Can we change the disease biology of multiple myeloma?

Abstract

Despite improvements in disease management, multiple myeloma (MM) remains incurable. Conventional treatment methods are unsatisfactory, leading to a pattern of regression and remission, and ultimately failure. This pattern suggests that one of the possible strategies for improving outcomes is continuous therapy to maintain suppression of the surviving tumor cells. Optimal management of MM requires potent agents and modalities with direct tumoricidal activity, which can also provide continuous suppression of the residual tumor to prevent disease relapse. Immunomodulatory agents exert immunomodulatory and tumoricidal effects, and cause disruption of stromal cell support from the bone marrow microenvironment. Therefore continuous therapy with immunomodulatory agents may be able to provide both tumor reduction and tumor suppression, enabling physicians to consider the possibility of incorporating continuous therapy into the treatment paradigm of patients with MM.

Fig. 1

Characteristic pattern of remission and relapse following conventional chemotherapy in multiple myeloma. MGUS, monoclonal gammopathy of undetermined significance.

Fig. 2

B-cell maturation and cell-surface marker expression. * Or other Ig isotype. Ig, immunoglobulin; VDJ, variable diversity, and joining.

Fig. 3

Multiple myeloma (MM) cell–bone marrow stromal cell (BMSC) interaction. Reproduced with permission from [36] © 2002, Rights Managed by Nature Publishing Group. AKT, protein kinase B; CRE, cyclic AMP-responsive element; ICAM1; intercellular adhesion molecule 1; IGF1, insulin-like growth factor-1; IL-6, interleukin-6; JAK, janus kinase; LFA1, lymphocyte function-associated antigen 1; MAPK, mitogen-activated protein kinase; muc1, mucin 1; NF-κB, nuclear factor κB; PI3K, phosphatidylinositol 3-kinase; SDF-1α, stromal-cell-derived factor-1α; SRE, serum response element; STAT3, signal transducer and activator of transcription 3; TNF-α, tumor necrosis factor-α; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VLA4, very-late antigen 4.

Fig. 4

Continuous therapy with IMiD^® immunomodulatory agents versus conventional chemotherapy.