Current and developing synthetic pharmacotherapy for treating relapsed/refractory multiple myeloma

ABSTRACT

Introduction: The introduction of novel agents has significantly improved multiple myeloma (MM) patient outcome during the last two decades. MM received the most drug approvals for any one malignancy during this time period, both in the United States as well as in Europe.

Areas covered: Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are prototype drug classes, which target both specific MM cell functions, as well as the tumor supportive bone marrow microenvironment, and represent current cornerstones of MM therapy. Importantly, the unprecedented extent and frequency of durable responses, in relapsed/refractory multiple myeloma (RRMM), in particular, is predominantly based on the combinatorial use of these agents with conventional chemotherapeutics or representatives of other drug classes. This article will summarize past landmark discoveries in MM that led to the dramatic progress of today’s clinical practice. Moreover, developing strategies will be discussed that are likely to yet improve patient outcome even further.

Expert opinion: Despite significant therapeutic advancements, MM remains an incurable disease. With several novel agents in the preclinical and early clinical pipeline, among those novel CD38 and BCMA mAbs, immune checkpoint inhibitors, as well as ricolinostat, selinexor, venetoclax, CAR-T cells, and vaccines, further advances in MM patient outcome are expected in the near future.

KEYWORDS:

• Multiple myeloma
• relapsed/refractory disease
• proteasome inhibitors
• immunomodulatory drugs
• immune checkpoint inhibition
• daratumuamb
• elotuzumab
• selinexor
• venetoclax

Article highlights

• the introduction of novel therapies (thalidomide, lenalidomide, bortezomib) into MM treatment strategies significantly increased the survival of patients during the last two decades; however most, if not all patients, eventually relapse

• next-generation novel agents including carfilzomib, ixazomib, pomalidomide, and panobinostat, as well as daratumumab and elotuzumab have been recently approved for the treatment of RRMM. They are now tested in a multitude of trials to optimize combination therapies and their sequencing not only in RRMM but also in NDMM.

• phase 3 trials demonstrate unprecedented anti-MM activity of daratumumab- containing combination regimens with cases of MRD negativity

• immune checkpoint inhibitors, selinexor, venetoclax, and CAR T cells evolving, the future of therapeutic options remains exciting

• the identification of reliable biomarkers will be pivotal for the rational design of up-to-date clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

K Podar has acted as a consultant for Celgene and for Amgen. 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

Additional information

Funding

This paper was not funded