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Acute dexamethasone-related toxicities such as insomnia or pedal edema, even if low-grade by clinical criteria, can significantly interfere with patient quality of life. In the past 5 years, several trials have demonstrated the efficacy and improved tolerability of corticosteroid-sparing regimens in MM. In this review, we discuss these and other studies to comprehensively assess the role of dexamethasone in the modern era. In newly diagnosed MM, robust data support planned dexamethasone discontinuation after one to two cycles in older and frailer patients. In the maintenance setting, the risk-benefit ratio of prolonged dexamethasone is unfavorable. While randomized trials have shown that once-weekly dexamethasone adds value within doublet regimens in relapsed\/refractory MM, its contribution to triplet and quadruplet regimens is uncertain. Furthermore, data suggest that indefinite dexamethasone may actually limit the feasibility and efficacy of subsequent postprogression therapies. In AL amyloidosis, dexamethasone 40 mg once weekly for 6 months is excessive and may predispose patients to volume overload. In our review, we also discuss dexamethasone as a premedication for CD38-targeted monoclonal antibodies (where it is no longer required after one to two cycles) and for supportive care (where lower doses of 4-8 mg as needed can often suffice). Despite the historical inertia of corticosteroid-containing regimens in clinical trials and practice guidelines, corticosteroid-sparing regimens warrant prospective investigation across the gamut of plasma cell disorders.<\/jats:p>","DOI":"10.1200\/jco-25-01713","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:00:36Z","timestamp":1769547636000},"page":"903-913","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Past, Present, and Future of Dexamethasone in Multiple Myeloma and AL Amyloidosis"],"prefix":"10.1200","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-5441","authenticated-orcid":true,"given":"Rahul","family":"Banerjee","sequence":"first","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"King","sequence":"additional","affiliation":[{"name":"Royal Prince Alfred Hospital, NSW, Sydney, Australia"},{"name":"University of Sydney, Faculty of Medicine and Health, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8153-0438","authenticated-orcid":true,"given":"Beth","family":"Faiman","sequence":"additional","affiliation":[{"name":"Taussig Cancer Center, Cleveland Clinic, Cleveland, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0925-221X","authenticated-orcid":true,"given":"Susie","family":"Harding","sequence":"additional","affiliation":[{"name":"HonorHealth Research Institute, Scottsdale, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0714-734X","authenticated-orcid":true,"given":"Aaron S.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"University of California Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6307-2445","authenticated-orcid":true,"given":"Vaishali","family":"Sanchorawala","sequence":"additional","affiliation":[{"name":"Amyloidosis Center, Boston Medical Center and Boston University Chobanian &amp; Avedisian School of Medicine, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Mikhael","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute (TGen), City of Hope, Phoenix, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1880-7094","authenticated-orcid":true,"given":"Andrew J.","family":"Cowan","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2152-2650(24)01895-0"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-200210"},{"key":"e_1_3_6_4_2","unstructured":"SWOG Cancer Research Network: S2213: A phase III randomized study of daratumumab cyclophosphamide bortezomib and dexamethasone (Dara-VCD) induction followed by autologous stem cell transplant or Dara-VCD consolidation and daratumumab maintenance in patients with newly diagnosed AL amyloidosis. https:\/\/www.swog.org\/clinical-trials\/s2213"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.soncn.2025.151943"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1588"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70284-0"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(25)00280-3"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009507"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2006.06405.x"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-538835"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008209"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.278655"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2312054"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003454"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024026814"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195005252422105"},{"key":"e_1_3_6_18_2","first-page":"257","article-title":"A comparison of the effect of prednisone and a placebo in the treatment of multiple myeloma","volume":"16","author":"Mass RE","year":"1962","unstructured":"Mass RE: A comparison of the effect of prednisone and a placebo in the treatment of multiple myeloma. 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