Prognostic indicators of lenalidomide for multiple myeloma: consensus and controversy

Abstract

The long-term outcome of multiple myeloma (MM) has been greatly improved through new agents, one being lenalidomide (LEN). Based upon the findings of in vitro experiments, its mode of action against MM occurs through a combination of direct tumoricidal effects on myeloma cells, modulatory effects on tumor immunity and tumor microenvironment-regulatory effects. However, it has not been clearly defined whether the clinical response and long-term outcome of MM with LEN treatment truly reflect the mechanisms of action of LEN proposed by in vitro studies. To ascertain what is known and what remains to be elucidated with LEN, we review the current literature on the mode of action of LEN in association with myeloma pathophysiology, and discuss the prognostic indicators in the treatment of MM with LEN.

Keywords:

• cereblon
• cytogenetics
• immunomodulatory drug
• lenalidomide
• mode of action
• multiple myeloma
• prognostic indicators
• treatment history

Financial & competing interests disclosure

This work was supported in part by Grants-in-Aid for Scientific Research from the National Cancer Center Research and Development Fund of Japan (23-A-17), and the Ministry of Education, Culture, Sports, Science and Technology of Japan (J Kuroda, M Taniwaki). 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

• Recent advances of novel anti-multiple myeloma (MM) agents, that is, proteasome inhibitor, or immunomodulatory drugs, have dramatically improved the treatment outcome of MM.

• Lenalidomide (LEN) is a second-generation immunomodulatory drug, which has shown significant activities both in newly diagnosed and relapsed/refractory MM.

• MM is a highly molecularly complex disease with significant inter-patient diversity and intra-clonal heterogeneity even in a single patient, it is essential to understand the mode of action and prognostic factors of individual therapeutics to take advantage of them.

• In vitro and preclinical studies have suggested that the anti-MM effect of LEN involves pleotropic biologic effects on various types of immune cells, modulatory effects on the tumor microenvironment and direct cytotoxic effects, including cereblon-mediated substrate modification, such as Ikaros transcription factors.

• Although LEN treatment may ‘improve’ the long-term outcome of MM with poor cytogenetics, it may not completely ‘overcome’ the prognostic impact of poor cytogenetics, especially del(17p), in MM.

• Cereblon expression level in myeloma cells may be a potential molecular biomarker for predicting treatment outcome with LEN in MM.

• So far, no immunologic biomarker has been promising as the prognostic indicator of LEN in MM.

• An increased number of prior lines of therapy may associate with shorter progression-free survival period with LEN.

Notes