Limited treatment options in refractory multiple myeloma: promising therapeutic developments

ABSTRACT

Introduction: Combinations of proteasome inhibitors, immunomodulators, and monoclonal antibodies are highly active against multiple myeloma. Consequently, several combinations have moved from the relapsed to the front-line setting. In the context of lenalidomide and bortezomib being used upfront, salvage options need to be evaluated.

Areas covered: This manuscript reviews available data for the treatment of patients progressing on optimal frontline strategies, with a focus on the role of second-generation proteasome inhibitors and immunomodulators, monoclonal antibodies and immunotherapy.

Expert opinion: Remarkable progress has been made in myeloma treatment due to the integration of immunomodulators, proteasome inhibitors and more recently monoclonal antibodies in the front-line setting. However, we work on the assumption that most individuals will eventually relapse. Optimized upfront therapy negatively selects more resistant patients among still relapsing individuals. Bortezomib and lenalidomide-exposed patients are under-represented in trials leading to currently approved combinations. Evidence needs to be reviewed taking into account how the improvement of frontline therapy has modified the characteristics of patients at the time of relapse. Second generation immunomodulatory agents and proteasome inhibitors, monoclonal antibodies and other agents have shown efficacy in this new landscape. Immunotherapeutic agents, including CAR-T cells are promising for patients failing standard combinations, despite current data are still immature.

KEYWORDS:

• Bispecific antibodies
• CAR-T cells
• immunoconjugates
• immunotherapy
• lenalidomide-resistance
• monoclonal antibodies
• relapsed and refractory multiple myeloma

Article highlights

• Currently approved combinations to treat relapsed and refractory multiple myeloma are based on trials where patients bortezomib and lenalidomide-exposed frontline are under-represented.

• Patients exposed to several agents in combination are likely to present some degree of refractoriness to such drugs. Biologically, refractoriness is a continuous rather than a discrete variable.

• Alternative agents should be preferred over retreatment with agents to which the patient ha already been exposed.

• Alternative combinations of second-generation immunomodulating agents and proteasome inhibitors with monoclonal antibodies have been explored with positive results.

• Patients with a suboptimal response to best available combinations include primary refractory patients, patients relapsing within 1 year of frontline treatment (particularly if treatment included autologous stem-cell transplantation) and patients with high-risk baseline features still harboring a positive minimal residual disease after full intensity first-line treatment.

• Patients with suboptimal response to the best available first-line combination are unlikely to obtain prolonged benefit from similar strategies at relapse despite the incorporation of alternative agents.

• Such patients are in urgent need of effective alternatives. At present, immunotherapeutic approaches are promising. However, early results must be taken with caution, the role of immunotherapy in the relapsed and refractory multiple myeloma setting still needs to be established.

Declaration of interest

Albert Oriol has participated in advisory boards and sponsored symposiums for Celgena, Amgen, and Janssen. 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.

Reviewer disclosures

A peer reviewer on this manuscript has received honoraria from Bristol-Myers Squibb, Celgene, Amgen, and Janssen, has served on the advisory board of Amgen, Karyopharm, Janssen, and Celgene, and has received consultancy fees from Takeda and Janssen. Peer reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper received no funding. The authors receive institutional support from Josep Carreras Research Institute.