High-Risk Myeloma: Definitions and Treatments


  • Rintu Sharma, MD Princess Margaret Cancer Center Division of Medical Oncology and Hematology Department of Medicine Temerty of Medicine, University of Toronto
  • Karla Alexandra Sánchez Hernández, MD Princess Margaret Cancer Centre, Toronto, Ontario
  • Guido Lancman, MD, MSc




Multiple myeloma is characterized by clonal proliferation of biologically heterogeneous plasma cells, leading to diverse clinical presentations and outcomes. Although outcomes have improved dramatically over the past decade with the rapid change in the treatment paradigm in standard-risk myeloma, a subset of patients remains who respond poorly to treatment and experience early relapses. These patients are considered high-risk and can be identified at the time of diagnosis based on several factors and their response to treatment (Table 1). Therefore, it is important to consider high-risk status as a dynamic assessment. 

Author Biographies

Rintu Sharma, MD, Princess Margaret Cancer Center Division of Medical Oncology and Hematology Department of Medicine Temerty of Medicine, University of Toronto

Rintu Sharma is a Clinical Research Fellow focusing on myeloma, lymphoma, and autologous stem cell transplantation. She has completed her internal medicine and hematology training in India and is now a Chief Fellow for the Malignant Hematology Program. Her areas of interest span multiple myeloma, amyloidosis, lymphoproliferative disorders, and cellular therapies. She is particularly intrigued by the potential of immunotherapies in myeloma and is eager to contribute to this exciting field.

Karla Alexandra Sánchez Hernández, MD, Princess Margaret Cancer Centre, Toronto, Ontario

Karla Alexandra Sánchez Hernández is a multiple myeloma clinical and research fellow at Princess Margaret Cancer Centre. She initially undertook her medical training at Mexico's National University. Thereafter she pursued residency training in Internal Medicine and subspecialty training in Hematology at Mexico's City General Hospital. She also has a fellowship at hematologic stem cell transplantation at Mexico's National Cancer Institute.

Guido Lancman, MD, MSc

Guido Lancman is a clinical associate at the Princess Margaret Cancer Centre and adjunct Assistant Professor in the Department of Medicine at the University of Toronto. Prior to coming to Toronto, he obtained his M.D. at the Icahn School of Medicine at Mount Sinai in New York, and his M.Sc. in Clinical Trials with distinction at University College London in the UK. He completed his Internship and Residency in Internal Medicine, as well as his Fellowship in Hematology and Medical Oncology at Mount Sinai. Dr. Lancman was involved in research throughout his training, receiving the Mount Sinai Summer Research Scholars Award in medical school, the SOHO Young Investigator Travel Award in residency, and obtaining funding for two investigator-initiated studies during his fellowship. His research has focused on optimizing the efficacy and safety of novel therapies in multiple myeloma, with a particular interest in immunotherapies. He is involved in the development of multiple myeloma clinical trials through Princess Margaret and through the Canadian Myeloma Research Group. 


Moore, K.L.F., Turesson, I., Genell, A., Klausen, T.W., Knut-Bojanowska, D., Redder, L., et al. (2022). Improved survival in myeloma patients–a nationwide registry study of 4,647 patients ≥75 years treated in Denmark and Sweden. Haematologica, 108(6), 1640–1651. doi: 10.3324/haematol.2021.282251.

Kazmi, S.M., Nusrat, M., Gunaydin, H., Cornelison, A.M., Shah, N., Kebriaei, P., et al. (2015). Outcomes Among High-Risk and Standard-Risk Multiple Myeloma Patients Treated with High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation. Clinical Lymphoma Myeloma Leukemia, 15(11), 687–693.

Greipp, P.R., San Miguel, J., Durie, B.G.M., Crowley, J.J., Barlogie, B., Bladé, J., et al. (2005). International staging system for multiple myeloma. Journal of Clinical Oncology, 23(15), 3412–3420.

Palumbo, A., Avet-Loiseau, H., Oliva, S., Lokhorst, H.M., Goldschmidt, H., Rosinol, L., et al. (2015). Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. Journal of Clinical Oncology, 33(26), 2863–2869.

Stewart, A.K., Bergsagel, P.L., Greipp, P.R., Dispenzieri, A., Gertz, M.A., Hayman, S.R., et al. (2007). A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia, 21(3), 529–534.

D’Agostino, M., Cairns, D.A., Lahuerta, J.J., Wester, R., Bertsch, U., Waage, A., et al. (2022). Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. Journal of Clinical Oncology, 40(29), 3406–3418.

mSMART [Internet]. [cited 2024 Apr 17]. mSMART. Available from: https://www.msmart.org

Schavgoulidze, A., Talbot, A., Perrot, A., Cazaubiel, T., Leleu, X., Manier, S., et al. (2023). Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor. Blood, 141(11), 1308–1315.

