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1.
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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ASCT vs CART for Patients with Relapsed LBCL in PR: Role of TMTV
Strati, P., Pasvolsky, O., Feng, L., Xu, G., Tewari, S., Varghese, J., Ow, K., Santiago, M. S., Al Zaki, A., Jallouk, A., et al
Blood advances. 2023
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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.
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High-dose chemotherapy and autologous stem-cell transplant for relapsed or refractory primary mediastinal b-cell lymphoma
Alkhaldi, H., Reinhardt, A., Barnett, M., Kundu, S., Hosing, C., Ramdial, J., Saini, N., Srour, S., Alousi, A., Kebriaei, P., et al
Transplantation and cellular therapy. 2023
Abstract
Primary mediastinal large B cell lymphoma (PMBCL) is an uncommon aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy ± radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. Sixty patients received rituximab-BEAM (N=37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) ± vorinostat (N=23), with ASCT. Forty-six patients received mediastinal RT, either as prior consolidation of frontline therapy or following ASCT. At median follow-up of 6 years (range, 0.3-21), the 5-year progression-free survival (PFS) and overall survival (OS) rates of the whole group are 58% and 77%, respectively, 51% and 65%, respectively, for R-BEAM patients, and 69% and 82%, respectively, for R-vorinostat/GemBuMel patients. Multivariable analyses showed that negative PET at ASCT [hazard ratio (HR), 0.28)] and involvement of only 1 organ (HR, 0.33) were independently associated with improved PFS. In addition, receiving R-vorinostat/GemBuMel (HR, 0.23) was an independent favorable predictor of OS. In conclusion, HDC/ASCT is effective in R/R PMBCL, with improved outcomes in patients receiving R-vorinostat/GemBuMel.
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Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant
Pasvolsky, O., Bassett, R. L., Ghanem, S., Cuglievan, B., Tewari, P., Hosing, C., Srour, S., Ramdial, J., Mahadeo, K. M., Khazal, S., et al
BMC cancer. 2023;23(1):1258
Abstract
BACKGROUND There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). METHODS Patients aged 0-39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. RESULTS Two hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6-39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03). Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0-196.6) months after ASCT, and SPM was the cause of death in five (50%) of them. CONCLUSIONS CAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.
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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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Outcomes of young adults (aged ≤ 40 years) with newly diagnosed multiple myeloma after up-front autologous stem cell transplant
Pasvolsky, O., Marcoux, C., Milton, D. R., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., Nieto, Y., et al
British journal of haematology. 2023
Abstract
Multiple myeloma (MM) primarily affects older patients. There are scarce data on the outcomes of young adults undergoing autologous transplantation (auto-HCT). In this single-centre analysis, we included 117 younger patients, with a median age of 37 years (range 22-40) at transplant. Seventeen (15%) patients had high-risk cytogenetics. Before transplant, 10% of patients achieved ≥CR and 44% achieved ≥VGPR. At best post-transplant response, 56% and 77% of patients achieved ≥CR and ≥VGPR respectively. With a median follow-up for survivors of 72.6 months (range 0.9-238.0), median PFS and OS were 43.1 months (95% CI 31.2-65.0) and 146.6 months (95% CI 100.0-208.1) respectively. Patients who underwent auto-HCT after 2010 had better median PFS (84.9 months vs. 28.2 months, p < 0.001) and OS (NR vs. 91.8 months, p < 0.001) compared with those transplanted earlier. In multi-variate analysis, achieving ≥CR as best post-transplant response was associated with improved PFS (HR [95% CI] 0.55 [0.32-0.95], p = 0.032), while achieving ≥VGPR was predictive of superior OS (0.32 [0.16-0.62], p < 0.001). Three patients (3%) developed a second primary malignancy. Younger MM patients had durable survival after auto-HCT, which further improved after the availability of novel anti-myeloma drugs in recent years. Depth of response following transplant remains a key predictor of survival.
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Single-agent lenalidomide maintenance after upfront autologous stem cell transplant for newly diagnosed multiple myeloma: The MD Anderson experience
Pasvolsky, O., Milton, D. R., Masood, A., Sami, S. S., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., Lin, P., Ramdial, J., et al
American journal of hematology. 2023
Abstract
The optimal duration of lenalidomide (Len) maintenance for patients with multiple myeloma (MM) after autologous stem cell transplantation (autoHCT) is unknown. We conducted a retrospective single-center analysis of adult MM patients that received upfront autoHCT between 2005 and 2021, followed by single-agent Len maintenance. A total of 1167 patients were included with a median age of 61.4 (range 25.4-82.3) years, and high-risk chromosomal abnormalities in 19%. Median duration of maintenance was 22.3 (range 0.03-139.6) months. After a median follow-up of 47.9 (range 2.9-171.7) months, median PFS and OS for the entire cohort were 56.6 (95% CI 48.2-61.4) months and 111.3 (95% CI 101.7-121.5) months, respectively. In MVA, high-risk cytogenetics was associated with a worse PFS (HR 1.91) and OS (HR 1.73) (p < .001 for both). Use of KRD induction and achievement of MRD-negative ≥ VGPR before autoHCT were associated with an improved PFS (HR 0.53 and HR 0.57, respectively; p < .001 for both). Longer maintenance duration, even with a 5-year cutoff, was associated with superior PFS and OS (HR 0.17 and 0.12, respectively; p < .001 for both). A total of 106 patients (9%) developed a second primary malignancy (SPM), mostly solid tumors (39%) and myeloid malignancies (30%). Longer maintenance duration was associated with a higher risk of SPM, reaching statistical significance after >2 years (odds ratio 2.25; p < .001). In conclusion, outcomes with Len maintenance were comparable to those reported in large clinical trials. Longer duration of maintenance, even beyond 5 years, was associated with improved survival.
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Impact of clonal plasma cells in autografts on outcomes in high-risk multiple myeloma patients
Pasvolsky, O., Milton, D. R., Rauf, M., Ghanem, S., Masood, A., Mohamedi, A. H., Tanner, M. R., Bashir, Q., Srour, S., Saini, N., et al
Blood cancer journal. 2023;13(1):68
Abstract
Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC- in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC- (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC- groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.