Slow and Steady Advances in Treatment of Newly-Diagnosed Multiple Myeloma
| Dec 9, 2013
Multiple Myeloma has had significant new advances in the past year, with the U.S. Food and Drug Administration (FDA) approval of Kyprolis® (carfilzomib, Onyx/Amgen) and the U.S. and European approvals of Pomalyst® (Imnovid® in Europe, pomalidomide, Celgene), both in the relapsed/refractory setting. The relapsed/refractory setting is poised for further evolution with the recently announced success of the PANORAMA-2 Phase III trial of panobinostat (LBH589, Novartis)1 and ongoing Phase III trials with numerous other promising agents. Although these developments in the management of relapsed/refractory disease are significant, there is still a high unmet need to delay relapse among newly-diagnosed patients. In the first-line setting, several standard options exist, and choice of therapy varies by patient characteristics (most notably by their eligibility for stem cell transplantation) and by geography. In the United States, transplant eligible patients most commonly receive a triplet regimen, RVD [Revlimid® (lenalidomide, Celgene), Velcade® (bortezomib, Millennium/Janssen), dexamethasone] whereas in Europe the standard of care remains a Velcade-based doublet2. In transplant-ineligible patients, Velcade- or Revlimid-based regimens are both commonly used in the U.S., while in Europe Velcade again remains the predominant choice of therapy2. The reason for the discordance, in part lies with the data-and compendia-supported off-label use of Revlimid in newly-diagnosed patients in the U.S., while in Europe (where Velcade has a frontline label that Revlimid does not) off-label utilization is much less common.
To support regulatory approval of Revlimid for newly-diagnosed patients in both markets, Celgene and various cooperative groups have conducted multiple studies of Revlimid in newly-diagnosed patients. The MM-015 trial (NCT00405756) was reported at the American Society of Hematology (ASH) 2012 annual meeting (Abstract 944)3, and showed that a significant improvement in progression-free survival (PFS) was obtained in transplant-ineligible patients who received the MPR-R regimen (melphalan, prednisone, Revlimid induction followed by Revlimid maintenance) compared to patients who received MP alone or MPR induction only (PFS: 31 months vs. 13 months vs. 14 months; HR 0.40, p<0.001); there was, however, no improvement in overall survival at the interim analysis. A companion study, FIRST (MM-020, NCT00689936), also evaluated the efficacy of Revlimid in newly-diagnosed transplant-ineligible patients, but with a different regimen and comparator: FIRST randomized patients to continuous RevDex until progression versus RevDex for a fixed 18 cycles (72 weeks) vs. MPT (melphalan, prednisone, thalidomide) for a fixed 12 cycles (72 weeks). A first look at the FIRST data came in the plenary session on December 8 at the 2013 ASH conference4. There was a significant improvement in PFS for patients treated with continuous RevDex compared to MPT and compared to RevDex18 (see Table 1). The Kaplan-Meyer curves for all three arms overlapped for the first 18 months of treatment, after which the continuous RevDex curve quickly separated from the curves of the other two arms. Other secondary endpoints significantly favored the continuous RevDex arm as well, most importantly that of overall survival: there was a 22% reduction in the risk of death in the continuous RevDex arm compared to the MPT arm at this interim analysis (35% of ITT events).
Treatment with RevDex was associated with some increases in adverse events (higher rates of infection, deep vein thrombosis and/or pulmonary embolism, and cataracts); the RevDex arms had markedly lower rates of neutropenia and peripheral sensory neuropathy compared to MPT. Perhaps even more important was the analysis of secondary primary malignancies (SPM). At this latest follow-up, there is no significant difference in the SPM rate among the three arms; in fact, there was a slightly lower rate of hematologic SPM in the continuous RevDex arm compared with the MPT arm. The lack of increased SPM in the RevDex arms may support the hypothesis that the worrisome SPM observed in the MM-015 trial was due to the melphalan used in that regimen rather than attributable to Revlimid.
With a significant PFS and OS benefit favoring continuous RevDex along with a safety profile that may alleviate some prior concerns regarding SPM, the FIRST trial is certainly a positive study that will have significant market impact. But just what will that market impact be? This study establishes RevDex as superior to MPT in newly-diagnosed transplant-ineligible patients. The most significant impact will be that the results are likely to support regulatory approval of Revlimid in the first-line setting in both the U.S. and Europe. As noted earlier, the lack of European approval in first-line has limited Revlimid’s utilization in this setting in Europe, so gaining this label expansion will be critical for its further success. But how will treatment patterns change? Although MP-based regimens have long been considered the standard of care for transplant-ineligible patients, in reality they have very little use in the modern day: in 14% of U.S. patients and 21% of Western Europe patients2; dexamethasone-based doublets or triplets have evolved to become the preferred regimen in both transplant-eligible and -ineligible patients in recent years. So while a change in practice from MPT to RevDex is unlikely to emerge from this study and its approval, a more likely outcome is a shift in the balance between use of Velcade-based regimens and Revlimid-based regimens in newly-diagnosed patients. As mentioned above, Velcade-based regimens are heavily utilized in Europe, due to the OS benefit as demonstrated in multiple Phase III trials5,6. With Revlimid now able to claim an OS benefit in frontline, a shift in treatment patterns may emerge, with RevDex posing a new competitive threat to VelDex in Europe and posing a renewed competitive threat to VelDex in the U.S. How do the two regimens compare? VelDex has not been extensively studied in transplant-ineligible patients, so a comparison of efficacy and safety outcomes between these two regimens is not possible. In the Phase III VISTA trial in newly-diagnosed transplant- ineligible patients, Velcade + MP (VMP) resulted in a 24 month median time to progression (TTP) and 69% 3-year OS5. The 32.5 month median TTP of RevDex in the FIRST trial4 and the 31 month PFS of MPR-R in the MM-015 trial3 (TTP was not reported) compare favorably with the 24 months reported for VMP; OS may be comparable or slightly favoring RevDex (~75% if we extrapolate 3-year OS from the Kaplan-Meyer curve presented by Dr. Facon4) and is comparable for MPR-R (70%)3. Acknowledging the weaknesses in these cross-trial comparisons, they do at least suggest the possibility for RevDex to become adopted as a new standard of care in newly-diagnosed transplant-ineligible myeloma, and most certainly will support regulatory approval by the European Medicines Agency and the FDA. Regulatory approval for Revlimid in the first-line setting will not only impact its utilization, but also that of several agents and new regimens in development that build off of a Revlimid-based backbone in first-line. Advancements may be making greater leaps and bounds in the relapsed/refractory setting, but first-line treatments continue to progress at a slow and steady pace, and in the end, it’s the patients who reap the rewards.
- Novartis press release, December 6, 2013
- Kantar Health, CancerMPact® Treatment Architecture U.S. and Western Europe, accessed December 8, 2013
- Dimopoulos et al., Abstract 944, ASH 2012; Palumbo, et al., N Engl J Med; 366:1759-1769, 2012
- Facon et al., Abstract 2, ASH 2013
- San Miguel et al., N Engl J Med; 359:906-91, 2008
- Harousseau et al., J Clin Oncol, 28: 4621-4629, 2010