1.
Characteristics and outcomes of patients with multiple myeloma who developed therapy-related acute myeloid leukemia and myelodysplastic syndrome following autologous cell transplantation
Yalniz, F. F., Greenbaum, U., Pasvolsky, O., Milton, D. R., Kanagal-Shamanna, R., Ramdial, J., Srour, S., Mehta, R., Alousi, A., Popat, U. R., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing the therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). METHODS We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1/1/2000 and 12/31/2018, and later developed t-MDS/AML. RESULTS Among the 2982 patients that underwent at least one Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n=52; AML, n=3). The median age at t-MDS/AML diagnosis was 66 years (range, 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range, 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with tMDS had high-risk disease, per ELN2022 and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed t-MDS/AML were older at MM diagnosis (median: 61 vs. 59 years; p=0.06), more often were male (73% vs. 58%; p=0.029), received more than 2 years of lenalidomide maintenance (57% vs. 39%; p=0.014) and experienced complete remission more frequently following Auto-HCT compared to those who did not develop t-MDS/AML (56% vs. 40%; p=0.012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplant (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months vs. 11.1 months for Allo-HCT recipients vs. nonrecipients, respectively (P=0.25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% CI]: 2.9 [1.3-6.3]; P=0.009), age > 60 years (3.1 [1.2-8.2]; P=0.025), and higher risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. CONCLUSION T-MDS/AML following an Auto-HCT for MM is associated with aggressive disease characteristics, including high risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted.
2.
Vorinostat combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-term Study Outcomes
Alatrash, G., Saberian, C., Bassett, R., Thall, P. F., Ledesma, C., Lu, Y., Daher, M., Valdez, B. C., Kawedia, J., Popat, U., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of intravenous (IV) busulfan (Bu) as part of the conditioning chemotherapy has been shown to be effective in controlling disease relapse. However, disease relapse remains a major cause of death following allo-HSCT. OBJECTIVE To determine the long-term outcomes of vorinostat with IV Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. STUDY DESIGN This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard IV Bu Flu Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). RESULTS Fifty-eight patients (85%) were in morphologic complete remission at time of transplant and 38 patients (56%) received matched unrelated donor grafts. Over the median follow up of 37.6 months, among the 68 patients, 29 (43%) died, and the non-relapse mortality (NRM) rate was 22% (n=15). Median overall survival (OS) and median NRM were not reached. Nineteen patients (28%) experienced disease progression. Median PFS was 36.8 months. Thirty-seven patients (57%) developed grade 2-4 acute GVHD and 20 patients (31%) developed chronic GVHD. CONCLUSION Our results suggest a lack of benefit from adding a short course of vorinostat to IV Bu/Flu/Clo conditioning regimen for leukemia patients undergoing allo- HSCT.
3.
Long-term outcomes of allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma
Afrough, A., Alsfeld, L. C., Milton, D. R., Delgado, R., Popat, U. R., Nieto, Y., Kebriaei, P., Oran, B., Saini, N., Srour, S., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) have disease that relapses. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative option for a subgroup of patients with high- risk disease. OBJECTIVE This study assesses the long-term outcome of MM patients who received allo-HCT at the first remission as consolidation treatment. METHODS/RESULTS Thirty-three patients with newly diagnosed MM who received allo-HCT as part of consolidation therapy from 1994 to 2016 were retrospectively reviewed. Of those, 70% received autologous HCT before allo-HCT. All patients were chemo-sensitive and achieved at least partial response before proceeding to allo-HCT. Most received nonmyeloablative/reduced-intensity conditioning (88%) and matched sibling donor (85%) grafts. Acute graft versus host disease (aGVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. The median follow-up was 64.1 months (range, 1.4 - 199.2) for all patients and 164.4 months (range, 56.0 -199.2) in survivors. The median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 -73.0). The median treatment to progression (TTP) was 73.0 months (95% CI, 30.6 -not reached). The median overall survival (OS) was 131.9 months (95% CI, 38.4 -not reached). Of all patients, 39% were alive more than 10 years, with 46% (n=6) without progression or relapse. The cumulative incidence of relapse was 18% at 1-year, 39% at 5-years, and 46% at 10-year post-allo-HCT. The cumulative incidence of non-relapse mortality (NRM) was 3% at 100-day, 18% at 1-year, 21% at 3-years, and 24% at 5-year post-allo-HCT. On multivariable analysis, high-risk cytogenetics were associated with a shorter PFS (HR 2.7; 95% CI [1.01-7.21], p-value=0.047) and OS (HR 4.91, 95% CI [1.48-16.27], p-value=0.009). In addition, achieving complete remission after allo-HCT was also associated with longer PFS (HR 0.24, 95% CI [0.09-0.64], p-value=0.004) and OS (HR 0.23; 95% CI [0.07-0.72], p-value=0.012). CONCLUSIONS Allo-HCT may result in a survival advantage in a selected population of MM patients when performed early in the disease course. Additional data on the optimal patient selection who would benefit the most are needed.
PICO Summary
Population
Adults with newly diagnosed multiple myeloma at a single centre in Texas, USA (n=33)
Intervention
Allogeneic hematopoietic cell transplantation (allo-HCT)
Comparison
None
Outcome
Acute graft versus host disease (aGVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. Median follow-up was 64.1 months (range, 1.4 - 199.2) for all patients and 164.4 months (range, 56.0 -199.2) in survivors. Median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 -73.0). Median treatment to progression (TTP) was 73.0 months (95% CI, 30.6 -not reached). Median overall survival (OS) was 131.9 months (95% CI, 38.4 -not reached). Of all patients, 39% were alive more than 10 years, with 46% (n=6) without progression or relapse. Cumulative incidence of relapse was 18% at 1-year, 39% at 5-years, and 46% at 10-year post-allo-HCT. Cumulative incidence of non-relapse mortality (NRM) was 3% at 100-day, 18% at 1-year, 21% at 3-years, and 24% at 5-year post-allo-HCT. On multivariable analysis, high-risk cytogenetics were associated with a shorter PFS (HR 2.7; 95% CI [1.01-7.21]) and OS (HR 4.91, 95% CI [1.48-16.27]). In addition, achieving complete remission after allo-HCT was also associated with longer PFS (HR 0.24, 95% CI [0.09-0.64]) and OS (HR 0.23; 95% CI [0.07-0.72]).