According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of "monoclonal gammopathy of undetermined significance-like", in which patients never progress during their lifetimes, to "early multiple myeloma", in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a "split personality" makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.

Aldo Moro University School of Medicine Unit of Hematology and Stem Cell Transplantation AOUC Policlinico Bari

Amsterdam UMC Vrije Universiteit Amsterdam Department of Hematology Cancer Center Amsterdam Amsterdam

Amyloidosis and Myeloma Unit Department of Hematology Hospital Clínic IDIBAPS University of Barcelona Barcelona

Department of Clinical Hematology CHU of Liège Liège Belgium; Laboratory of Hematology GIGA I3 University of Liège Liège

Department of Hemato oncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology Rigshospitalet Copenhagen

Department of Medicine 1 Medical Center University of Freiburg Freiburg Faculty of Medicine University of Freiburg

Division of Hematology Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano Italy; Department of Oncology and Onco Hematology University of Milan Milano

Erasmus MC Cancer Institute and Erasmus University of Rotterdam Rotterdam

Fondazione IRCCS Policlinico S Matteo Pavia

Myeloma Unit Division of Hematology University of Torino Azienda Ospedaliero Universitaria Città della Salute e della Scienza Torino

National and Kapodistrian University of Athens School of Medicine Department of Clinical Therapeutics Athens

Seràgnoli Institute of Hematology Bologna University School of Medicine Bologna

Stem Cell Transplantation Unit Plasma Cell Dyscrasias Unit Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Alexandra General Hospital Athens

The Institute of Cancer Research Division of Molecular Pathology London UK; The Royal Marsden Hospital Department of Haematology London

Universidad de Navarra CIMA IDISNA CIBERONC Pamplona

University Hospital Heidelberg Internal Medicine 5 and National Center for Tumor Diseases Heidelberg

University Hospital of Salamanca IBSAL CIC IBMCC Salamanca

University Hospital Würzburg Internal Medicine 2 Würzburg

Wilhelminen Cancer Research Institute 1st Department of Medicine Center for Oncology Hematology and Palliative Care Wilhelminenspital Vienna

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Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302(24):1347-1349. PubMed

Kyle RA, Child JA, Anderson K, et al. . Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121(5):749-757. PubMed

Rajkumar SV, Dimopoulos MA, Palumbo A, et al. . International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. PubMed

Caers J, Fernández de Larrea C, Leleu X, et al. . The changing landscape of smoldering multiple myeloma: a European perspective. Oncologist. 2016;21(3):333-342. PubMed PMC

Ravindran A, Bartley AC, Holton SJ, et al. . Prevalence, incidence and survival of smoldering multiple myeloma in the United States. Blood Cancer J 2016;6(10):e486. PubMed PMC

Kyle RA, Remstein ED, Therneau TM, et al. . Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590. PubMed

Rajkumar SV, Landgren O, Mateos M-V. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075. PubMed PMC

Lonial S, Dhodapkar MV, Rajkumar SV. Smoldering myeloma and the art of war. J Clin Oncol. 2020;38(21):2363-2365. PubMed

Ahn IE, Mailankody S, Korde N, Landgren O. Dilemmas in treating smoldering multiple myeloma. J Clin Oncol. 2015;33(1):115-123. PubMed PMC

Fonseca R, Gonzalez-Velez M. Treatment of smoldering multiple myeloma: expectant observation should still be the standard. Am Soc Clin Oncol Educ Book. 2020;40:1-7. PubMed

Joseph NS, Dhodapkar MV, Lonial S. The role of early intervention in high-risk smoldering myeloma. Am Soc Clin Oncol Educ Book. 2020;40:1-9. PubMed

Biran N, Vesole DH, Donato ML, et al. . Treatment of smoldering myeloma: problems with study design as well as biological and clinical implications. J Clin Oncol. 2020;38(12):1367-1368. PubMed

Ho M, Patel A, Goh CY, Moscvin M, Zhang L, Bianchi G. Changing paradigms in diagnosis and treatment of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) Leukemia. 2020;34(12):3111-3125. PubMed

