Paul Richardson, MD
In the past 20 years, we’ve been very fortunate in the development of effective myeloma therapies and have seen remarkable progress for our patients. Median survivals have improved from 2 to 3 years—at best—to 3 to 5 years with transplant for younger patients, and now we’re seeing median survivals in excess of 10 years, with long-term, durable remissions in an increasing proportion of patients. This speaks volumes to the progress made against a hitherto incurable and otherwise deadly disease. While this expansion of therapeutic opportunity has been incremental in some ways, it’s been continuous and, when seen in aggregate, the impact is considerable.
For example, in the past several years there have been numerous advances specifically in relapsed and refractory multiple myeloma. Perhaps the most important has been the introduction of monoclonal antibodies—in particular, the first-in-class monoclonal antibody daratumumab (Darzalex), which targets CD38, isatuximab in the same class, and elotuzumab (Empliciti), particularly when combined with immunomodulators. Elotuzumab is involved in the activation of natural killer cells and the engagement of a receptor, SLAMF7, that is uniquely expressed in myeloma, and distinct from CD38. In terms of the pipeline, the CD38 space continues to be promising given the current successes with isatuximab. In the same context, we have very exciting new constructs such as antibody–drug conjugates, including GSK’916 (GSK2857916), a particularly active agent under development targeting BCMA that has shown evidence of efficacy as both a single agent and in combination.
Beyond the monoclonal antibodies, we have continued significant progress with already approved next-generation immunomodulatory therapy in the form of pomalidomide (Pomalyst) and next-generation proteasome inhibition in the form of both carfilzomib (Kyprolis) and ixazomib (Ninlaro). Highly potent immunomodulatory agents called Cell-Mods are showing impressive activity and tolerability in early studies even after pomalidomide and monoclonal antibody treatment failure (specifically, the oral agents CC9220 and CC9480).
Furthermore, next-generation proteasome inhibitors continue to emerge and may have an increasing role not only when other agents have failed but also in special patient populations, such as those with central nervous system (CNS) myeloma. The leading candidate in this space is marizomib, an irreversible beta lactone proteasome inhibitor which targets multiple proteasomal subunits and has the ability to overcome resistance, as well as penetrate the CNS. In addition, we have continued to explore the role of histone deacetylation and its inhibition by examining the evolving role of panobinostat (Farydak), and other next-generation inhibitors in the same class.
What is important to recognize in the relapsed/refractory arena is the essential nature of targeting the immune system. In that regard, cellular therapy has been tremendously important in my view; the promising results from chimeric antigen receptor (CAR) T-cell therapy are remarkable, and especially the encouraging results seen from numerous platforms, including the leading BB2121 technology, which is currently the most advanced and is now moving into Phase III studies.
Beyond CAR T, other immunotherapeutic strategies hold promise, including bispecific T-cell engagers, which show remarkable activity but, like all early phase development, careful attention to toxicity and efficacy overall remain very important as we go forward.
In this context, it is also important to recognize the continued benefit of targeting mutational burden and, in particular, the role of venetoclax (Venclexta); the drug has been focused on 11;14 translocated myeloma [t(11;14)] which occurs in a significant subset of patients. There has been a recent safety and efficacy concern with venetoclax, but I am very hopeful that in the t(11;14) population, where efficacy is substantial, the agent will continue to have momentum and confer benefit.
In the setting of mutational burden, a variety of other novel small molecule inhibitors are under evaluation; perhaps one of the most pertinent is the selective inhibition of nuclear export proteins, with the XPO1-targeting small molecule selinexor. This drug is particularly interesting as an oral agent that is administered up to twice a week and targets a unique mechanism of action. Once a week in combination also appears to be active, particularly with other drugs such as bortezomib (Velcade). Selinexor works by blocking the export of key proteins by myeloma cells that would otherwise suppress the malignant genome. It suppresses oncogenic thrust and allows a stabilization of the malignant genome, in turn being proapoptotic, therefore, and so further driving tumor control. The construct around this agent is particularly fascinating in my view because it may be especially important in high-risk and advanced, resistant disease, as well as being effective in combination.
In that same spirit, there is a new targeted chemotherapeutic melflufen that is activated through aminopeptidases, which are characteristically overexpressed in myeloma. This agent is effective in targeting tumor selectively as a result, although myelosuppression can occur, but mucositis, alopecia, and other more traditional cytotoxic adverse effects do not. Early studies with this drug have been very promising, showing manageable toxicity and efficacy, in particular against extramedullary disease, which is emerging as an increasing challenge in this space.
In summary, there is steady and exciting progress with a variety of novel agents and new strategies in relapsed and refractory myeloma, which remains an exquisite unmet need. I am especially encouraged that we continue to be able to bring these approaches together, using them sequentially and in combination, and so further improve patient outcome in the longer term.
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