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1.
Incidence and Risk Factors of Early Onset VOD/SOS Differ in Younger vs Older Adults After Stem Cell Transplantation
Marcoux, C., Saliba, R. M., Wallis, W., Khazal, S. J., Ragoonanan, D., Rondon, G., Tewari, P., Popat, U. R., Oran, B., Olson, A. L., et al
Blood advances. 2024
Abstract
Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). While increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with post-transplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single center analysis of adult patients 18 years or older undergoing allo-SCT (N=1561) using predominately PTCy as GVHD prophylaxis (72%). We found a higher rate of VOD at 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Within patients aged 18-25 years, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Incidence of VOD in patients > 25 years of age consistently ranged between 3-5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase (AST), alanine aminotransferase (ALT)) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared to those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors in VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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2.
Outcomes of patients with multiple myeloma and 1q gain/amplification receiving autologous hematopoietic stem cell transplant: the MD Anderson cancer center experience
Pasvolsky, O., Ghanem, S., Milton, D. R., Rauf, M., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., et al
Blood cancer journal. 2024;14(1):4
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Editor's Choice
Abstract
The prognostic impact of additional copies of chromosome 1q (1q + ) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008-2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p < 0.001), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, p = 0.030, 2.33, p = 0.023 and 3.00, p = 0.047, respectively). In conclusion, patients with 1q+ NDMM, especially 1q amplification, have inferior survival outcomes compared to standard-risk disease after upfront autoSCT, though outcomes are better than other high-risk cytogenetic abnormalities.
PICO Summary
Population
Adults with newly-diagnosed myeloma (NDMM) patients with 1q21 gain/amplification (3 or >/=4 copies of 1q, respectively) that received autoSCT between from a single centre in USA (n=213)
Intervention
Assess the prognostic impact of additional copies of chromosome 1q (1q+) on autologous transplantation outcomes
Comparison
None
Outcome
At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved very good partial response or better (>/=VGPR) and 38% and 50% achieved MRD-negative >/=VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative >/=VGPR before autoSCT (HR 0.52) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03). On multivariate analysis for OS, achieving MRD negative >/=VGPR at best post-transplant response was associated with superior survival (0.29), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, 2.33, and 3.00, respectively).
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3.
Effect of donor age in patients with acute myeloid leukemia undergoing haploidentical hematopoietic cell transplantation vary by conditioning intensity and recipient age
Saliba, R. M., Kanakry, C. G., Gadalla, S., Kebriaei, P., Rezvani, K., Champlin, R. E., Shpall, E. J., Weisdorf, D., Mehta, R. S.
American journal of hematology. 2023
Abstract
We investigated the impact of donor age (younger [≤35 years] vs. older [>35 years]) after accounting for other non-HLA and HLA factors on outcomes of patients with acute myeloid leukemia undergoing HLA-haploidentical hematopoietic cell transplantation (n = 790). The effect differed by conditioning-partly related to the differences in the recipient age in myeloablative (MAC; median 46 years) versus reduced-intensity/non-myeloablative conditioning (RIC/NMA; median 61 years) groups. With MAC (n = 320), donor age had no impact on acute graft-versus-host disease (GVHD), but older donors were associated with a significantly higher risk of chronic GVHD (hazard ratio [HR]: 1.6, 95% confidence interval [CI]: 1.10-2.30, p = .02) independent of recipient age and other factors. Donor age had no impact on either relapse or non-relapse mortality (NRM). The impact of donor/recipient age on overall survival changed over time. Older donors were associated with significantly higher late overall mortality (>6 months) in younger recipients (≤ 50 years; HR: 2.2, 95% CI: 1.03-4.6, p = .04) but not older recipients. With RIC/NMA (n = 470), neither recipient's nor donor's age influenced the risk of GVHD. Donor age had no significant impact on the risk of relapse, but older donors were associated with a significantly higher risk of NRM (HR: 1.6, 95% CI: 1.02-2.6, p = .04) independent of recipient age. Older donor age was associated with significantly higher late overall mortality (>9 months) in older recipients (>50 years; HR: 1.66, 95% CI: 1.0-2.67; p = .049) but not in younger recipients. Donor selection based on donor age may require a tailored approach for a particular recipient.
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4.
Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation
Zou, J., Kongtim, P., Oran, B., Srour, S. A., Greenbaum, U., Carmazzi, Y., Rondon, G., Ciurea, S. O., Ma, Q., Shpall, E. J., et al
Cancer. 2023
Abstract
BACKGROUND An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). METHODS In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. RESULTS In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of SSC (SHR 0.34, p = .021). CONCLUSIONS These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
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Clinical relevance of MYC/BCL2 expression and cell of origin in patients with diffuse large b-cell lymphoma treated with autologous transplant
Al-Juhaishi, T., Wang, Y., Milton, D. R., Xu-Monette, Z. Y., Jabbour, E., Daher, M., Im, J. S., Bashir, Q., Iyer, S. P., Marin, D., et al
Bone marrow transplantation. 2023
Abstract
Dual expression of MYC and BCL2 proteins (double-expressor lymphoma [DEL]) as well as cell of origin (COO) are important prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) after conventional chemotherapy. We studied the prognostic impact of DEL and COO in patients with relapsed DLBCL treated with autologous stem cell transplant (ASCT). Three-hundred and three patients with stored tissue samples were identified. Classification was successful in 267 patients: 161 (60%) were DEL/non-double hit (DHL), 98 (37%) were non-DEL/non-DHL, and 8 (3%) were DEL/DHL. Compared to non-DEL/non-DHL, DEL/DHL had worse overall survival while DEL/non-DHL did not significantly differ in overall survival. On multivariable analysis, DEL/DHL, age >60 years, and >2 prior therapies, but not COO, were important prognostic factors for overall survival. When we explored the interaction of COO and BCL2 expression, patients with germinal center B-cell (GCB)/BCL2 (+) had inferior progression-free survival (PFS) compared to GCB/BCL2 (-) patients (HR, 4.97; P = 0.027). We conclude that the DEL/non-DHL and non-DEL/non-DHL subtypes of DLBCL have similar survival after ASCT. The negative impact of GCB/BCL2 (+) on PFS warrants future trials targeting BCL2 after ASCT. The inferior outcomes in DEL/DHL need to be verified in a larger number of patients.
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6.
Impact of Donor Age in Haploidentical-Post-Transplantation Cyclophosphamide versus Matched Unrelated Donor Post-Transplantation Cyclophosphamide Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia
Mehta, R. S., Ramdial, J., Marin, D., Alousi, A., Kanakry, C. G., Champlin, R. E., Rezvani, K., Shpall, E. J., Page, K., Gadalla, S. M., et al
Transplantation and cellular therapy. 2023;29(6):377.e1-377.e7
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Editor's Choice
Abstract
Haploidentical hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis is associated with inferior overall survival (OS) compared to HLA-matched unrelated donor (MUD) HCT with PTCy prophylaxis in patients receiving reduced-intensity conditioning (RIC). Given prognostic implications of donor age, we investigated the differences in outcomes of patients with acute myeloid leukemia (AML; n = 775) undergoing RIC-HCT with a younger MUD (age <35 years; n = 84) versus a younger haploidentical donor (age <35 years; n = 302) versus an older haploidentical donor (age ≥35 years; n = 389). The older MUD group was excluded from the analysis because of small numbers. The younger haploidentical donor group (median age, 59.5 years) was somewhat younger than the younger MUD group (median age, 66.8 years) and the older haploidentical donor group (median age, 64.7 years). More patients in the MUD group received peripheral blood grafts (82%) compared to the haploidentical donor groups (55% to 56%). In multivariate analysis, compared to the younger MUD group, the younger haploidentical donor group (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.12; P = .005) and the older haploidentical donor group (HR, 2.36; 95% CI, 1.50 to 3.71; P < .001) had a significantly inferior OS, and the younger haploidentical donor group (HR, 3.72; 95% CI, 1.39 to 9.93; P = .009) and older haploidentical donor group (HR, 6.91; 95% CI, 2.75 to 17.39; P < .001) had a significantly higher risk of nonrelapse mortality. The older haploidentical group had a significantly higher risk of grade II-IV acute GVHD (HR, 2.29; 95% CI, 1.38 to 3.80; P = .001) and grade III-IV acute GVHD (HR, 2.70; 95% CI, 1.09 to 6.71; P = .03). There were no significant differences across the groups in the incidence of chronic GVHD or relapse. Among adult AML patients in CR undergoing RIC-HCT with PTCy prophylaxis, a young MUD may be preferred over a young haploidentical donor.
