Proteasome inhibitors and immunomodulators (IMiDs) are the mainstay of therapy for multiple myeloma. For years, treatment has relied on Velcade® (bortezomib, Millennium/Takeda/Johnson & Johnson) and Revlimid® (lenalidomide, Celgene) as part of first-line and second-line therapy, usually in sequence. Recently, two advances have changed this paradigm. The first is the development of triplet therapy that combines both an IMiD and a proteasome inhibitor together with steroid: The RVD regimen (Revlimid, Velcade, dexamethasone) is now the most commonly used first-line regimen in the U.S. in transplant-eligible myeloma (37% of patients), and the similar VTD regimen (Velcade, thalidomide, dexamethasone) is most commonly used in these patients in Western Europe (25% of patients).1 The second recent advance is the introduction of next-generation agents within both of these classes – the proteasome inhibitor Kyprolis® (carfilzomib, Onyx/Amgen) was approved in the U.S. in July 2012 and the IMiD Pomalyst® (Imnovid® in Europe, pomalidomide, Celgene) was approved in the U.S. in February 2013 and in Europe in August 2013. Both Kyprolis and Pomalyst are currently approved for use in relapsed/refractory myeloma patients who have previously been treated with a proteasome inhibitor and an IMiD, but expectations are high that both drugs may ultimately be used in earlier lines of therapy.
Kyprolis received an accelerated approval in the U.S. based on a single-arm study. Confirmation of activity and European regulatory submission would be based on two randomized Phase III trials – the FOCUS trial (which compared Kyprolis versus best supportive care in third-line or later myeloma) and the ASPIRE trial. As was reported at the 2014 European Society of Medical Oncology (ESMO) annual meeting, the FOCUS trial failed to show significantly prolonged overall survival or progression-free survival (PFS) for Kyprolis versus best supportive care and also highlighted acute renal failure as a significant toxicity in this patient population.2 The failure of the FOCUS study placed greater onus on the ASPIRE trial to confirm activity of Kyprolis. The first results of the ASPIRE trial were reported at the 2014 American Society of Hematology (ASH) conference.3
ASPIRE randomized 792 patients to treatment with KRd (Kyprolis + Revlimid + low-dose dexamethasone) or Rd in myeloma patients who had received one to three prior regimens (median two prior lines). Unlike FOCUS, the ASPIRE trial did meet the primary endpoint, showing significantly prolonged PFS in favor of the KRd arm versus the Rd arm: 26.3 months versus 17.6 months, HR 0.69, p<0.0001. The triplet combination also significantly improved response rate (ORR 87.1% versus 66.7%; CR/VGPR 69.9% versus 40.4%; and CR/sCR 31.8% versus 9.3%), and there was a trend toward improved overall survival (two-year OS 73.3% versus 65.0%; medians not reached; HR 0.79, p=0.018, which did not cross the pre-specified stopping boundary for significance at this interim analysis). Although not reported in the presentation, Dr. Stewart noted during discussions that there was a low rate of post-study Kyprolis in both arms due to the lack of regulatory approval for Kyprolis in Europe. This lack of extensive crossover may prevent the OS analysis from being confounded and give us greater confidence when interpreting the data when final analysis is available.
Encouragingly, there were no safety signals, including no significant increase in renal failure (all grades: 8.4% versus 7.2%) or cardiac failure (all grades: 6.4% versus 4.1%). One potential reason for discordance between the FOCUS and ASPIRE trials in terms of renal toxicity may be the trial enrollment criteria: The ASPIRE trial predominantly enrolled patients with creatinine clearance (CrCl) of at least 50 mL/min, whereas the FOCUS trial included some patients with CrCl of less than 30 mL/min. Other adverse events were similar or only mildly increased in the KRd arm, with those increases typically being in the incidence of Grade 1/2 toxicity, which likely contributed to the significant improvement in EORTC Global Health Status that was observed in the KRd arm versus the Rd arm (p<0.0001).
Of note, in this study Kyprolis was administered for only the first 18 cycles, while the Rd regimen continued to be administered to patients until disease progression or intolerance (in both arms). The reasons for this are unclear although likely represent uncertainty with regard to long-term toxicity of the triplet regimen. Interestingly, the PFS curves reached maximal separation at the 18-month timepoint, after which they appeared to begin to converge. One wonders if an even greater level of PFS or OS benefit could have been achieved if Kyprolis had been maintained along with Rd until progression, especially in light of the safety data that suggest little concerning adverse events and the improved quality of life that was achieved during the 18-month period of triplet therapy.
What will be the impact of these results? Most significantly, the ASPIRE trial should support regulatory approval of Kyprolis in Europe. With the FOCUS trial having failed, ASPIRE is the nearest term hope to launch the drug in that market. In both the U.S. and Europe, the trial design should be sufficient for approval, since Revlimid plus dexamethasone is approved in the second-line setting. Is there a role for triplet therapy in second-line, especially in the new era of triplet therapy in first-line? Perhaps. Currently, U.S. physicians use second-line Kyprolis monotherapy most commonly in patients who received first-line RVD (24%), and only 7% use Rd post-RVD. While there is strong proof that Kyprolis is active in patients who were previously treated with Velcade, the use of Revlimid in two lines back-to-back may be less desirable to U.S. physicians, especially in an era when alternative IMiDs are available. This may limit adoption of KRd in second-line in the U.S. In contrast, European physicians use second-line Rd most commonly in patients who received first-line VTD, so the addition of Kyprolis to this standard regimen sequence might be easily adopted into practice. A key influence in both markets, however, will also be cost of therapy. Revlimid plus low-dose dexamethasone costs approximately $8,000 per month, and adding Kyprolis to that would bring the monthly cost to approximately $14,000. Patients will have to weigh the financial toxicity of this regimen against the efficacy gains, and while the U.S. tends to be more accepting of high-priced regimens, there could be a larger battle brewing in Europe. Last, but certainly not least, is the significant number of new agents with novel mechanisms of action (MOAs) that are currently in development in myeloma. When launched, will these novel MOAs be viewed more favorably than another proteasome-IMiD combination? On the horizon are HDAC inhibitors (the fate of panobinostat (Novartis) currently lies in the hands of the U.S. FDA and European Medicines Agency), anti-CD38 monoclonal antibodies (daratumumab (Genmab/Johnson & Johnson) and SAR650984 (sanofi) both presented encouraging data at ASH 2014; daratumumab has Breakthrough Therapy Status from the U.S. FDA and is already being studied in Phase III), and anti-SLAMF7 monoclonal antibodies (previously known as anti-CS-1; elotuzumab (AbbVie/BMS/Ono) also has Breakthrough Therapy Status and is currently in two Phase III trials), all of which are being studied in combination with a doublet regimen (either VelDex or Rd) in relapsed/refractory multiple myeloma.
However these various treatment options ultimately compete in the marketplace, patients will certainly be better off. With the KRd regimen demonstrating median PFS in excess of two years in a median third-line setting and overall survival estimated to be in excess of three years, these outcomes are certainly something for us to aspire to.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health
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