Current and emerging triplet combination therapies for relapsed and refractory multiple myeloma

ABSTRACT

Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10–15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide-based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients.

KEYWORDS:

• Multiple myeloma
• IMiDs
• proteasome inhibitors
• monoclonal antibodies
• relapsed refractory

Financial & competing interests disclosure

Michele Cavo has received honoraria and has been a member of the advisory board for Celgene, Janssen and Millennium. 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.

Key issues

• Despite these major advances, MM remains an incurable malignancy, with patients ultimately succumbing to their disease.

• Outcomes of patients who have failed prior bortezomib- and lenalidomide-based therapies are particularly dismal.

• Second-generation proteasome inhibitors, third-generation immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies have been developed and are under investigation, further increasing treatment options for RRMM patients.

• Novel agent-based combinations are likely to increase treatment options for RRMM patients.

• Triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens.

• The addition of a third agent does not add any relevant additional toxicity.

• Salvage triplet therapies are likely to play a key role in overcoming drug-resistance, and it is believed that they will further improve long-term outcomes of RRMM patients.

• A standard of care for the management of RRMM still cannot be defined.

• Optimal salvage therapy and treatment sequencing are still the matter of debate. Treatment choice has to be made taking into account disease-related and patient-related factors.