PICO Summary
Population
Adults with acute myeloid leukemia undergoing reduced intensity conditioning and transplant, identified from the CIBMTR database (n = 775)
Intervention
Younger (age <35 years) matched unrelated donor (MUD, n = 84)
Comparison
Younger (age <35 years) haploidentical donor (n = 302) older (age ≥35 years) haploidentical donor (n = 389)
Outcome
The younger haploidentical donor group (median age, 59.5 years) was somewhat younger than the younger MUD group (median age, 66.8 years) and the older haploidentical donor group (median age, 64.7 years). More patients in the MUD group received peripheral blood grafts (82%) compared to the haploidentical donor groups (55% to 56%). In multivariate analysis, compared to the younger MUD group, the younger haploidentical donor group (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.12) and the older haploidentical donor group (HR, 2.36; 95% CI, 1.50 to 3.71) had a significantly inferior OS, and the younger haploidentical donor group (HR, 3.72; 95% CI, 1.39 to 9.93) and older haploidentical donor group (HR, 6.91; 95% CI, 2.75 to 17.39) had a significantly higher risk of nonrelapse mortality. The older haploidentical group had a significantly higher risk of grade II-IV acute GVHD (HR, 2.29; 95% CI, 1.38 to 3.80) and grade III-IV acute GVHD (HR, 2.70; 95% CI, 1.09 to 6.71). There were no significant differences across the groups in the incidence of chronic GVHD or relapse.
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Autologous Stem Cell Transplantation for Patients with Multiple Myeloma with Translocation (4;14): The MD Anderson Cancer Center Experience: Transplant in t(4;14) MM
Pasvolsky, O., Gaballa, M. R., Milton, D. R., Masood, A., Sami, S. S., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Ramdial, J., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Translocation between chromosomes 4 and 14, t(4;14), has been reported in 15% of patients with multiple myeloma (MM), and is considered a high-risk cytogenetic abnormality that is associated with inferior outcomes. Autologous hematopoietic stem cell transplantation (auto-HCT) is standard of care for patients with high-risk MM (HRMM), yet there is scarce data on post-transplant outcomes of patients with t(4;14) MM patients. OBJECTIVE The aim of the study was to evaluate outcomes of MM patients with t(4;14) who underwent an auto-HCT, and received contemporary anti-myeloma agents for induction and post-transplant maintenance. STUDY DESIGN We conducted a retrospective analysis of MM patients with t(4;14), detected by fluorescence in situ hybridization (FISH), who underwent auto-HCT between 2008-2018 at MD Anderson Cancer Center. Primary endpoints were progression free survival (PFS) and overall survival (OS), and secondary endpoints were hematological response and minimal residual disease (MRD) status after auto-HCT. MRD status on the bone marrow biopsy was evaluated using 8-color next generation flow cytometry with a sensitivity of 1/10(-5) cells. RESULTS Seventy nine patients were included, with a median age of 60 (range: 32-78) years, and 52% were male. Forty-four (56%) patients had an additional HR cytogenetic abnormality. Fifty patients (63%) achieved ≥VGPR prior to auto-HCT and 20 (25%) had minimal residual disease (MRD) negative ≥VGPR. At best post-transplant evaluation, 90% and 63% had ≥VGPR and MRD-negative ≥VGPR, respectively. Median follow-up for survivors was 35.7 (range 7.7-111.6) months. Median PFS and OS for the entire cohort were 22.9 months and 60.4 months, respectively. Patients with MRD negative ≥VGPR prior to transplant had improved PFS and OS on both univariate analysis (UVA) and multivariate analysis (MVA): (HR [95% CI] 0.35 [0.16-0.76], p=0.008) and (0.12 [0.03-0.44], p=0.002), respectively. The presence of additional high-risk cytogenetic abnormalities was not associated with inferior PFS (p=0.57) or OS (p=0.70). Post-transplant lenalidomide-based combinations were associated with improved OS in both UVA and MVA (0.14 [0.04-0.45], p=0.001), while their impact on PFS was not statistically significant (p=0.37). CONCLUSIONS Our results consolidate t(4;14) as a high-risk abnormality associated with poor outcomes despite novel-agent induction, auto-HCT and post-transplant maintenance. Despite some inherent study design limitations including a relatively small cohort and heterogeneity in treatment, we observed that deeper pre-transplant response and post-transplant maintenance with lenalidomide-based combination were associated with improved outcomes. Novel immune- and cellular therapies are needed to improve the outcomes in patients with t(4;14).
