MITCHELL R. SMITH, MD, PHD, is Director of Lymphoid Malignancies at the Cleveland Clinic.
For take-home messages from the myeloma sessions at ASH 2013, I will focus on several large randomized Phase III trials aimed at optimizing initial therapy for older patients with multiple myeloma (MM) not considered to be candidates for stem cell transplantation (SCT). These studies also inform discussion of the role of continuous (or maintenance) therapy. Of course, there was also news about additional exciting new agents and combinations.
In the plenary session, Facon presented results of the randomized Phase III FIRST (MM-020/IFM0701) trial for newly diagnosed patients with multiple myeloma not eligible for SCT (Abstract 2). As at least six randomized trials have shown improved progression-free survival (PFS) when thalidomide (T) is added to melphalan-prednisone (MP), and three of these showed overall survival benefit as well, MP-T has become a commonly used regimen in older non-SCT eligible patients.
Lenalidomide plus once-weekly dexamethasone (Rd) is another commonly used regimen for MM patients of all ages. In this large (500-plus patients per arm) study, patients age 65 and older or otherwise not candidates for SCT were randomly assigned to one of three treatments: Rd until disease progression or toxicity, Rd for 18 28-day cycles (72 weeks), or MP-T every six weeks for 12 cycles (also 72 weeks). Median age was 73, and median follow-up was three years.
The trial met its primary endpoint of prolonged PFS in the continuous-Rd arm versus MP-T (26 vs. 21 months), and continuous Rd was also better in terms of response rate and duration. One concern for continued treatment is that we may select for resistance and toxicity, which might make subsequent therapy less tolerable and less effective.
In this trial, a recently described endpoint of time to progression after the next treatment (or death) was captured as PFS2, and this favored continuous Rd therapy as well. In fact, there was a 22 percent reduction in risk (hazard ratio [HR] 0.78) for both PFS2 and death with continuous Rd, including overall survival at four years being 59 percent for continuous Rd, 56 percent for Rd for 18 cycles, and 51 percent for MP-T.
As for overall survival, for most other endpoints data for Rd given only for 72 weeks, the same length as MP-T therapy, appeared to be intermediate between MP-T and continuous Rd, although the statistical significance and interpretation as to how much of the benefit of continuous Rd is from the Rd and how much from ongoing therapy awaits further analysis.
Grade 3/4 toxicity for continuous Rd compared with MP-T was less in terms of neuropathy and neutropenia, but with more infections. There actually appeared to be fewer second hematologic malignancies with Rd—likely reflecting increased alkylating agent-induced myeloid neoplasms, and no difference in solid tumors. Overall, these data support use of Rd in the non-SCT setting.
Palumbo reported results of another randomized Phase III trial of front-line therapy in older non-SCT patients with MM (Abstract 536). In this community-based trial, one cohort received either MP-lenalidomide (MP-R) or oral cyclophosphamide in place of melphalan (CPR), while the other cohort received Rd. Responding patients were to receive lenalidomide therapy until progression, randomized to be given with or without prednisone. As in MM-020, median age was 73.
There were no significant differences among the three treatments in terms of response rates, or in progression-free or overall survival at two years. MP-R was the most myelosuppressive.
These data also support the use of Rd as a platform for treatment in non-SCT patients. How Rd compares with proteasome inhibitor based therapies, such as MP-bortezomib or MP-carfilzomib, and Rd + proteasome inhibitor, and how such studies are interpreted given different approaches to continuous therapy, remain open questions. Fortunately, neither of these studies suggested any concerns about ongoing lenalidomide leading to increased second malignancies, as had been observed in the post-SCT maintenance lenalidomide trials.
A third trial in this non-SCT population, MM-015, was updated again (Abstract 405) and analyzed for the PFS2 endpoint. This randomized Phase III trial compared three regimens: MP for one year, MP-R for one year, and MP-R followed by continuous lenalidomide (MPR-R).
As previously reported, MPR-R prolonged PFS, but not overall survival. PFS for MP and MP-R was not different, suggesting disease progression soon after stopping therapy and that most, if not all, of the benefit observed for MPR-R was from ongoing lenalidomide.
