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Reduced intensity allogeneic hematopoietic stem cell transplantation is a safe and effective treatment option in high-risk myeloma patients - a single centre experience
Jurgensen-Rauch, A., Gibbs, S., Farrell, M., Aries, J., Grantham, M., Eccersley, L., Gribben, J., Hallam, S., Oakervee, H., Cavenagh, J., et al
British journal of haematology. 2021
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Long-term follow-up of CALGB (Alliance) 100001: Autologous followed by non-myeloablative allogeneic transplant for multiple myeloma
Holstein, S. A., Suman, V. J., Owzar, K., Santo, K., Benson, D. M., Jr., Shea, T. C., Martin, T., Silverman, M., Isola, L., Vij, R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by non-myeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than one prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m(2)). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m(2)/day IV on days -7 through -3) and cyclophosphamide (1 g/m(2)/day IV on days -4 through -3). The primary objective was to determine the six-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host (GVHD), disease-free survival (DFS) and overall survival (OS). Sixty patients were enrolled, of which 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49, 90% CI 0.10-9.3%). Moderate to severe (grade 2-3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of non-protocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.
PICO Summary
Population
Patients with multiple myeloma who had received no more than 18 months of prior therapy (n=60)
Intervention
Autologous stem cell transplant (ASCT) followed by non-myeloablative allogeneic stem cell transplant (alloSCT) (n=49)
Comparison
None
Outcome
The TRM rate was 2%. Moderate to severe (grade 2-3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of non-protocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years.
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3.
Radioimmunotherapy in combination with reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with advanced multiple myeloma
Fasslrinner, F., Stolzel, F., Kramer, M., Teipel, R., Brogsitter, C., Morgner, A., Arndt, C., Bachmann, M., Hanel, M., Rollig, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Radioimmunotherapy (RIT) has the potential to reduce the incidence of relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with advanced-stage multiple myeloma (MM). In this study, we evaluated the efficacy of RIT in combination with chemotherapy-based reduced-intensity conditioning (RIC). RIT was based on the coupling of an anti-CD66 antibody to the beta emitter 188-rhenium (188-re) for targeted bone marrow irradiation. Between 2012 and 2018, 30 MM patients, most of them heavily pretreated including various therapies with proteasome inhibitors, immunomodulatory drugs, anti CD38 antibodies, and autologous hematopoietic cell transplantation (auto-HCT), were treated with a RIT-RIC combination prior to allo-HCT. In addition to a fludarabine plus melphalan- or treosulfan-based RIC a median dose of 18.1 Gy (interquartile range (IQR) 14.6 to 24.1) was applied to the bone marrow. After a median follow-up time for surviving patients of 2.1 years (IQR 1.3-3.0), the two-year progression-free survival and overall survival rates were 43 % (95% CI 26-73%) and 55 % (95% CI 38-79), respectively. The two-year non-relapse mortality and cumulative incidence of progression were 17% (95% CI 3-30%) and 46 % (95% CI 25-67%), respectively. Renal toxicity and mucositis were the most frequently observed extramedullary side effects. In conclusion, the addition of RIT to RIC was safe and feasible, and resulted in promising outcomes compared to those previously reported for RIC-based allo-HCT-treated relapsed/refractory MM patients without RIT addition. Nevertheless, in spite of RIT addition, relapse after allo-HCT remained a major determinant of therapeutic failure. Therefore, development of novel RIT strategies (e.g., dual targeting strategies or combinations with adapter chimeric antigen receptor T cell-based therapies) are warranted.
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Time from autologous to allogeneic hematopoietic stem cell transplantation impacts post-transplant outcomes in multiple myeloma
Fiorenza, S., Routledge, D., Collins, J., Shipton, M., Harrison, S., Bajel, A., Cavet, J., Tholouli, E., Gauthier, J., Ritchie, D.
Bone marrow transplantation. 2019
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5.
Allogeneic transplantation of multiple myeloma patients may allow long-term survival in carefully selected patients with acceptable toxicity and preserved quality of life
Greil, C., Engelhardt, M., Ihorst, G., Schoeller, K., Bertz, H., Marks, R., Zeiser, R., Duyster, J., Einsele, H., Finke, J., et al
Haematologica. 2018
Abstract
Despite significantly improved survival and response rates in patients diagnosed with multiple myeloma, it still remains an incurable disease with a poor outcome especially in high-risk groups. Allogeneic stem cell transplantation offers a potentially curative option but is discussed controversially due to considerable treatment related toxicity. We analyzed 109 consecutive myeloma patients who received reduced-intensity conditioning allogeneic transplantation at the Freiburg University Medical Center between 2000 and 2017. Although most patients were heavily pretreated in high-risk constellations, the overall response rate was high with 70%, the median overall survival 39.2 and the median progression free survival 14.2 months, with a median follow-up of 71.5 months. Survival was significantly better in patients with response to previous therapies than in those with progressive disease (median OS 65 vs. 11.5 months, p=0.003; median PFS 18.4 vs. 5.1 months, p=0.001). Moreover, survival of patients transplanted in first-line was significantly prolonged compared to relapsed/refractory disease (median OS not reached vs. 21.6 months, p<0.001; median PFS 47.7 vs. 9.6 months, p<0.001). The non-relapse mortality was relatively low with a cumulative incidence of 12.4% at 10 years. Acute graft-versus-host disease II-IV occurred in 25%, moderate or severe chronic graft-versus-host disease in 24%. Quality of life assessed with the revised Myeloma Comorbidity Index before and after transplantation remained unchanged. Our data suggest that allogeneic transplantation in the context of novel immunotherapeutic approaches may enable long-term survival and even potential cure in a carefully selected subgroup of high-risk multiple myeloma patients with acceptable toxicity and preserved quality of life.
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6.
Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation
Ahmad, I., LeBlanc, R., Cohen, S., Lachance, S., Kiss, T., Sauvageau, G., Roy, D. C., Busque, L., Delisle, J. S., Bambace, N., et al
Bone Marrow Transplantation. 2016;51(4):529-35
Abstract
Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged 65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.