Why do we not have more drugs approved for MDS? A critical viewpoint on novel drug development in MDS.

Approval of new agents to treat higher risk (HR) myelodysplastic syndrome (MDS) has stalled since the approval of DNA methyltransferase inhibitors (DNMTi). In addition, the options for patients with lower risk (LR) MDS who have high transfusion needs and do not harbor ring sideroblasts or 5q- syndrome are limited. Here, we review the current treatment landscape in MDS and identify areas of unmet need, such as treatment after failure of erythropoiesis-stimulating agents or DNMTis, TP53-mutated disease, and MDS with potentially targetable mutations. We discuss how our understanding of MDS pathogenesis can inform therapy development, including treating HR-MDS similarly to AML and pursuing therapies to address splicing factor mutations and dysregulated inflammation. We then bring a critical lens to current methodology of MDS studies and propose solutions to improve the efficiency and yield of these clinical trials, including using the most meaningful response metrics and expanding enrollment.
Competing Interests: Declaration of Competing Interest M.S. has consulted for Curis Oncology and Boston Consulting and is a member of the advisory boards for Novartis, Kymera, GSK and Sierra Oncology. R.M.S. reports support from AbbVie, AbbVie/Genentech, Actinium, Aprea, Arog, AvenCell, BerGenBio, BMS, Boston Pharmaceuticals, CTI Pharma, Elevate Bio, Foghorn Therapeutics, Gemoab, GSK, Innate, Janssen, Jazz, Kura Onc, Novartis, and Syros (Advisory Boards) and from Aptevo, Syntrix/ACI Clinical, Epizyme and Takeda (DSMB). D.J.D. has received funding/grant support from AbbVie, Blueprint Medicines, GlycoMimetics, and Novartis and honoraria or consulting fees from Amgen, Astella, Bristol-Myers Squibb, Blueprint Medicines, Gilead, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. A.M.Z. is a Leukemia and Lymphoma Society Scholar in Clinical Research. A.M.Z. received research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. A.M.Z. served on clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, ALX Oncology, Geron and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology.
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