Goodman AM, Kim MS, Prasad V. Persistent challenges with treating multiple myeloma early. Blood. 2021;137(4):456-458. PubMed

Bolli N, Sgherza N, Curci P, et al. . What Is new in the treatment of smoldering multiple myeloma? J Clin Med. 2021;10(3):421. PubMed PMC

Landgren O, Kyle RA, Pfeiffer RM, et al. . Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412-5417. PubMed PMC

Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12(5):335-348. PubMed

Boyle EM, Deshpande S, Tytarenko R, et al. . The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma. Nat Commun. 2021;12(1):293. PubMed PMC

Neben K, Jauch A, Hielscher T, et al. . Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol. 2013;31(34):4325-4332. PubMed

Zandecki M, Laï JL, Geneviève F, et al. . Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood. 1997;90(9):3682-3690. PubMed

Drach J, Angerler J, Schuster J, et al. . Interphase fluorescence in situ hybridization identifies chromosomal abnormalities in plasma cells from patients with monoclonal gammopathy of undetermined significance. Blood. 1995;86(10):3915-3921. PubMed

Oliva S, De Paoli L, Ruggeri M, et al. . A longitudinal analysis of chromosomal abnormalities in disease progression from MGUS/SMM to newly diagnosed and relapsed multiple myeloma. Ann Hematol. 2021;100(2):437-443. PubMed

Mailankody S, Kazandjian D, Korde N, et al. . Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma. Blood Adv. 2017;1(22):1911-1918. PubMed PMC

Mikulasova A, Wardell CP, Murison A, et al. . The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica. 2017;102(9):1617-1625. PubMed PMC

Bolli N, Maura F, Minvielle S, et al. . Genomic patterns of progression in smoldering multiple myeloma. Nat Commun. 2018;9(1):3363. PubMed PMC

Ledergor G, Weiner A, Zada M, et al. . Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med. 2018;24(12):1867-1876. PubMed

Walker BA, Wardell CP, Melchor L, et al. . Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014;28(2):384-390. PubMed PMC

Zhao S, Choi M, Heuck C, et al. . Serial exome analysis of disease progression in premalignant gammopathies. Leukemia. 2014;28(7):1548-1552. PubMed PMC

Dutta AK, Fink JL, Grady JP, et al. . Subclonal evolution in disease progression from MGUS/SMM to multiple myeloma is characterised by clonal stability. Leukemia. 2019;33(2):457-468. PubMed PMC

Da Vià MC, Ziccheddu B, Maeda A, Bagnoli F, Perrone G, Bolli N. A journey through myeloma evolution: from the normal plasma cell to disease complexity. Hemasphere. 2020;4(6):e502. PubMed PMC

Misund K, Keane N, Stein CK, et al. . MYC dysregulation in the progression of multiple myeloma. Leukemia. 2020;34(1):322-326. PubMed PMC

Oben B, Froyen G, Maclachlan KH, et al. . Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities Nat Commun 2021 Mar 25;12(1):1861. PubMed PMC

Maura F, Degasperi A, Nadeu F, et al. . A practical guide for mutational signature analysis in hematological malignancies. Nat Commun. 2019;10(1):2969. PubMed PMC

Maura F, Petljak M, Lionetti M, et al. . Biological and prognostic impact of APOBEC-induced mutations in the spectrum of plasma cell dyscrasias and multiple myeloma cell lines. Leukemia. 2018;32(4): 1044-1048. PubMed PMC

Shah V, Johnson DC, Sherborne AL, et al. . Subclonal TP53 copy number is associated with prognosis in multiple myeloma. Blood. 2018;132(23):2465-2469. PubMed PMC

Manzoni M, Marchica V, Storti P, et al. . Application of next-generation sequencing for the genomic characterization of patients with smoldering myeloma. Cancers (Basel). 2020;12(5):1332. PubMed PMC

Manier S, Sacco A, Leleu X, Ghobrial IM, Roccaro AM. Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol. 2012;2012:157496. PubMed PMC

Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125(20):3049-3058. PubMed PMC

