“For patients with relapsed or refractory symptomatic multiple myeloma, the overall survival improvement in ENDEAVOR to a median of 47.5 months following a carfilzomib-containing regimen is a good start.”— George Somlo, MD
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WITH THE INCLUSION of proteasome inhibitors and immunomodulatory agents first into salvage and then as components of first-line, consolidation, and maintenance regimens, response rates, depth of response, and median progression-free and overall survival have all improved for patients suffering from multiple myeloma. While the combined use of high-dose melphalan and autologous stem cell transplantation plays a prominent consolidative role in transplant-eligible patients following induction therapy as well as in relapse, there is an ongoing need to improve upon both salvage and induction regimens to further prolong survival on our way to curing this disease.
Proteasome Inhibitors in Myeloma
THE FIRST-GENERATION reversible proteasome inhibitor bortezomib (Velcade) has been extensively tested in both salvage and early-disease settings in combination with steroids vs steroids alone, and then as part of doublet and triplet combinations. Although its toxicity profile is manageable—and despite innovations in delivery, moving from the intravenous to subcutaneous route without losing efficacy—one of the most significant and cumulative toxicities, peripheral neuropathy, remains a potentially treatment-compromising and quality-of-life–threatening problem.
Carfilzomib (Kyprolis), an irreversible proteasome inhibitor, has shown promising activity in a pivotal phase II trial of patients who either have not responded to or had disease progression on prior therapies, which could have included bortezomib. Carfilzomib was combined with dexamethasone and was administered at doses of 20 to 27 mg/ m2 on days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle. The results of this trial1 led to approval of carfilzomib by the U.S. Food and Drug Administration (FDA) and incorporation into the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®).
Subsequently, ENDEAVOR, a phase III, open-label, randomized, prospective, controlled trial, was carried out in patients with relapsed or refractory multiple myeloma, and the overall survival data are the focus of this report. The study was designed to compare the efficacy of carfilzomib vs bortezomib. Carfilzomib was infused at a higher than previously approved dose (administered in ENDEAVOR at 56 mg/m2), and the drug was given at a similar frequency (on days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle) to the schedule in the pivotal phase II trial. Bortezomib, at the standard dose of 1.3 mg/m2, was given either intravenously or as a subcutaneous injection on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone was prescribed in both arms at previously established standards.
The primary endpoint of the trial was progression-free survival, and that outcome had been reported previously, describing a significant and clinically meaningful benefit associated with the delivery of carfilzomib—a median progression-free survival of 18.7 months (95% confidence interval [CI] = 15.6 months to not estimable) vs 9.4 months (95% CI = 8.4–10.4 months) was reported. Subgroup analysis at that time revealed a benefit in favor of carfilzomib in patients with high-risk cytogenetics and prior bortezomib exposure.2
Second Interim Analysis
AN AUGUST 23, 2017, online publication in The Lancet Oncology by Dimopoulos et al, reviewed in this issue of The ASCO Post, describes the results of a preplanned second interim analysis of overall survival among patients who participated in the ENDEAVOR study.3 Of 1,096 patients screened at 198 centers internationally, 929 were randomly assigned at a 1:1 ratio to carfilzomib vs bortezomib. Eligibility criteria included age ≥ 18 years, relapsed or refractory multiple myeloma with measurable disease (ie, serum M-protein ≥ 0.5 g/dL, urine M-protein ≥ 200 mg/24 h, or, in patients without detectable serum or urine M-protein, serum free light chain ≥ 100 mg/L and an abnormal serum free light chain ratio).
Patients had received one to three prior regimens, and those with prior proteasome exposure had to have a prior response, had to come off proteasome inhibitor therapy for reasons other than toxicity, and must have been off proteasome inhibitor therapy for 6 months or more. Indeed, approximately half of the patients on both treatment arms received prior bortezomib (and 70% and 75%, respectively, received an immunomodulatory drug). All patients were required to receive antiviral therapy and a proton pump inhibitor.
Overall survival was assessed as a secondary endpoint, defined as the time from randomization to death from any cause. The initial statistical design called for 631 overall survival events, but subsequent projections suggested that such would occur by 2021; hence the protocol was amended to permit overall survival analysis at 496 events and interim analysis at 394 events. The boundary for prespecified stopping with a one-sided alpha of 0.025 was to allow for detection of a 20% risk reduction of death with 69% power; the data presented represent what is stated as the final analysis.
