Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group

Laubach, Jacob P.; Garderet, Laurent; Mahindra, Anuj; Gahrton, Goesta; Caers, Jo; Sezer, Orhan; Voorhees, Peter M.; Leleu, Xavier; Johnsen, Hans Erik; Streetly, Matthew; Jurczyszyn, Artur; Ludwig, Heinz; Mellqvist, Ulf‐Henrik; Chng, Wee Joo; Pilarski, Linda M.; Einsele, Hermann; Hou, Jian; Turesson, Ingemar; Zamagni, Elena; Chim, Chor Sang; Mazumder, Amitabha; Westin, Jan; Lu, Jiachuan; Reiman, Tony; Kristinsson, Sigurður Y.; Joshua, Douglas; Roussel, Murielle; O’Gorman, Peter; Terpos, Evangelos; McCarthy, Philip L.; Dimopoulos, Meletios A.; Moreau, Philippe; Orłowski, Robert Z.; Miguel, Jesús San; Anderson, Kenneth C.; Palumbo, Antônio; Kumar, Shaji; Rajkumar, Vincent; Durie, Brian G.M.; Richardson, Paul G.

doi:10.1038/leu.2015.356

Cited by 204 publications

(183 citation statements)

References 125 publications

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“…Although recent progress in understanding the biology of MM and developing novel agents and strategies, the prognosis of majority of MM patients remains poor, and resistance to chemotherapy frequently occurs [1–3]. Recent studies have focused on exploring the combinations of multiple agents and their mechanisms in regulation of aberrant signaling pathways [4], with a hope to identify novel strategies overcoming chemotherapy resistance for the treatment of MM.…”

Section: Introductionmentioning

confidence: 99%

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

et al. 2018

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Cladribine (2CdA), a synthetic purine analog interfering with DNA synthesis, is a medication used to treat hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, shows antitumor activity in various human cancers, including hematological malignancies. The therapeutic potential of cladribine and entinostat against multiple myeloma (MM) remains unclear. Here we investigate the combinatorial effects of cladribine and entinostat within the range of their clinical achievable concentrations on MM cells. While either agent alone inhibited MM cell proliferation in a dose-dependent manner, their combinations synergistically induced anti-proliferative/anti-survival effects on all MM cell lines (RPMI8226, U266, and MM1.R) tested. Further studies showed that the combinations of cladribine and entinostat as compared to either agent alone more potently induced mitotic catastrophe in the MM cells, and resulted in a marked increase of the cells at G1 phase associated with decrease of Cyclin D1 and E2F-1 expression and upregulation of p21waf−1. Apoptotic ELISA and western blot analyses revealed that the combinations of cladribine and entinostat exerted a much more profound activity to induce apoptosis and DNA damage response, evidenced by enhanced phosphorylation of histone H2A.X and the DNA repair enzymes Chk1 and Chk2. Collectively, our data demonstrate that the combinations of cladribine and entinostat exhibit potent activity to induce anti-proliferative/anti-survival effects on MM cells via induction of cell cycle G1 arrest, apoptosis, and DNA damage response. Regimens consisting of cladribine and/or entinostat may offer a new treatment option for patients with MM. Abbreviations: MM, multiple myeloma; HCL, hairy cell leukemia; HDAC, histone deacetylase; Ab, antibody; mAb, monoclonal Ab; FBS, fetal bovine serum; CI, combination index; PAGE, polyacrylamide gel electrophoresis; ELISA, enzyme-linked immunosorbent assay; PARP, poly(ADP-ribose) polymerase; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt

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Section: Introductionmentioning

confidence: 99%

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

et al. 2018

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“…In the treatment algorithm, a second autologous transplant should be discussed. IMWG has recommended a guideline to treat these cases [17].…”

Section: Management Of Relapsed Myeloma [16]mentioning

confidence: 99%

Developments in the Field of Myeloma in the Last Decade

Saikia

2017

Indian J Hematol Blood Transfus

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The plasma cell disorders constitute a heterogeneous group of diseases. Accumulation of knowledge in the field has helped us to understand these diseases better, stage them more precisely, prognosticate more accurately and manage them more effectively. The paradigm shift in the management of multiple myeloma over the last oneand-a-half decades shows no signs of slackening. In addition to novel therapies, better supportive care and highdose melphalan with autologous hematopoietic stem cells have contributed to this positive outcome. This review summarizes the developments in this sphere in the recent past.

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“…[ 2 ; intravenous bolus or subcutaneous injection). Median progression-free survival was superior in the carfilzomib group compared to the bortezomib group (18.7 months vs. 9.4 months).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Treatment options for relapse after autograft in multiple myeloma – report from an EBMT educational meeting

Garderet

Cook

Auner

et al. 2016

Leukemia & Lymphoma

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Major improvements have been made in the treatment of myeloma. However, all patients, perhaps with some exceptions, eventually relapse, even after autologous stem cell transplantation (ASCT). In that setting, the combinations of new drugs, namely the IMiDs and the proteasome inhibitors along with steroids, give encouraging results in relapsed patients. The median progression-free survival (PFS) is 20 months with lenalidomide plus dexamethasone plus ixazomib and 26 months with lenalidomide plus dexamethasone plus carfilzomib. Monoclonal antibodies have emerged as an additional new treatment option. The antibody anti-SLAMF7, elotuzumab, in combination with lenalidomide plus dexamethasone gives a median PFS of 20 months. The antibody daratumumab, targeting CD38, alone has an outstanding activity in previously heavily treated patients. Its use in combination is ongoing. Transplantation remains a major treatment option. For patients who relapse at least 18 months from the initial ASCT, a second ASCT can be performed with an expected time to progression of 19 months from the time of transplantation. For patients relapsing earlier and/or with high-risk characteristics and who are still chemosensitive, with a suitable donor, an allogeneic transplantation can be considered. The optimal treatment combination and sequence remain to be determined.

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Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group

Cited by 204 publications

References 125 publications

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

Developments in the Field of Myeloma in the Last Decade

Treatment options for relapse after autograft in multiple myeloma – report from an EBMT educational meeting

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