Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

ABSTRACT

Introduction: In the last few years, monoclonal antibodies have rapidly modified the therapeutic strategies for treating patients with multiple myeloma.

Areas covered: In this review, the most recent literature data regarding indications for which monoclonal antibodies are currently or will be shortly approved as salvage therapies in relapsed/refractory myeloma are discussed. In particular, updated results until March 22, 2020 of antibodies directed against CD38 (daratumumab and isatuximab), SLAMF7 (elotuzumab), BCMA (GSK2857916/belantamab mafodotin), and PD-1/PD-1 L axis (nivolumab and pembrolizumab) will be analyzed in detail.

Expert opinion: Monoclonal antibodies represent a new, very effective approach that will open novel and dynamic treatment scenarios for myeloma patients in the coming years. Optimal positioning and selection of different antibodies that are or will be soon available, appropriate combinations and careful evaluation of possible new toxicities should be considered in the future management of these patients.

KEYWORDS:

• Multiple myeloma
• relapse
• daratumumab
• isatuximab
• elotuzumab
• GSK2857916/belantamab mafodotin
• check-point inhibitors
• pembrolizumab
• nivolumab
• indatuximab ravtansine

Article Highlights

• Immunotherapy with MoAbs represents one of the most significant advances ever developed for the treatment of MM.

• Currently approved MoAbs daratumumab and elotuzumab have, respectively, limited and absent activity as single agents in advanced RRMM.

• Long-term evaluations of triplets combining daratumumab with bortezomib and dexamethasone (DVd) or with lenalidomide and dexamethasone (DRd), have instead confirmed that they are significantly more effective than corresponding doublets without daratumumab in terms of rates and quality of response (including MRD-negativity), PFS, PFS2, and, in a realistic perspective, OS.

• Although clinical results in RRMM with the association of elotuzumab with lenalidomide and dexamethasone (Elo-RD) have been to some extent less striking than other combinations including daratumumab, selected patients may benefit from this triplet.

• DVd, DRd, and Elo-RD regimens are generally effective across different subgroups of patients, including age, cytogenetic risk, and number of previous lines of therapy; however, they perform better when used as earlier lines of salvage therapy.

• Network metanalyses have indicated that DRd currently has the greatest possibility of being the best treatment for RRMM in an appropriate context.

• Safety profiles of DRd, DVd, and Elo-Rd have been confirmed in long term follow-ups, without additional new toxicity signals, excluding initial IRRs. Infections, however, remain a possible issue.

• Subcutaneous infusion of daratumumab significantly reduces the time of administration to only 3–5 min and is as effective as the intravenous route.

• Pomalidomide is another effective partner for both daratumumab and elotuzumab combinations.

• Isatuximab is a novel MoAb directed against CD38 in advanced phases of clinical development that will probably be available in the near future for the treatment of RRMM.

• Anti BCMA, drug-conjugated GSK2857916/belantamab mafodotin MoAb, is another extremely interesting agent with relevant efficacy in heavily pre-treated RRMM close to approval; however, its possible corneal toxicity should be appropriately prevented and managed.

• Check-point inhibitors combinations with IMIDs in MM have been associated with an unexpected excess of deaths and other possible immunological toxicities. In particular, available data indicate that the benefit-risk profile of the combination of pembrolizumab with dexamethasone and pomalidomide is unfavorable for patients with RRMM.

Acknowledgments

The authors greatly thank Dr. Donata Grazia Coladonato and Dr. Vito Pier Gagliardi for their support to the final draft of the paper.

Declaration of Interest

P Musto has previously received honoraria and/or served on the scientific advisory boards for Celgene, Janssen, Takeda, Bristol-Myers Squibb, Amgen, Novartis, Jazz, Sanofi, Gilead and Abbvie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer Disclosures

A reviewer of this manuscript discloses being a consultant for Amgen (maker of carfilzomib), Celgene (maker of len and pomalidomide), Sanofi (maker of isatuximab) and has been a principal investigator on several studies involving these agents as well as daratumumab.

A separate reviewer discloses receiving research funding from Janssen, serving on an advisory board for Janssen and Sanofi and being an investigator on phase 3 studies for Sanofi.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.