{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:10:25Z","timestamp":1790071825405,"version":"4.0.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>The approach to the management of smoldering multiple myeloma has changed over the years, which has evolved from observation towards early therapeutic intervention. Yet, a comprehensive examination of several key clinical trials reveals methodological challenges and limitations, ranging from inconsistent risk stratification of SMM to biased interpretations of results due to artifactual inflation of benefit arising from lead-time bias. Intervention for patients with a largely asymptomatic disease needs to be re-assessed carefully, where toxicities arising from treatment are not well justified. Until a more precise risk stratification is developed, the principle of \u201cprimum non nocere\u201d (first, do no harm) should curb enthusiasm for early intervention in a condition in which a substantial number of patients will remain progression-free without treatment.<\/jats:p>","DOI":"10.3389\/fonc.2026.1834686","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:53:58Z","timestamp":1790070838000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Primum non nocere: a critical analysis of early intervention clinical trials in smoldering multiple myeloma"],"prefix":"10.3389","volume":"16","author":[{"given":"Harsh","family":"Parmar","sequence":"first","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noa","family":"Biran","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Phull","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Doucette","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Di Palma-Grissi","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Franz","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vesole","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Siegel","sequence":"additional","affiliation":[{"name":"Division of Multiple Myeloma, Department of Oncology, John Theurer Cancer Center at Hackensack University Medical Center","place":["Hackensack, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v56.3.521.bloodjournal563521","article-title":"Localized and indolent myeloma","volume":"56","author":"Alexanian","year":"1980","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejm198006123022405","article-title":"Smoldering multiple myeloma","volume":"302","author":"Kyle","year":"1980","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021011670","article-title":"How I approach smoldering multiple myeloma","volume":"140","author":"Vaxman","year":"2022","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2014.04.012","article-title":"The road to treating smoldering multiple myeloma","volume":"14","author":"Korde","year":"2014","journal-title":"Clin Lymphoma Myeloma Leukemia"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-021-00623-7","article-title":"Progress in the management of smoldering multiple myeloma","volume":"16","author":"Schmidt","year":"2021","journal-title":"Curr Hematol Malignancy Rep"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cells11010130","article-title":"Risk stratification and treatment in smoldering multiple myeloma","volume":"11","author":"Lussier","year":"2022","journal-title":"Cells"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018021220","article-title":"POINT timing of treatment of smoldering myeloma: Early treatment","volume":"2","author":"Mateos","year":"2018","journal-title":"Blood Adv"},{"key":"B8","article-title":"Curative strategy for high-risk smoldering myeloma (GEM-CESAR): Carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with Krd and maintenance with Rd","volume":"130","author":"Mateos","year":"2017","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-142584","article-title":"Aggressive smoldering curative approach evaluating novel therapies (ASCENT): A phase 2 trial of induction, consolidation and maintenance in subjects with high risk smoldering multiple myeloma (SMM): Initial analysis of safety data","volume":"136","author":"Kumar","year":"2020","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70442-5","article-title":"International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma","volume":"15","author":"Rajkumar","year":"2014","journal-title":"Lancet Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2012.309","article-title":"Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease","volume":"27","author":"Kastritis","year":"2013","journal-title":"Leukemia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2012.296","article-title":"Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma","volume":"27","author":"Larsen","year":"2013","journal-title":"Leukemia"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.101910","article-title":"SLiM CRAB criteria revisited: Temporal trends in prognosis of patients with smoldering multiple myeloma who meet the definition of \u2018biomarker-defined early multiple myeloma\u2019\u2014a systematic review with meta-analysis","volume":"58","author":"Ludwig","year":"2023","journal-title":"EClinicalMedicine"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/jco.19.01740","article-title":"Randomized trial of lenalidomide versus observation in smoldering multiple myeloma","volume":"38","author":"Lonial","year":"2020","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(16)30124-3","article-title":"Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): Long-term follow-up of a randomised, controlled, phase 3 trial","volume":"17","author":"Mateos","year":"2016","journal-title":"Lancet Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2021.3971","article-title":"Carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance for prevention of symptomatic multiple myeloma in patients with high-risk smoldering myeloma: A phase 2 nonrandomized controlled trial","volume":"7","author":"Kazandjian","year":"2021","journal-title":"JAMA Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0718-z","article-title":"Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: A randomized, open-label, multicenter, phase 2 study (CENTAURUS)","volume":"34","author":"Landgren","year":"2020","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2013.764419","article-title":"Modeling progression risk for smoldering multiple myeloma: Results from a prospective clinical study","volume":"54","author":"Cherry","year":"2013","journal-title":"Leukemia Lymphoma"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2022.2068008","article-title":"Smoldering multiple myeloma: Reviewing the rationale for intervention","volume":"63","author":"Gertz","year":"2022","journal-title":"Leukemia