Costa, L.J., Chhabra, S., Medvedova, E., Dholaria, B.R., Schmidt, T.M., Godby, K.N., et al. (2022). Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. Journal of Clinical Oncology, 40(25), 2901–2912.

Kaiser, M.F., Sonneveld, P., Cairns, D., Raab, M.S., Larocca, A., Brown, S.R., et al. (2022). Co-Occurrence of High-Risk Lesions Is a Consistent Predictor of Ultra-High Risk Multiple Myeloma in Newly Diagnosed and Relapsed/Refractory Patients - Meta-Analysis of 5,808 Trial Patients. Blood, 140(Supplement 1), 1556–1558.

Kuiper, R., Zweegman, S., van Duin, M., van Vliet, M.H., van Beers, E.H., Dumee, B., et al. (2020). Prognostic and predictive performance of R-ISS with SKY92 in older patients with multiple myeloma: the HOVON-87/NMSG-18 trial. Blood Advances, 4(24), 6298–6309.

Shah, V., Sherborne, A.L., Johnson, D.C., Ellis, S., Price, A., Chowdhury, F., et al. (2020). Predicting ultrahigh risk multiple myeloma by molecular profiling: an analysis of newly diagnosed transplant eligible myeloma XI trial patients. Leukemia, 34(11), 3091–3096.

Banerjee, R., Cicero, K.I., Lee, S.S., Cowan, A.J. (2023). Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling. Frontiers in Oncology, 13. Available from: https://www.frontiersin.org/articles/10.3389/fonc.2023.1240966/full

Gonsalves, W.I., Leung, N., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., et al. (2015). Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma. Blood Cancer Journal, 5(3), e296.

Bladé, J., Beksac, M., Caers, J., Jurczyszyn, A., von Lilienfeld-Toal, M., Moreau, P., et al. (2022). Extramedullary disease in multiple myeloma: a systematic literature review. Blood Cancer Journal, 12(3), 1–10.

Mina, R., Joseph, N.S., Kaufman, J.L., Gupta, V.A., Heffner, L.T., Hofmeister, C.C., et al. (2019). Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents. Cancer, 125(3), 416–423.

Palumbo, A., Bringhen, S., Mateos, M.V., Larocca, A., Facon, T., Kumar, S.K., et al. (2015). Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood, 125(13), 2068–2074.

Bygrave, C., Pawlyn, C., Davies, F., Craig, Z., Cairns, D., Hockaday, A., et al. (2021). Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma. British Journal of Haematology, 193(3), 551–555.

Kumar, S.K., Dispenzieri, A., Fraser, R., Mingwei, F., Akpek, G., Cornell, R., et al. (2018). Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. Leukemia, 32(4), 986–995.

Corre, J., Montes, L., Martin, E., Perrot, A., Caillot, D., Leleu, X., et al. (2020). Early relapse after autologous transplant for myeloma is associated with poor survival regardless of cytogenetic risk. Haematologica, 105(9), e480–e483.

D’Agostino, M., Zaccaria, G.M., Ziccheddu, B., Rustad, E.H., Genuardi, E., Capra, A., et al. (2020). Early Relapse Risk in Patients with Newly Diagnosed Multiple Myeloma Characterized by Next-generation Sequencing. Clinical Cancer Research, 26(18), 4832–4841.

Dhakal, B., D’Souza, A., Callander, N., Chhabra, S., Fraser, R., Davila, O., et al. (2020). Novel Prognostic Scoring System for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. British Journal of Haematology, 191(3), 442–452.

Zaccaria, G.M., Bertamini, L., Petrucci, M.T., Offidani, M., Corradini, P., Capra, A., et al. (2021). Development and Validation of a Simplified Score to Predict Early Relapse in Newly Diagnosed Multiple Myeloma in a Pooled Dataset of 2,190 Patients. Clinical Cancer Research, 27(13), 3695–3703.

Beksac, M., Iacobelli, S., Koster, L., Cornelissen, J., Griskevicius, L., Rabin, N.K., et al. (2023). An early post-transplant relapse prediction score in multiple myeloma: a large cohort study from the chronic malignancies working party of EBMT. Bone Marrow Transplantation, 58(8), 916–923.

Munshi, N.C., Avet-Loiseau, H., Anderson, K.C., Neri, P., Paiva, B., Samur, M., et al. (2020). A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Advances, 4(23), 5988–5999.