Clinically Meaningful Survival Benefit
THIS FINAL PRESPECIFIED ANALYSIS, with a total of 398 deaths recorded, reported overall survival at a median follow-up of 37.5 months in the carfilzomib group and 36.9 months in the bortezomib group. The median overall survival was 47.6 months (95% CI = 42.5 months to not estimable) in the carfilzomib group vs 40.0 months (95% CI = 32.6–42.3 months) in the bortezomib group (hazard ratio = 0.791, 95% CI = 0.648–0.964; one-sided P = .01).
Of interest, approximately the same percentage of patients participating in long-term follow-up (69% of the carfilzomib group and 70% of the bortezomib group) received postprogression salvage therapy (balanced between the treatment arms), and their median overall survival in a post hoc landmark analysis measured from the time of disease progression was similar (21.5 months [95% CI = 16.3–25.1 months] and 21.5 months [95% CI = 18.3–26.2 months]) for the carfilzomib vs bortezomib group. However, only 8% of patients in the bortezomib group received carfilzomib upon disease progression.
The toxicity profile between the two regimens confirmed the findings reported previously, with grade 2 or greater peripheral neuropathy noted in 35% of the bortezomib group vs 7% in the carfilzomib group, and grade 3 or worse cardiac failure was noted in 6% of the carfilzomib group vs 2% in the bortezomib group. There was a numerically higher incidence of adverse event–associated deaths in the carfilzomib-treated cohort (7% vs 5%).
The clinically meaningful overall survival benefit described by the ENDEAVOR investigators is impressive. Overall survival benefit data from randomized trials are hard to come by due to the plethora of novel and effective treatment options available. The ENDEAVOR findings demonstrate the need to await sufficiently long follow-up in all randomized myeloma trials when the goal is to detect overall survival differences. Indeed, the survival curves in this trial started to separate only after 15 months from randomization. It should be noted, however, that due to the lower than initially projected rate of events, the actual median follow-up is still only approximately 3 years, and the > 0.2 decrease in the hazard ratio as well as the Kaplan-Meier estimates are significant at a one-sided P value of .01 but were powered by design at 69%—ie, less than the customary 80% to 85%.
THE AUTHORS ARE TO BE COMPLIMENTED for their efforts in proving that carfilzomib is a strong candidate for incorporation into salvage therapy regimens. There remain several outstanding questions, however.
There are insufficient data to prove that higher doses (56 mg/m2) are really necessary to achieve the reported benefit. It is also unclear from this most recent analysis whether prior bortezomib exposure is an adverse factor in benefiting from carfilzomib. Whether carfilzomib is more effective in terms of overall survival in high-risk patients is also undefined. Finally, one has to wonder whether patients would have fared better on the bortezomib arm with greater access to salvage carfilzomib.
The overall survivorship data are encouraging, but a reanalysis at longer follow-up would be advisable. One can also postulate that triple regimens including carfilzomib, an immunomodulatory agent, and dexamethasone (ASPIRE trial)4 may turn out to be superior to the reported doublets such as lenalidomide (Revlimid) and dexamethasone. Indeed, other trials, such as ELOQUENT-2, point toward a potential overall survival benefit with triplet therapy (elotuzumab [Empliciti], lenalidomide, and dexamethasone5 vs the doublet lenalidomide and dexamethasone).
Cross-study comparisons aside, the potential overall survival benefit of an oral proteasome inhibitor,6 the incorporation of novel immunotherapeutic agents such as daratumumab (Darzalex),7 and other novel strategies combining single-target, dual-target, and conjugated antibodies into a doublet or triple regimen need to be assessed from already completed and ongoing clinical trials—and at longer follow-up time points.
In summary, for patients with relapsed/refractory symptomatic multiple myeloma, the overall survival improvement in ENDEAVOR to a median of 47.5 months following a carfilzomib-containing regimen is a good start. Randomized triplet vs doublet trials, the addition of immunotherapeutic approaches to salvage regimens, and even more importantly, the prevention of relapse by improving our upfront strategies should provide further hope to our patients aiming for a cure of their disease. ■
DISCLOSURE: Dr. Somlo is an advisor for and has received grant support from Celgene and is on the speakers bureau for Takeda.
1. Siegel DS, Martin T, Wang M, et al: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120:2817-2825, 2012.
2. Dimopoulos MA, Moreau P, Palumbo A, et al: Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. Lancet Oncol 17:27-38, 2016.
3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al: Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): An interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol 18:1327-1337, 2017.
4. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142- 152, 2015.
5. Dimopoulos MA, Lonial S, White D, et al: Eloquent-2 update: A phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma-3-year safety and efficacy follow-up. Blood 126:28, 2015.
6. Moreau P, Masszi T, Grzasko N, et al: Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374:1621-1634, 2016.
7. Palumbo A, Chanan-Khan A, Weisel K, et al: Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754-766, 2016.