Durable Remission of Highly Refractory Multiple Myeloma and Therapy‐Related MDS/AML After Allogeneic Hematopoietic Cell Transplantation: Reconsidering Its Role in the CAR‐T Era

ABSTRACT

Therapy‐related myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) are increasingly recognized as late complications of multiple myeloma (MM) treatment and are associated with a dismal prognosis. We report on a patient with highly refractory MM who developed therapy‐related MDS/AML during the course of multiple lines of anti‐myeloma therapy, including proteasome inhibitors, immunomodulatory drugs, anti‐CD38 monoclonal antibodies, and repeated autologous stem cell transplantation. Progressive cytopenias led to bone marrow evaluation and the diagnosis of therapy‐related MDS/AML. Allogeneic hematopoietic cell transplantation (allo‐HCT) was performed primarily for therapy‐related MDS/AML and resulted in durable disease control of both MDS/AML and MM. At the latest follow‐up, approximately 3 years after allo‐HCT, the patient remains in complete remission from therapy‐related MDS/AML and in stringent complete response with sustained minimal residual disease negativity in MM, without any post‐transplant maintenance therapy. Although chimeric antigen receptor T‐cell therapies have demonstrated remarkable efficacy in relapsed and refractory MM, they are not currently regarded as curative. This case highlights that allo‐HCT may still play a clinically meaningful role in selected and complex clinical settings, even in the era of cellular immunotherapy.

1. Introduction

Therapy‐related myeloid neoplasms (t‐MN) are increasingly recognized as late complications in patients with multiple myeloma (MM) due to prolonged survival achieved with novel agents, including cellular immunotherapies and bispecific antibodies [1, 2]. Outcomes of therapy‐related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) remain extremely poor, and allogeneic hematopoietic cell transplantation (allo‐HCT) is often the only potentially curative option [3, 4]. In the contemporary era of immunotherapy, the role of allo‐HCT in MM has become limited; however, complex clinical scenarios may still mandate its use. We report a patient with refractory MM who developed therapy‐related MDS/AML and achieved sustained, treatment‐free remission of both diseases following allo‐HCT.

2. Case Presentation

A 42‐year‐old woman was initially diagnosed with a plasmablastic plasma cell neoplasm showing overlapping features between plasmablastic lymphoma and plasmablastic myeloma, as previously reported [5]. At presentation, she had multiple bulky extramedullary tumors involving the breast and other organs, markedly elevated serum free light chains with Bence–Jones proteinuria, and lytic bone lesions. Repeated bone marrow examinations showed no detectable clonal plasma cells by morphology or multiparameter flow cytometry.

Histopathological examination of the breast tumor demonstrated diffuse proliferation of large atypical plasmablastic cells. Immunohistochemical analysis showed that the tumor cells were positive for CD138, CD79a, MUM1, and c‐MYC, and negative for CD20 and Epstein–Barr virus‐encoded small RNA (EBER). The Ki‐67 labeling index exceeded 90%. Cytogenetic analysis of the breast tumor specimen was attempted; however, conventional G‐banding was unsuccessful because of insufficient metaphase cells. Fluorescence in situ hybridization analysis of the same specimen revealed deletion of 17p.

Given this borderline clinicopathologic presentation—characterized by aggressive extramedullary disease without overt bone marrow involvement—induction therapy with bortezomib‐containing dose‐adjusted EPOCH (V‐EPOCH) was selected to control the rapidly progressive disease. The patient subsequently underwent high‐dose melphalan–conditioned autologous peripheral blood stem cell transplantation (auto‐PBSCT) as consolidation therapy, followed by maintenance with ixazomib, lenalidomide, and dexamethasone (IRd).

Approximately 4 years after the initial diagnosis, the patient experienced disease relapse and was treated with daratumumab, carfilzomib, and dexamethasone (DKd). Although transient disease control was achieved, the disease progressed again after nine cycles. Three additional cycles of V‐EPOCH were administered to control disease activity, after which the patient underwent a second auto‐PBSCT with high‐dose melphalan conditioning approximately 5 years after diagnosis. Despite these intensive treatments, serum free light chain levels gradually increased, and elotuzumab, pomalidomide, and dexamethasone (EPd) therapy was started several months later.