Nakamura K, Smyth MJ, Martinet L. Cancer immunoediting and immune dysregulation in multiple myeloma. Blood. 2020;136(24): 2731-2740. PubMed

Das R, Strowig T, Verma R, et al. . Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nat Med. 2016;22(11): 1351-1357. PubMed PMC

Zavidij O, Haradhvala NJ, Mouhieddine TH, et al. . Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat Cancer. 2020;1(5):493-506. PubMed PMC

Wu V, Moshier E, Leng S, et al. . Risk stratification of smoldering multiple myeloma: predictive value of free light chains and group-based trajectory modeling. Blood Adv. 2018;2(12):1470-1479. PubMed PMC

Hillengass J, Usmani S, Rajkumar SV, et al. . International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. Lancet Oncol. 2019;20(6):e302-e312. PubMed

Jamet B, Bailly C, Carlier T, et al. . Imaging of monoclonal gammapathy of undetermined significance and smoldering multiple myeloma. Cancers (Basel). 2020;12(2):486. PubMed PMC

Hillengass J, Moulopoulos LA, Delorme S, et al. . Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group. Blood Cancer J. 2017;7(8):e599. PubMed PMC

Gavriatopoulou M, Βoultadaki A, Koutoulidis V, et al. . The role of low dose whole body CT in the detection of progression of patients with smoldering multiple myeloma. Blood Cancer J. 2020;10(9):93. PubMed PMC

Wennmann M, Hielscher T, Kintzelé L, et al. . Spatial distribution of focal lesions in wholebody MRI and influence of MRI protocol on staging in patients with smoldering multiple myeloma according to the new SLiM-CRAB criteria. Cancers (Basel). 2020;12(9):2537. PubMed PMC

Cavo M, Terpos E, Nanni C, et al. . Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Lancet Oncol. 2017;18(4):e206-e217. PubMed

Kyle RA, Durie BGM, Rajkumar SV, et al. . Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121-1127. PubMed PMC

Cocito F, Mangiacavalli S, Ferretti VV, et al. . Smoldering multiple myeloma: the role of different scoring systems in identifying high-risk patients in real-life practice. Leuk Lymphoma. 2019;60(12):2968-2974. PubMed

Pérez-Persona E, Vidriales M-B, Mateo G, et al. . 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. Blood. 2007;110(7):2586-2592. PubMed

Dispenzieri A, Kyle RA, Katzmann JA, et al. . Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111(2):785-789. PubMed PMC

Waxman AJ, Mick R, Garfall AL, et al. . Classifying ultra-high risk smoldering myeloma. Leukemia. 2015;29(3):751-753. PubMed

Sørrig R, Klausen TW, Salomo M, et al. . Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study. Eur J Haematol. 2016;97(3):303-309. PubMed

Fernández de Larrea C, Isola I, Pereira A, et al. . Evolving M-protein pattern in patients with smoldering multiple myeloma: impact on early progression. Leukemia. 2018;32(6): 1427-1434. PubMed

González-Calle V, Dávila J, Escalante F, et al. . Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma. Leukemia. 2016;30(10):2026-2031. PubMed

Ravi P, Kumar S, Larsen JT, et al. . Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma. Blood Cancer J. 2016;6(7):e454. PubMed PMC

Bustoros M, Kastritis E, Sklavenitis-Pistofidis R, et al. . Bone marrow biopsy in low-risk monoclonal gammopathy of undetermined significance reveals a novel smoldering multiple myeloma risk group. Am J Hematol. 2019;94(5):E146-E149. PubMed

Sanoja-Flores L, Flores-Montero J, Garcés JJ, et al. . Next generation flow for minimallyinvasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). Blood Cancer J. 2018;8(12):117. PubMed PMC

Aljama MA, Sidiqi MH, Lakshman A, et al. . Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma. Blood Adv. 2018;2(22):3149-3154. PubMed PMC

Merz M, Hielscher T, Wagner B, et al. . Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia. 2014;28(9):1902-1908. PubMed

Zamagni E, Nanni C, Gay F, et al. . 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia. 2016;30(2):417-422. PubMed

