Incidence and characteristics of myeloid neoplasms in patients with multiple myeloma treated with novel myeloma-directed therapies

Abstract

Abstract BackgroundTherapy-related myeloid neoplasms (t-MNs), including therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML), are increasingly recognized as complications in patients with multiple myeloma (MM) undergoing prolonged or intensive treatment. While advances such as proteasome inhibitors, immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT) have markedly improved MM survival, they may also contribute to clonal evolution and leukemogenesis. However, the incidence, latency, molecular features, and clinical outcomes of secondary myeloid neoplasms in this setting remain incompletely defined. AimsTo investigate the clinical features, cytogenetic and molecular landscape, and outcomes of myeloid neoplasms arising in MM patients treated with modern myeloma-directed regimens, and to identify potential risk factors contributing to their development. MethodsWe conducted an observational study of MM patients who developed t-MDS or t-AML between 2009 and 2023 at the Division of Hematology, AOU Città della Salute e della Scienza di Torino and the University of Torino, Italy. Diagnoses were based on WHO 2022 criteria. Clinical and treatment history, bone marrow findings, cytogenetics, and next-generation sequencing (NGS) profiles were analyzed. The Mantel–Byar test was used to assess the impact of allogeneic stem cell transplantation (allo-SCT), treated as a time-dependent covariate, on overall survival. ResultsBetween 2009 and 2023, 1,960 new MM cases were diagnosed at our institution (average 140/year), with 493 ASCT procedures performed. Thirty-six patients developed t-MNs (9 AML, 27 MDS). Median age at t-MN diagnosis was 69 years (range 59–85), and median time from MM diagnosis to t-MN onset was 80 months (range 23–267). Twenty-three patients had undergone ASCT, 9 of whom received a second ASCT. Maintenance therapy was administered in 20 patients: 17 received lenalidomide (median 17 cycles; range 4–115), and 3 received thalidomide (median 13 cycles; range 11–48). Cytogenetic abnormalities were observed in 26 patients, including 9 with complex karyotypes. Frequent abnormalities included -7/del(7q), -5/del(5q), del(17q)/i17, and 3p26 rearrangements. NGS data were available for 7 patients, revealing mutations in RUNX1, TP53, DNMT3A, CSF3R, NRAS, and KRAS; 3 patients had ≥2 mutations, and 1 had no detectable mutations. Among AML cases, 6 received intensive induction (FLAI+venetoclax in 4, CPX-351 in 2); 2 received azacitidine+venetoclax. Seventeen patients had high/very high-risk MDS by IPSS-R; 8 received azacitidine, and the rest received supportive care. Six patients (4 AML, 2 MDS) underwent allo-SCT. Compared to transplant-ineligible patients, these patients were younger (median age 67 vs. 74 years, p=0.014) and had a lower ECOG performance status (median 1 vs. 2, p=0.03). Conditioning was myeloablative in 3 cases. Stem cell sources included peripheral blood (n=5) and bone marrow (n=1), from haploidentical (n=3) or 8/8 matched unrelated donors (n=3). GVHD prophylaxis included methotrexate, cyclosporine A, and rATG for matched donors, and post-transplant cyclophosphamide, mycophenolate mofetil, and tacrolimus for haploidentical transplants. Notably, all patients with high-risk t-MN who received allo-SCT were alive and in remission after a median follow-up of 24 months, while none survived without allo-SCT (p=0.004). ConclusionMyeloid neoplasms represent an emerging late complication in MM patients treated with current therapeutic strategies. Their development is associated with specific treatment exposures and clonal alterations. Early identification and molecular profiling are essential for diagnosis and risk stratification. Allo-SCT remains the only potentially curative approach. These findings underscore the need for long-term monitoring and individualized management strategies in MM survivors.