Around this time, progressive pancytopenia and morphological abnormalities in peripheral blood cells became apparent. Bone marrow examination revealed 17% blasts, leading to a diagnosis of therapy‐related MDS/AML according to the International Consensus Classification [6].

The 17p deletion identified in the initial extramedullary tumor specimen was not detected at the onset of MDS/AML. Instead, an independent myeloid clone characterized by Monosomy 7 and mutations in PTPN11 and WT1 emerged, supporting the diagnosis of therapy‐related MDS/AML rather than clonal evolution of MM [7, 8, 9]. Given the aggressive clinical course, one cycle of venetoclax plus azacitidine was administered as cytoreductive therapy.

The patient subsequently underwent umbilical cord blood transplantation (UCBT) using a serologically two‐antigen‐mismatched unit. Conditioning consisted of fludarabine, busulfan, melphalan, and total body irradiation (4 Gy). At the initiation of conditioning, bone marrow blasts had decreased to 4.4%, and multiparameter flow cytometry demonstrated minimal residual disease (MRD) negativity for MM. Graft‐versus‐host disease (GVHD) prophylaxis consisted of tacrolimus plus mycophenolate mofetil. Neutrophil and platelet engraftment occurred on Days 16 and 35, respectively. Post‐transplant bone marrow examination on Day 24 confirmed complete remission of both therapy‐related MDS/AML and MM.

The post‐transplant course was complicated by liver function abnormalities. Although total bilirubin remained within the normal range, alanine aminotransferase levels increased to 308 U/L on Day 28. Drug‐induced liver injury was initially suspected, and several medications were discontinued or modified; however, liver dysfunction persisted. A transjugular liver biopsy performed on Day 52 suggested mild acute GVHD. Methylprednisolone was initiated at 1 mg/kg, resulting in prompt improvement of liver function. The dose was subsequently tapered gradually. All immunosuppressive agents were successfully discontinued by Day 346 without the development of chronic GVHD.

At the latest follow‐up, approximately 3 years after allo‐HCT, the patient remains in complete remission of therapy‐related MDS/AML and in stringent complete response with sustained MRD negativity for MM without any post‐transplant maintenance therapy. The overall clinical course is summarized in Figure 1.

FIGURE 1.

Clinical timeline of multiple myeloma complicated by therapy‐related MDS/AML. The patient was initially diagnosed with a plasma cell neoplasm showing borderline features between plasmablastic lymphoma and plasmablastic myeloma. Induction therapy with bortezomib‐containing dose‐adjusted EPOCH (V‐EPOCH) resulted in a complete metabolic response, followed by high‐dose melphalan‐conditioned autologous peripheral blood stem cell transplantation (auto‐PBSCT) and IRd maintenance therapy. Approximately 4 years after the initial diagnosis, the patient experienced disease relapse and was treated with daratumumab, carfilzomib, and dexamethasone (DKd). After subsequent disease progression, additional V‐EPOCH therapy was administered for disease control, followed by a second auto‐PBSCT with high‐dose melphalan conditioning approximately 5 years after diagnosis. Several months later, progressive cytopenia and morphological abnormalities in peripheral blood emerged during EPd therapy. Bone marrow examination revealed 17% blasts, leading to a diagnosis of therapy‐related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). The patient subsequently underwent umbilical cord blood transplantation, which resulted in sustained, treatment‐free remission of both multiple myeloma (minimal residual disease–negative stringent complete response) and therapy‐related MDS/AML for more than 30 months. auto‐PBSCT, autologous peripheral blood stem cell transplantation; Aza + Ven, azacitidine plus venetoclax; CR, complete remission (for MDS/AML) or complete response (for multiple myeloma); DKd, daratumumab, carfilzomib, and dexamethasone; EPd, elotuzumab, pomalidomide, and dexamethasone; IRd, ixazomib, lenalidomide, and dexamethasone; MRD, minimal residual disease; UCBT, umbilical cord blood transplantation; V‐EPOCH, bortezomib‐containing dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.