Lymphoma"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-05-088443","article-title":"New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells","volume":"110","author":"P\u00e9rez-Persona","year":"2007","journal-title":"Blood"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-108357","article-title":"Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma","volume":"111","author":"Dispenzieri","year":"2008","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-018-0077-4","article-title":"Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria","volume":"8","author":"Lakshman","year":"2018","journal-title":"Blood Cancer J"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-020-00366-3","article-title":"International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)","volume":"10","author":"Mateos","year":"2020","journal-title":"Blood Cancer J"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/s2352-3026(22)00386-6","article-title":"Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): A retrospective, multicohort study","volume":"10","author":"Cowan","year":"2023","journal-title":"Lancet Haematol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2409029","article-title":"Daratumumab or active monitoring for high-risk smoldering multiple myeloma","volume":"392","author":"Dimopoulos","year":"2025","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-168930","article-title":"Fixed duration therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone for high risk smoldering multiple myeloma-results of the Ascent trial","volume":"140","author":"Kumar","year":"2022","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2023.41.16_suppl.8046","article-title":"ISAMAR: Multicenter phase II single arm trial of isatuximab (ISA) with\/without lenalidomide (LEN) in pts with high risk smoldering multiple myeloma (HRSMM)","volume":"41","author":"Manasanch","year":"2023","journal-title":"J Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1182\/blood-2024-202676","article-title":"Early safety and efficacy of CAR-T cell therapy in precursor myeloma: Results of the CAR-PRISM study using ciltacabtagene autoleucel in high-risk smoldering myeloma","volume":"1027","author":"Nadeem","year":"2024","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.00437","article-title":"Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression","volume":"38","author":"Bustoros","year":"2020","journal-title":"J Clin Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2023.12.001","article-title":"Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma","volume":"99","author":"Kumar","year":"2024","journal-title":"Am J Hematol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-181817","article-title":"Genomic profiling to interpret the outcomes of early intervention for high-risk smoldering myeloma","volume":"142","author":"Diamond","year":"2023","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30694-w","article-title":"Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes","volume":"13","author":"Bustoros","year":"2022","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.060780","article-title":"Genomic analysis of high-risk smoldering multiple myeloma","volume":"97","author":"L\u00f3pez-Corral","year":"2012","journal-title":"Haematologica"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.124651","article-title":"Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG s0120)","volume":"100","author":"Khan","year":"2015","journal-title":"Haematologica"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-02-556308","article-title":"A phase 2 single-center study of carfilzomib 56 mg\/m2 with or without low-dose dexamethasone in relapsed multiple myeloma","volume":"124","author":"Lendvai","year":"2014","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-538835","article-title":"Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: A randomized phase 2 study","volume":"123","author":"Richardson","year":"2014","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)01120-4","article-title":"Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial","volume":"387","author":"Lonial","year":"2016","journal-title":"Lancet"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31594-X","article-title":"Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial","volume":"389","author":"Durie","year":"2017","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2017.31","article-title":"Carfilzomib-lenalidomide-dexamethasone vs lenalidomide- dexamethasone in relapsed multiple myeloma by previous treatment","volume":"7","author":"Dimopoulos","year":"2017","journal-title":"Blood Cancer J"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v130.suppl_1.739.739","article-title":"Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Updated efficacy and safety analysis of Pollux","volume":"130","author":"Dimopoulos","year":"2017","journal-title":"Blood"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-021-08544-7","article-title":"Trends in survival from myeloma, 1990\u20132015: A competing risks analysis","volume":"21","author":"Sneyd","year":"2021","journal-title":"BMC Cancer"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.380","article-title":"Trends in overall survival and costs of multiple myeloma, 2000-2014","volume":"31","author":"Fonseca","year":"2017","journal-title":"Leukemia"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2018.01.015","article-title":"Trends of incidence, mortality, and survival of multiple myeloma in Switzerland between 1994 and 2013","volume":"53","author":"Andres","year":"2018","journal-title":"Cancer Epidemiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2020.1827253","article-title":"Trends in the multiple myeloma treatment landscape and survival: A U.S. analysis using 2011\u20132019 oncology clinic electronic health record data","volume":"62","author":"Braunlin","year":"2021","journal-title":"Leuk Lymphoma"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13537","article-title":"Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century","volume":"171","author":"Pulte","year":"2015","journal-title":"Br J Haematol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1834686\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:53:59Z","timestamp":1790070839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1834686\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":45,"alternative-id":["10.3389\/fonc.2026.1834686"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1834686","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"article-number":"1834686"}}