primary endpoint of progression-free survival (PFS) was 18.7 months in the carfilzomib arm and 9.4 months in bortezomib arm (HR, 0.53, 95% CI, 0.44—0.65; P <.0001). The differences in PFS are clinically important, says Rafael Fonseca, MD. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR, 0.79; P = .066). The objective response rate (ORR) was 77% with carfilzomib versus 29% with bortezomib.
Clinicians should not interpret these results to mean that the higher response rates are due to doubling the carfilzomib dose, notes Jatin J. Shah, MD. As a single agent, carfilzomib 56 mg/m2 is likely the ideal dose; lower doses are appropriate in later-line settings when used in combination with other therapies, says Shah.
The ENDEAVOR results are practice-changing, comments Morie A. Gertz, MD, both in terms of the efficacy and the neurotoxicity findings. In the study, peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% versus 6%; P <.0001).
The CHAMPION study evaluated the schedule of weekly carfilzomib in patients with relapsed and refractory multiple myeloma who had received one to three prior lines of therapy. Investigators administered carfilzomib at 70 mg/m2 over 30 minutes. The study demonstrated an ORR of 67%. Approximately half of these patients were bortezomib-refractory, notes Shah, commenting that these results cannot be compared with ENDEAVOR data, where most patients were bortezomib-sensitive or -naïve.
Although carfilzomib is associated with an increased risk of cardiac toxicity, treatment with the next-generation proteasome inhibitor was able to salvage many patients, states Heather J. Landau, MD. Other ongoing studies are evaluating carfilzomib dosing schedules will reveal more information concerning cardiac and renal toxicities and its potential incremental benefit in earlier lines of therapy.
Ixazomib is another proteasome inhibitor under investigation. This oral agent has been combined with cyclophosphamide and dexamethasone as well as lenalidomide and dexamethasone. Taking a fixed-dose formulation by mouth has a real impact on the patient’s quality of life, comments Gertz.
Another important targeted agent in myeloma is filanesib, states Shah, which has demonstrated single-agent activity in patients refractory to bortezomib and lenalidomide. Additionally, the recent success of monoclonal antibodies in multiple myeloma has generated a great deal of excitement, adds Shah.