Richardson, P.G., Jacobus, S.J., Weller, E.A., Hassoun, H., Lonial, S., Raje, N.S., Medvedova, E., McCarthy, P.L., Libby, E.N., Voorhees, P.M., Orlowski, R.Z., Anderson, L.D. Jr, Zonder, J.A., Milner, C.P., Gasparetto, C., Agha, M.E., Khan, A.M., Hurd, D.D., et al.; DETERMINATION Investigators. (2022). Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. New England Journal of Medicine, 387(2), 132–147. doi: 10.1056/

Sonneveld, P., Dimopoulos, M.A., Boccadoro, M., Quach, H., Ho, P.J., Beksac, M., et al.; PERSEUS Trial Investigators. (2024). Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine, 390(4), 301–313. doi: 10.1056/NEJMoa2312054.

Cavo, M., Gay, F., Beksac, M., Pantani, L., Petrucci, M.T., Dimopoulos, M.A., et al. (2020). Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. The Lancet Haematology, 7(6), e456–e468. doi: 10.1016/S2352-3026(20)30099-5.

Hari, P., et al. (2020). Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). Journal of Clinical Oncology, 38, 8506–8506. DOI:10.1200/JCO.2020.38.15_suppl.8506

De La Torre, A., Atenafu, E.G., Smith, A.C., Kukreti, V., Prica, A., Bhella, S., et al. (2021). Myeloma Patients with Deletion of 17p: Impact of Tandem Transplant and Clone Size. Blood, 138(Supplement 1), 460. doi:10.1182/blood-2021-153011.

Barlogie B, Anaissie E, Van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007 Jul;138(2):176-185. doi:10.1111/j.1365-2141.2007.06639.x

Rosiñol L, Oriol A, Ríos R, et al. Lenalidomide and dexamethasone maintenance with or without ixazomib, tailored by residual disease status in myeloma. Blood 2023; 142 (18): 1518–1528.

Dimopoulos, M.A., Moreau, P., Palumbo, A., Joshua, D., Pour, L., Hájek, R., et al. (2016). Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. The Lancet Oncology, 17(1), 27–38. doi: 10.1016/S1470-2045(15)00464-7.

Costa, L.J., Chhabra, S., Medvedova, E., Dholaria, B.R., Schmidt, T.M., Godby, K.N., et al. (2023). Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. The Lancet Haematology, 10(11), e890–e901. doi: 10.1016/S2352-3026(23)00236-3.

Touzeau, C., Perrot, A., Hulin, C., Manier, S., Macro, M., Chretien, M.-L., et al. (2023). Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04. Blood, 142(Supplement 1), 207. doi: https://doi.org/10.1182/blood-2023-174044

Kaiser, M.F., Hall, A., Walker, K., Sherborne, A., De Tute, R.M., Newnham, N., et al. (2023). Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma. Journal of Clinical Oncology, 41(23), 3945–3955. doi: 10.1200/JCO.22.02567.

Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, Lesokhin A, Deol A, Munshi NC, O'Donnell E, Avigan D, Singh I, Zudaire E, Yeh TM, Allred AJ, Olyslager Y, Banerjee A, Jackson CC, Goldberg JD, Schecter JM, Deraedt W, Zhuang SH, Infante J, Geng D, Wu X, Carrasco-Alfonso MJ, Akram M, Hossain F, Rizvi S, Fan F, Lin Y, Martin T, Jagannath S. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021 Jul 24;398(10297):314-324. doi: 10.1016/S0140-6736(21)00933-8. Epub 2021 Jun 24. Erratum in: Lancet. 2021 Oct 2;398(10307):1216. PMID: 34175021.

Moreau, P., Garfall, A.L., van de Donk, N.W.C.J., Nahi, H., San-Miguel, J.F., Oriol, A., et al. (2022). Teclistamab in Relapsed or Refractory Multiple Myeloma. New England Journal of Medicine, 387(6), 495–505. doi: 10.1056/NEJMoa2203478.

Lesokhin, A.M., Tomasson, M.H., Arnulf, B. et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med 29, 2259–2267 (2023).

San-Miguel, J., et al. (2023). Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. New England Journal of Medicine, 389(4), 335–347. doi: 10.1056/NEJMoa2303379.



How to Cite

Sharma R, Sánchez Hernández KA, Lancman G. High-Risk Myeloma: Definitions and Treatments. Can Hematol Today [Internet]. 2024 Jun. 27 [cited 2024 Jul. 23];3(2):41–47. Available from: https://canadianhematologytoday.com/article/view/3-2-sharma_et_al