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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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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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Full text
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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.
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Lenalidomide-Based Maintenance After Autologous Hematopoietic Stem Cell Transplant for Patients with High-Risk Multiple Myeloma
Pasvolsky, O., Milton, D. R., Rauf, M., Tanner, M. R., Bashir, Q., Srour, S., Tang, G., Saini, N., Ramdial, J., Masood, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMM) may need a more intense regimen. OBJECTIVE We hypothesized that adding another anti-myeloma drug to Len maintenance would lead to improved outcomes. STUDY DESIGN We conducted a retrospective single-center chart review analysis of adult HRMM patients who received autoHCT between 2008-2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization (FISH). We divided patients into those who received either single-agent Len maintenance (Len-only) or Len-based combinations (Len-combo). We compared non-relapse mortality (NRM), day 100 and best post-transplant responses, minimal residual disease (MRD) status, PFS, and overall survival (OS) between the two groups. We also performed sensitivity analyses using inverse probability weights to correct for potential bias due to nonrandomization of the two groups. RESULTS A total of 231 patients with HRMM were included in our analysis, with a median age of 62.4 (range 33.5-79.9) years, and 55% were male. There were 153 patients in the Len-only group and 78 in the Len-combo group. Len-combo regimens were either doublets (Len with dexamethasone [dex: n=10], elotuzumab [n=28] or ixazomib [n=14]) or triplets (Len with bortezomib/dex [n=10], ixazomib/dex [n=10] or carfilzomib/dex [n=6]). More patients in the Len-combo group had ≥2 high-risk cytogenetic abnormalities compared to the Len-only group (32% vs. 12%: p<0.001). Median follow-up was 40.7 and 37.0 months in the Len-only and Len-combo groups, respectively. Median PFS and OS for all patients were 25.5 and 82.6 months, respectively. There was no significant difference in PFS (hazard ratio [95% CI]: 1.01 [0.71-1.44], p=0.94) or OS (0.84 [0.49-1.43], p=0.52) between the Len-only and the Len-combo groups, respectively. However, for patients with high-risk cytogenetic abnormalities other than 1q+, there was a trend towards better PFS in the Len-combo group (0.59 [0.32-1.09], p=0.09), but no difference in OS (0.79 [0.37-1.65], p=0.53). CONCLUSIONS In this single center retrospective analysis, use of Len-based combinations for post-transplant maintenance did not show improvements in HRMM patient outcomes. However, there was a trend towards improved PFS in patients with high-risk abnormalities other than 1q+.
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Melphalan dose intensity for autologous stem cell transplantation in multiple myeloma
Srour, S. A., Milton, D. R., Bashir, Q., Nieto, Y., Saini, N., Daher, M., Ramdial, J., Im, J., Hosing, C., Delgado, R., et al
Haematologica. 2021
Abstract
Not available.
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Busulfan and melphalan conditioning is superior to melphalan alone in autologous stem cell transplantation for high-risk MM
Saini, N., Bashir, Q., Milton, D. R., Tang, G., Delgado, R., Rondon, G., Popat, U. R., Hosing, C. M., Nieto, Y., Kebriaei, P., et al
Blood advances. 2020;4(19):4834-4837
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Impact of autologous transplantation in multiple myeloma patients with t(11;14): a propensity-score matched analysis
Saini, N. Y., Ma, J., Milton, D. R., Patel, R. D., Varma, A., Bashir, Q., Delgado, R. E., Tang, G., Rondon, G., Popat, U., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2019
Abstract
PURPOSE Multiple myeloma (MM) patients with t(11;14) have been considered to have standard-risk disease. However, several recent reports have shown contradictory results. We identified 95 MM patients with t(11;14) on Fluorescence In Situ Hybridization (FISH) studies, who underwent upfront autologous hematopoietic stem cell transplant (auto-HCT) at our center. We compared their outcome with a group of standard-risk MM patients who had diploid cytogenetics by both conventional cytogenetics (CC) and FISH (n=287). EXPERIMENTAL DESIGN To reduce the bias between the groups, we performed a 1:1 propensity score matching technique for analysis. A total of 160 patients, 80 in each group, were identified. RESULTS Patients in t(11;14) group had a post auto-HCT overall response rate (ORR) of 97.5%(78/80), compared to 100% (80/80) in the standard-risk control group (p=0.50). CR rate in the t(11;14) group was 35%(28/80), compared to 45%(36/80) in the standard-risk control group (p=0.26). The four-year PFS rates were 40.8% (95% CI: 29.6%-56.1%) and 51.1% (95%CI: 39.4%-66.3%) in the t(11;14) and standard-risk control groups, respectively (p=0.14). The four-year OS rates were 74.9% (95%CI: 63.3%-88.7%) and 88.3% (95%CI: 80.4%-97.0%) in the t(11;14) and standard-risk control groups, respectively(p=0.17). Also, patients with t(11;14) with concurrent cytogenetics had significantly poor PFS and OS compared to a propensity matched standard-risk control group. CONCLUSIONS Our study confirms that t(11;14) MM undergoing upfront autologous transplantation had similar outcomes as MM patients with normal cytogenetic and FISH studies. Existence of additional genomic aberrations by CC or FISH was associated with a worse outcome.