Second treatment after MP and even after MP-R, most often included lenalidomide, while after MPR-R most commonly utilized bortezomib. Thus, even PFS2 does not entirely encompass the desired information, since the longer PFS2 after MPR-R may reflect that more patients have now been exposed to a proteasome inhibitor.
This is an admirable attempt to assess the recently described PFS2 endpoint and to collect data on additional treatment, but demonstrates the difficulty in determining the ultimate effects of continuous therapy.
Attal updated the post-SCT maintenance lenalidomide vs. observation IFM 2005-02 trial in the younger patient population (Abstract 406 ). Because this study was stopped early due to increased hematologic malignancies in the lenalidomide arm, the median duration of lenalidomide therapy was two years post-SCT. This duration of lenalidomide significantly prolonged PFS, but not overall survival. Patients re-treated with an immunomodulatory drug (IMiD) had a shorter second remission if they had been on maintenance lenalidomide, while those treated with a bortezomib-containing regimen had similar second response duration regardless of prior maintenance or not.
Overall, patients who had received maintenance then had shorter survival from second progression, balancing the longer first PFS, so overall survival was not prolonged.
There is an evolving paradigm shift towards continuous treatment of patients with MM, even after SCT, despite the fact that one benefit of SCT used to be being in remission and off therapy. We will need to ask whether continuous therapy is beneficial for all patients or whether there are some, perhaps defined by baseline cytogenetic or gene expression profile risk factors and/or in a response-adapted approach by depth of response or achievement of MRD negativity, in whom treatment could be interrupted and re-instituted at progression.
Among the new, here are a few that represent new therapeutic classes not previously approved for MM therapy.
There was little new regarding the anti-CS1 antibody elotuzumab, as we await data from Phase III combination trials. The unlabeled anti-CD38 monoclonal antibody daratumumab can be administered in combination with Rd (Abstract 1986). Antibody-drug conjugates that deliver cytotoxic agents directly to cells targeted by the antibody are an effective new class of anti-neoplastic agents—e.g., CD30 targeting by brentuximab vedotin in Hodgkin and other lymphomas and HER2 targeting in breast cancer (T-DM1). Now we have indatuximab ravtansine that targets CD138, a specific MM marker, and delivers the maytansanoid DM4 to MM cells. Based on single-agent activity reported at ASH 2012, it has now also been tolerably combined with Rd (Abstract 758).
The kinesin spindle protein (KSP) inhibitor ARRY-520 continues to progress through clinical development, showing activity as a single agent in Phase II trials of refractory patients. The acute phase reactant protein AAG binds ARRY-520, and patients with high AAG did not respond to the drug, so low AAG may serve as a biomarker for response (Abstract 285). While we usually consider histone deacetylase (HDAC) inhibitors to be epigenetic modulators, the selective HDAC6 inhibitor ACY-1215 targets the aggresome, an alternative pathway to the proteasome to clear misfolded proteins. As predicted, pre-clinically it synergizes with proteasome inhibitors since both protein degradation pathways are then blocked. A dose-escalation study demonstrated tolerability of ACY-1215 as a single agent and in combination with bortezomib (Abstract 759).
We have heard for the past few years about the AKT inhibitor perifosine in MM. Now, afuresertib (Abstract 283), another potent AKT inhibitor synergistic with bortezomib in preclinical models and with single-agent activity, has shown activity when combined with bortezomib-dexamethasone.
This exciting progress in novel agents, as well as later-generation proteasome inhibitors and IMiDs in various combinations, can now achieve deep responses with manageable toxicities in many patients—not only at initial therapy but also in the relapsed setting. Improved therapy for patients with high-risk disease is still required.
Still open for debate in the younger SCT-eligible population are how many and which drugs are optimal for induction, whether SCT is still the best choice in these eligible patients, and whether continuous therapy until progression is necessary in all patients.
Answers to these and other questions may well come by ASH 2014 given the rapid pace of progress in this disease.