Future agents and treatment directions in multiple myeloma

Abstract

The development of bortezomib and immunomodulatory agents resulted in a revolution in the treatment of multiple myeloma (MM). Moreover, second-generation proteasome inhibitors (carfilzomib) and immunomodulatory agents (pomalidomide) have recently been approved. Nevertheless, the incurability of this disease requires other drugs with different mechanisms of action to either prolong the survival of patients refractory to current therapies, or achieve cure. Active research has been done exploring the pathogenesis of MM and searching for novel, druggable targets. In this regard, some of these novel agents seem promising, such as monoclonal antibodies (anti-CD38 – daratumumab or anti-CS1 – elotuzumab) or the kinesin protein inhibitor Arry-520. Other agents under investigation are kinase inhibitors, signaling pathways inhibitors or deacetylase inhibitors. With so many novel agents under investigation, future therapy in MM will probably involve the combined use of the already approved drugs with some of those newly discovered.

Keywords::

• immunomodulatory agents
• monoclonal antibodies
• multiple myeloma
• proteasome inhibitors
• targeted agents
• targeted drugs

Financial & competing interests disclosure

EM Ocio: Consultancy: Onyx; Bristol Myers Squibb; Array Pharmaceuticals. Research Funding: Celgene; Onyx; Pharmamar; Array Pharmaceuticals. C Mitsiades: Consultancy: Millennium Pharmaceuticals, Celgene, Novartis Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Kosan Pharmaceuticals, Pharmion, Centocor, Arno Therapeutics. Curis & Axios Biosciences (pro bono); Licensing royalties from PharmaMar; Research support from Amgen, AVEO Pharma, OSI, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme and Johnson & Johnson. RZ Orlowski: Consultancy: Abbott Laboratories; Centocor Ortho Biotech; Cephalon; Millennium; Novartis; Onyx. Research Funding: Celgene; Johnson and Johnson; Millennium; Onyx. KC Anderson: Consultancy: Gilead; Sanofi-Aventis; Onyx; Celgene. Stock Ownership; Acetylon; Oncoprep. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Survival of multiple myeloma (MM) has significantly increased in the last years mainly due to the development and approval of two families of novel agents: proteasome inhibitors and immunomodulatory drugs (IMIDs). These agents have improved not only the survival of MM patients but also their quality of life.

• These novel agents (bortezomib and IMIDs) along with alkylators and steroids currently compose the backbone of the treatment of MM patients, either young or elderly.

• Second and third-generation agents from these same families (carfilzomib, ixazomib, marizomib, pomalidomide) have been developed and have demonstrated similar or even higher activity in some cases to their parental drugs.

• These second-generation agents have some activity even in patients refractory to the first-generation drugs in their respective families. This suggests the lack of complete cross-resistance between components of the same families.

• Drugs with novel mechanisms of action are currently being explored both preclinically and in the clinical setting. This includes: monoclonal antibodies, deacetylase inhibitors, kinase inhibitors and agents interfering with different signaling pathways among others. None of them has yet reached approval from the regulatory authorities.

• After active research on monoclonal antibodies for several years without clear success, two have recently demonstrated activity in relapsed refractory MM: elotuzumab (anti-CS1) in combination with lenalidomide and dexamethasone and daratumumab (anti-CD38) in monotherapy.

• The activation of the immune system against MM is an attractive approach, as derived from the good results obtained with IMIDs and also with the combination with elotuzumab. Novel agents and monoclonal antibodies are currently being explored searching for this immunotherapy.

• DACi had great promise some years ago. Results to date have been discouraging, but we still have to wait for data on different combinations with bortezomib + dexamethasone and also for results of more specific DACi.