Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen

Abstract

Mesenchymal stem/stromal cells (MSCs) are self-renewing and multipotent progenitors, which constitute the main cellular compartment of the bone marrow stroma. Because MSCs have an important role in the pathogenesis of multiple myeloma, it is essential to know if novel drugs target MSCs. Melflufen is a novel anticancer peptide–drug conjugate compound for patients with relapsed refractory multiple myeloma. Here, we studied the cytotoxicity of melflufen, melphalan and doxorubicin in healthy human bone marrow-derived MSCs (BMSCs) and how these drugs affect BMSC proliferation. We established co-cultures of BMSCs with MM.1S myeloma cells to see if BMSCs increase or decrease the cytotoxicity of melflufen, melphalan, bortezomib and doxorubicin. We evaluated how the drugs affect BMSC differentiation into adipocytes and osteoblasts and the BMSC-supported formation of vascular networks. Our results showed that BMSCs were more sensitive to melflufen than to melphalan. The cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, as was the case for melphalan, bortezomib and doxorubicin. Adipogenesis, osteogenesis and BMSC-mediated angiogenesis were all affected by melflufen. Melphalan and doxorubicin affected BMSC differentiation in similar ways. The effects on adipogenesis and osteogenesis were not solely because of effects on proliferation, seen from the differential expression of differentiation markers normalized by cell number. Overall, our results indicate that melflufen has a significant impact on BMSCs, which could possibly affect therapy outcome.

Anti-Angiogenic Activity of Drugs in Multiple Myeloma

“…Furthermore, it also reduces VEGF-induced migration of MM cells through transwell insert without affecting their viability, suggesting that cell homing and metastatization are halted [ 113 ]. Gebraad and collaborators [ 114 ] showed that BMSCs are sensitive to mel-flufen, abrogating their protective effect on MM cells and affecting BMSCs-mediated angiogenesis. Accordingly, mel-flufen inhibits angiogenesis of HUVEC co-cultured with BMSCs through the reduction of ECs sproutings and of α-SMA-positive pericytes [ 114 ] ( Figure 2 g).…”

“…Gebraad and collaborators [ 114 ] showed that BMSCs are sensitive to mel-flufen, abrogating their protective effect on MM cells and affecting BMSCs-mediated angiogenesis. Accordingly, mel-flufen inhibits angiogenesis of HUVEC co-cultured with BMSCs through the reduction of ECs sproutings and of α-SMA-positive pericytes [ 114 ] ( Figure 2 g). Mel-flufen, in combination with dexamethasone, significantly improved MM patients’ overall survival and was approved for relapsed/refractory patients resistant to proteasome inhibitors, IMiDs, and anti-CD38 mAbs (NCT02963493).…”