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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\u2013drug 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.<\/jats:p>","DOI":"10.3390\/cells11091574","type":"journal-article","created":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T08:04:21Z","timestamp":1651997061000},"page":"1574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem\/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-237X","authenticated-orcid":false,"given":"Arjen","family":"Gebraad","sequence":"first","affiliation":[{"name":"Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roope","family":"Ohlsbom","sequence":"additional","affiliation":[{"name":"Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3987-1693","authenticated-orcid":false,"given":"Juho J.","family":"Miettinen","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland-FIMM, HiLIFE\u2013Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2546-3816","authenticated-orcid":false,"given":"Promise","family":"Emeh","sequence":"additional","affiliation":[{"name":"Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toni-Karri","family":"Pakarinen","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal Diseases, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikko","family":"Manninen","sequence":"additional","affiliation":[{"name":"Orton Orthopaedic Hospital, 00280 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti","family":"Eskelinen","sequence":"additional","affiliation":[{"name":"Coxa Hospital for Joint Replacement, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsi","family":"Kuismanen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Slipicevic","sequence":"additional","affiliation":[{"name":"Oncopeptides AB, 111 37 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7385-3870","authenticated-orcid":false,"given":"Fredrik","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Oncopeptides AB, 111 37 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina N.","family":"Nupponen","sequence":"additional","affiliation":[{"name":"Oncopeptides AB, 111 37 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4324-8706","authenticated-orcid":false,"given":"Caroline A.","family":"Heckman","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland-FIMM, HiLIFE\u2013Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Miettinen","sequence":"additional","affiliation":[{"name":"Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Research, Development and Innovation Centre, Tampere University Hospital, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1038\/leu.2017.138","article-title":"Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: A multicenter IMWG study","volume":"31","author":"Kumar","year":"2017","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.celrep.2019.06.031","article-title":"Mapping Distinct Bone Marrow Niche Populations and Their Differentiation Paths","volume":"28","author":"Wolock","year":"2019","journal-title":"Cell 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