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Outcomes of Autologous Stem Cell Transplant in Patients with Ultra High-Risk Multiple Myeloma
Pasvolsky, O., Ghanem, S., Milton, D. R., Masood, A., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Multiple myeloma (MM) patients with high-risk cytogenetic abnormalities (HRMM) have inferior survival outcome and are under-represented in clinical trials. There is scarce data on MM patients with more than one high-risk cytogenetic aberration (i.e. ultra high-risk MM). OBJECTIVE To evaluate outcomes of newly diagnosed MM patients with ultra high-risk MM who underwent autologous stem cell transplant (autoHCT). STUDY DESIGN We conducted a retrospective single-center chart review analysis of adult patients with ultra high-risk MM who received autoHCT between 2008-2018 at MD Anderson Cancer Center. High-risk cytogenetics were defined as del17p, t(4;14), t(14;16) or 1q21 gain or amplification (1q+) by fluorescence in situ hybridization (FISH). Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS Seventy-nine patients with two or more high-risk cytogenetic abnormalities were included in our analysis, with a median age of 61 (range 33.5-76.5) years and 57% were female. Sixty-seven patients had two HR cytogenetic abnormalities, while 12 patients had three. The most common combinations of HR abnormalities were [1q+, t(4:14)] (n=25, 32%) and [1q+, del17p] (n=21, 27%). The majority of patients received either bortezomib, lenalidomide and dexamethasone (VRD) (48%) or carfilzomib, lenalidomide and dexamethasone (KRD) (16%) as induction therapy. Prior to autoHCT, 52 (66%) patients achieved ≥VGPR, whereas 23 (29%) patients achieved MRD negative ≥VGPR. Fifty-six (71%) patients received post-transplant maintenance therapy. At day 100 post autoHCT and at best post-transplant response, 36 (46%) patients and 40 (51%) patients achieved MRD negative ≥VGPR, respectively. With a median follow-up in surviving patients of 38.3 (range 11.9 to 104.8) months, the median PFS and OS in the entire cohort were 22.9 and 71.5 months, respectively. For the subset of patients with three HR abnormalities, the median PFS and OS were 15.6 and 28.0 months, respectively. In multivariate analysis, achieving MRD negative ≥VGPR prior to autoHCT was associated with improved PFS (HR 0.42; p=0.045), while male gender (HR 0.15; p=0.009) and achieving MRD negative ≥VGPR post autoHCT (HR 0.27; p=0.026) were associated with improved OS. CONCLUSIONS MM patients with ultra high-risk MM have a median PFS of <24 months with the current standard of care that includes consolidation with autoHCT. These patients may benefit from earlier use of newer treatment modalities, such as CAR-T and bispecific antibodies.
PICO Summary
Population
Adults with multiple myeloma with two or more high-risk cytogenetic abonormalities from a single centre in USA (n=79)
Intervention
Upfront autologous transplant between 2008 and 2018.
Comparison
None
Outcome
At day 100 post transplant and at best post-transplant response, 36 (46%) patients and 40 (51%) patients achieved minimal residual disease (MRD)-negative >/=very good partial response (VGPR), respectively. With a median follow-up in surviving patients of 38.3 (range 11.9 to 104.8) months, the median progression free survival (PFS) and overall survival (OS) in the entire cohort were 22.9 and 71.5 months, respectively. For the subset of patients with three high-risk abnormalities, the median PFS and OS were 15.6 and 28.0 months, respectively. In multivariate analysis, achieving MRD negative >/=VGPR prior to autoHCT was associated with improved PFS (HR 0.42), while male gender (HR 0.15) and achieving MRD negative >/=VGPR post autoHCT (HR 0.27) were associated with improved OS.
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Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation
Pasvolsky, O., Pasyar, S., Bassett, R. L., Khan, H. N., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., et al
Cancer. 2023
Abstract
BACKGROUND The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.
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10.
Impact of gender on outcomes of patients with multiple myeloma undergoing autologous Haematopoietic stem cell transplant
Pasvolsky, O., Saliba, R. M., Masood, A., Mohamedi, A. H., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Ramdial, J., Nieto, Y., et al
British journal of haematology. 2023