Rajkumar SV, Gupta V, Fonseca R, et al. . Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013;27(8):1738-1744. PubMed PMC

Khan R, Dhodapkar M, Rosenthal A, et al. . Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120). Haematologica. 2015;100(9):1214-1221. PubMed PMC

Merz M, Hielscher T, Schult D, et al. . Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma. Leukemia. 2020;34(4):1192-1196. PubMed PMC

Visram A, Soof C, Rajkumar SV, et al. . Serum BCMA levels predict outcomes in MGUS and smoldering myeloma patients. Blood Cancer J. 2021;11(6):120. PubMed PMC

Dhodapkar MV, Sexton R, Waheed S, et al. . Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (swog s0120). Blood. 2014;123(1):78-85. PubMed PMC

Lakshman A, Rajkumar SV, Buadi FK, et al. . Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8(6):59. PubMed PMC

Mateos MV, Kumar S, Dimopoulos MA, et al. . International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;10(10):102. PubMed PMC

Hájek R, Sandecka V, Špička I, et al. . Identification of patients with smouldering multiple myeloma at ultra-high risk of progression using serum parameters: the Czech Myeloma Group model. Br J Haematol. 2020;190(2):189-197. PubMed

Bustoros M, Sklavenitis-Pistofidis R, Park J, et al. . Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression. J Clin Oncol. 2020;38(21):2380-2389. PubMed PMC

Zhao AL, Shen KN, Wang JN, Huo LQ, Li J, Cao XX. Early or deferred treatment of smoldering multiple myeloma: a metaanalysis on randomized controlled studies. Cancer Manag Res. 2019;11:5599-5611. PubMed PMC

Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I - a randomized study. Eur J Haematol. 2009;50(2):95-102. PubMed

Riccardi A, Ucci G, Luoni R, et al. . Treatment of multiple myeloma according to the extension of the disease: a prospective, randomised study comparing a less with a more aggressive cytostatic policy. Br J Cancer. 1994;70(6):1203-1210. PubMed PMC

Riccardi A, Mora O, Tinelli C, et al. . Longterm survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Br J Cancer. 2000;82(7): 1254-1260. PubMed PMC

Witzig TE, Laumann KM, Lacy MQ, et al. . A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013;27(1):220-225. PubMed PMC

Musto P, Petrucci MT, Bringhen S, et al. . A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer. 2008;113(7):1588-1595. PubMed

D'Arena G, Gobbi PG, Broglia C, et al. . Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma. 2011;52(5):771-775. PubMed

Brighton TA, Khot A, Harrison SJ, et al. . Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clin Cancer Res. 2019;25(13):3772-3775. PubMed

Mateos MV, Hernández MT, Giraldo P, et al. . Lenalidomide plus dexamethasone for highrisk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447. PubMed

Mateos MV, Hernández MT, Giraldo P, et al. . 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. Lancet Oncol. 2016;17(8):1127-1136. PubMed

Mateos M-V, Hernandez MT, Salvador C, et al. . Over ten years of follow-up for phase II trial in smoldering myeloma at high risk of progression to myeloma: sustained TTP and OS benefit with RD versus no treatment. Hemasphere. 2020;294867:EP950.

Paiva B, Mateos MV, Sanchez-Abarca LI, et al. . Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis. Blood. 2016;127(9):1151-1162. PubMed

Lonial S, Jacobus S, Fonseca R, et al. . Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020;38(11):1126-1137. PubMed PMC

Korde N, Roschewski M, Zingone A, et al. . Treatment with carfilzomib-lenalidomidedexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015;1(6):746-754. PubMed PMC

Kazandjian D, Hil E, Morrison C, et al. . Background:. Treatment of high risk (HR) smoldering multiple myeloma (SMM) with carfilzomib, lenalidomide, and dexamethasone (KRd) followed by lenalidomide maintenance (-R): a phase 2 clinical and correlative study. Blood. 2020;136(1):43-45.

