Long-term outcomes of syngeneic transplantation in multiple myeloma: Valuable legacy or obsolete option? a study from the chronic malignancies working party of the EBMT

Abstract Background: High-dose chemotherapy with melphalan followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard frontline therapy for eligible patients with multiple myeloma (MM). Although this approach offers durable disease control, it is not curative, and most patients eventually relapse. While novel therapies are typically favored in the relapsed setting due to proven efficacy and lower toxicity, syngeneic HCT (syn-HCT from an identical twin) represents a unique and underexplored alternative. Syn-HCT combines the advantages of a genetically matched donor with minimal graft-versus-host disease (GVHD) risk, and may offer improved outcomes due to uncontaminated grafts and enhanced immune recovery. However, data supporting its use in MM are limited, with the latest report to date including only 25 patients. Methods: This is a retrospective, registry-based multicenter analysis using data from the European Society for Blood and Marrow Transplantation (EBMT) registry, approved by the Chronic Malignancies Working Party. The aim is to assess the clinical outcomes of all adult MM patients who underwent syn-HCT between 2000 and 2021, regardless of conditioning regimen or disease status. Results: 109 patients from 81 centers were included. Median age was 55 years (interquartile range (IQR): 47–59), and 55% were male. The most common MM subtype was IgG (51%) followed by light chain disease (32%). The median year of syn-HCT was 2008, with a median time from diagnosis to syn-HCT of 10 months. Notably, 30% had received prior auto-HCT. At the time of syn-HCT, 24% were in complete response (CR), 13% in very good partial response (VGPR), 43% in PR, and 20% had stable or progressive disease (SD-PD). Peripheral blood stem cells were used in 93% of cases. Conditioning included melphalan in 83% and total body irradiation (TBI) in 15%. Median times to neutrophil and platelet engraftment were 12 (IQR: 10-13) and 13 (IQR: 10-17) days, respectively. There were no cases of graft failure. After a median follow-up of 106 months, the median overall survival (OS) was 120 (95% confidence interval (CI): 102-190) months, with 5- and 10-year OS rates of 78% and 52%, respectively. Median progression-free survival (PFS) was 51.3 (95% CI: 110-not reached) months, with 5- and 10-year PFS rates of 45% and 34%. Patients transplanted between 2010–2021 had better 5-year OS (84%) compared to those transplanted in earlier periods (75%). Outcomes were significantly better in patients who underwent transplant within 12 months of diagnosis (10-year OS: 58% vs. 38%, p=0.04) and in those without prior auto-HCT (10-year OS: 63% vs. 24%, p=0.006). Disease status at transplant also influenced relapse risk: 57% in CR at time of syn-HCT relapsed compared to 87% with PD (p=0.007). GVHD incidence remained low, as expected, with acute GVHD reported in 9% at day 100 and 2-year extensive chronic GVHD occurring in only 5%. The 2-year non-relapse mortality was 4%. At last follow-up, 44 patients had died (68% from disease progression, 7% from infection, and 2% from GVHD-related causes). Conclusion: Syn-HCT offers a safe and effective treatment option for selected patients with MM, with long-term disease control and minimal toxicity. Favorable outcomes were observed particularly in those transplanted early after diagnosis and without prior auto-HCT. These findings suggest that while syn-HCT may offer long-term benefit in select patients, its role relative to auto-HCT remains unclear, particularly in the arena of novel agents such as bispecific antibodies and CAR-T cells for MM.