3. Discussion

With advances in the treatment of MM, t‐MN, including myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), have been increasingly recognized as late complications [10, 11]. Although cytopenias in patients with MM are often attributed to treatment‐related bone marrow suppression, persistent or progressive cytopenias should prompt consideration of secondary myeloid neoplasms. Importantly, the development of therapy‐related MDS/AML during the course of MM is associated with a particularly poor prognosis [12, 13].

Against this background, the present case is notable for the development of therapy‐related MDS/AML in a patient with highly refractory MM. Despite multiple lines of therapy, including proteasome inhibitors, immunomodulatory drugs, anti‐CD38 monoclonal antibodies, and two courses of high‐dose melphalan with autologous stem cell transplantation, the myeloma remained aggressive and treatment‐refractory. Progressive cytopenias led to bone marrow evaluation and the diagnosis of therapy‐related MDS/AML.

Importantly, allo‐HCT remains the only potentially curative treatment option for therapy‐related MDS/AML, despite its substantial treatment‐related risks [3, 4, 13]. In the present case, allo‐HCT was undertaken primarily to treat therapy‐related MDS/AML; however, it also resulted in sustained disease control of highly refractory MM without any post‐transplant maintenance therapy.

The role of allo‐HCT in MM has markedly diminished with the advent of novel agents and cellular immunotherapies, including chimeric antigen receptor (CAR) T‐cell therapies. CAR T‐cell therapies have demonstrated unprecedented response rates and deep remissions in relapsed and refractory disease [1, 14]. However, they are not currently regarded as curative, as most patients ultimately experience disease relapse. In this context, the present case highlights that allo‐HCT may still exert meaningful anti‐myeloma activity in selected and complex clinical scenarios, particularly when concomitant hematologic malignancies coexist.

Notably, the choice of umbilical cord blood as the graft source may also have contributed to the favorable outcome in this complex and high‐risk clinical scenario. Emerging registry data from the CIBMTR suggest that UCBT may provide potent graft‐versus‐leukemia effects in patients with active or high‐risk acute myeloid leukemia, including those who are not in remission at the time of transplantation [15]. Although UCBT may be associated with increased non‐relapse mortality, a reduced relapse risk has been reported in difficult‐to‐treat settings. It is therefore conceivable that UCBT may have contributed, at least in part, to the durable disease control observed in this complex clinical setting.

This report is limited by its nature as a single case, and the findings may not be generalizable to broader patient populations. Accordingly, the present observation does not support routine use of allo‐HCT for MM. Selection bias and the unique clinical circumstances of this patient, including the coexistence of therapy‐related MDS/AML and highly refractory MM, must be carefully considered when interpreting the outcome. Nevertheless, this case provides clinically relevant insight into the potential role of allo‐HCT in complex disease settings and suggests that its indication may warrant reconsideration for carefully selected patients, even in the era of cellular immunotherapy.

Author Contributions

T.K., M.S., and K.Y. were responsible for the clinical management of the patient. T.K., M.S., S.T., F.Y., Y.F., and N.U. collected the clinical data and drafted the manuscript. K.Y. and S.Y. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report.

Conflicts of Interest

Satoshi Yoshihara has received honoraria for lectures from Bristol Myers Squibb, Ono Pharmaceutical Co. Ltd., and Johnson & Johnson. The other authors declare no conflicts of interest.

Kumamoto T., Yoshihara K., Samori M., et al. “Durable Remission of Highly Refractory Multiple Myeloma and Therapy‐Related MDS/AML After Allogeneic Hematopoietic Cell Transplantation: Reconsidering Its Role in the CAR‐T Era.” eJHaem 7, no. 2 (2026): e70282. 10.1002/jha2.70282

Data Availability Statement

The data supporting the conclusions of this article are included within the article. Additional details are available from the corresponding author upon reasonable request.