Mateos M-V, Martinez-Lopez J, Rodriguez Otero P, et al. . Curative strategy (GEMCESAR) for high-risk smoldering myeloma (SMM): carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd. Blood. 2019;134(1):781.

Puig N, Contreras T, Paiva B, et al. . Analysis of treatment efficacy in the GEM-CESAR trial for high-risk smoldering multiple myeloma patients: comparison between the standard and IMWG MRD criteria and QIPMS including FLC (QIP-FLC-MS). J Clin Oncol. 2020;38(15):8512.

Mailankody S, Salcedo M, Tavitian E, et al. . Ixazomib and dexamethasone in high risk smoldering multiple myeloma: a clinical and correlative pilot study. J Clin Oncol. 2019;37(15):8051. PubMed

Bustoros M, Liu C, Reyes K, et al. . Phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in highrisk smoldering multiple myeloma. Blood. 2018;132(1):804. PubMed

Musto P, La Rocca F. Monoclonal antibodies in newly diagnosed and smoldering multiple myeloma: an updated review of current clinical evidence. Expert Rev Hematol. 2020;13(5):501-517. PubMed

Landgren CO, Chari A, Cohen YC, et al. . Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, openlabel, multicenter, phase 2 study (CENTAURUS). Leukemia. 2020;34(7):1840-1852. PubMed PMC

Rajkumar SV, Voorhees PM, Goldschmidt H, et al. . Randomized, open-label, phase 3 study of subcutaneous daratumumab (DARA SC) versus active monitoring in patients (Pts) with high-risk smoldering multiple myeloma (SMM): AQUILA. J Clin Oncol. 2018;36(15):TPS8062.

Kumar SK, Abdallah AO, Badros AZ, et al. . 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. Blood. 2020;136(1):35-36.

Nadeem O, Redd R, Stampleman LV, et al. . A phase II study of daratumumab in patients with high-risk MGUS and low-risk smoldering multiple myeloma: first report of efficacy and safety. Blood. 2019;134(1):1898.

Manasanch EE, Jagannath S, Lee HC, et al. . A multicenter phase II single arm trial of isatuximab in patients with high risk smoldering multiple myeloma (HRSMM). Blood. 2019;134(1):3116.

Jagannath S, Laubach J, Wong E, et al. . Elotuzumab monotherapy in patients with smouldering multiple myeloma: a phase 2 study. Br J Haematol. 2018;182(4):495-503. PubMed PMC

Liu C, Ghobrial IM, Bustoros M, et al. . Phase II trial of combination of elotuzumab, lenalidomide, and dexamethasone in highrisk smoldering multiple myeloma. Blood. 2018;132(1):154.

Manasanch EE, Han G, Mathur R, et al. . A pilot study of pembrolizumab in smoldering myeloma: report of the clinical, immune, and genomic analysis. Blood Adv. 2019;3(15):2400-2408. PubMed PMC

Nooka AK, Wang ML, Yee AJ, et al. . Assessment of safety and immunogenicity of PVX-410 vaccine with or without lenalidomide in patients with smoldering multiple myeloma: a nonrandomized clinical trial. JAMA Oncol. 2018;4(12):e183267. PubMed PMC

Hill E, Dew A, Morrison C, et al. . Assessment of discordance among smoldering multiple myeloma risk models. JAMA Oncol. 2021;7(1):132-134. PubMed PMC

Gran C, Luong V, Bruchfeld JB, et al. . Dynamic follow-up of smoldering multiple myeloma identifies a subset of patients at high risk of progression. Am J Hematol. 2021;96(3):E63-E65. PubMed PMC

Jean-Baptiste M, Gries KS, Lenderking WR, Fastenau J. Symptom burden and healthrelated quality of life impacts of smoldering multiple myeloma: the patient perspective. J Patient Rep Outcomes. 2020;4(1):95. PubMed PMC

Dimopoulos MA, Moreau P, Terpos E, et al. . Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322. PubMed

Marinac CR, Ghobrial IM, Birmann BM, Soiffer J, Rebbeck TR. Dissecting racial disparities in multiple myeloma. Blood Cancer J. 2020;10(2):19. PubMed PMC