Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma strategy

Abstract

Given the prevalence of osteolytic bone disease in multiple myeloma (MM), novel therapies targeting bone microenvironment are essential. Previous studies have identified activin A to be of critical importance in MM-induced osteolysis. Lenalidomide is a known and approved treatment strategy for relapsed MM. Our findings demonstrate that lenalidomide acts directly on bone marrow stromal cells via an Akt-mediated increase in Jun N-terminal kinase-dependent signaling resulting in activin A secretion, with consequent inhibition of osteoblastogenesis. Here, we attempted to augment the antitumor benefits of lenalidomide while overcoming its effects on osteoblastogenesis by combining it with a neutralizing antibody to activin A. Increased activin A secretion induced by lenalidomide was abrogated by the addition of activin A-neutralizing antibody, which effectively restored osteoblast function and inhibited MM-induced osteolysis without negating the cytotoxic effects of lenalidomide on malignant cells. This provides the rationale for an ongoing clinical trial (NCT01562405) combining lenalidomide with an anti-activin A strategy.

The role of bone morphogenetic proteins in myeloma cell survival

“…[81,82] Lenalidomide treatment has been shown to cause activin A secretion by myeloma BMSC, providing a rationale for a combination treatment of lenalidomide with activin A inhibition. [83] TGF-β is abundant in the bone marrow of myeloma patients, and represses bone formation in osteolytic lesions. At first, TGF-β induces expansion of osteoblast progenitors and promotes bone mineralization.…”

A novel Bruton’s tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity

“…The BM microenvironment provides a permissive niche that enables myeloma cell growth; targeting the interactions within the bone microenvironment may represent an important strategy to suppress aberrant (or abnormal) plasma cell development. 12,[15][16][17] Given the role of the BM microenvironment in MM, new drugs (or treatment combinations) that target abnormal plasma cells and the BM microenvironment represent an exciting treatment strategy for patients with MM.…”

Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease

“…(8,9) Moreover, the BM microenvironment provides a permissive niche for MM cell growth, and targeting the interactions within the bone milieu represents an important strategy to suppress MM progression. (10)(11)(12)(13) Typically, the bone niche in MM has increased osteolytic activity with impaired/suppressed osteoblastic activity. This niche serves as a sanctuary site for the growth and proliferation of MM cells, resulting in homing of tumor, progression of disease, and development of drug resistance.…”

“…This underscores the importance of understanding the OB axis and targeting it with therapeutic intent. (10,(13)(14)(15)(16)(17) Sclerostin, encoded by the SOST gene, is a small glycoprotein secreted by osteocytes. (18)(19)(20) Sclerostin blocks canonical Wnt signaling by binding to LRP5 and LRP6, Wnt coreceptors on the surface of OBs.…”