Novel investigational drugs active as single agents in multiple myeloma

ABSTRACT

Introduction: Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of malignant plasma cells. patient outcome has improved markedly over the last decades due to the introduction of novel therapeutic agents such as bortezomib, thalidomide and lenalidomide. However, MM still remains largely incurable and patients eventually become refractory to available treatments. To address this unmet medical need, a variety of new molecules are currently being developed in preclinical models and/or are being investigated in clinical studies.

Areas covered: We summarized available data on new investigational drugs showing anti-myeloma single-agent activity and that might have a role in the future therapeutic armamentarium against MM. Besides their single-agent activity, the synergic potential of these new agents with the currently approved drugs will be pivotal in their integration into consolidated MM backbone therapies. The drugs discussed include alkylators, new proteasome inhibitors, novel anti-CD38 monoclonal antibodies, Bcl-2 inhibitors, Cyclin-Dependent-Kinase inhibitor, Kinesin-spindle protein inhibitors, MEK1/2 inhibitors, AKT inhibitors and PIM-Kinase inhibitors.

Expert opinion: Isatuximab, oprozomib, melflufen, venetoclax and filanesib seem to be the most promising agents with single agent activity. Nevertheless, lack of clinical activity as single agent does not imply clinical inefficacy in combination treatments.

KEYWORDS:

• Multiple myeloma
• single-agent
• alkylator
• proteasome inhibitor
• monoclonal antibody
• BCL-2 inhibitor
• CDK inhibitor
• kinesin-spindle protein inhibitor
• MEK inhibitor
• AKT inhibitor
• PIM-Kinase inhibitor

Article highlights

• MM is the second most frequent hematologic malignancy representing 10% of all hematologic cancers and causing about 60,000 annual deaths worldwide.

• Median OS doubled in the last decade, reaching a median of 7–10 years especially thanks to introduction of combination therapies incorporating PIs, IMiDs, and recently MoAbs.

• Despite the progresses, MM still remains an incurable disease. PIs and IMiDs refractory patients have poor outcomes, therefore there is an urgent clinical need for new drugs in MM field.

• In this paper we described the mechanism of action of promising experimental drugs used as single agents in MM therapy, summarizing safety and efficacy results.

• Anti-CD38 MoAb isatuximab, oral PI oprozomib, alkylating agent melflufen, oral Bcl-2 inhibitor venetoclax, and KSP inhibitor filanesib appear to be the most promising drugs with single-agent activity. Indeed, they showed at least 20% of ORR among heavily pretreated MM patients with an acceptable toxicity profile. Their role within combination treatment is currently being evaluated.

• Molecules with lower single-agent activity deserve further evaluation in synergic combination regimens, especially in the presence of a strong biological rationale.

This box summarizes key points contained in the article.

Declaration of interest

F. Gay has acted in an advisory capacity for Takeda, Seattle Genetics, Roche, MundiPharma and Johnson & Johnson. F. Gay also declares honoraria from Takeda, Amgen, Celgene, Johnson & Johnson and Bristol Myers Squibb. A. Palumbo is an employee of Takeda. A. Larocca declares honoraria from Amgen, Bristol Myers Squibb, Celgene and Jansen-Cilag. 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.