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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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Radiation Therapy Can Be Safely Incorporated into Pretransplantation Treatment Regimens for Patients with Multiple Myeloma
Damron, E. P., Qazilbash, M. H., Fang, P. Q., Wu, S. Y., Dabaja, B. S., Rondon, G., Hosing, C., Champlin, R. E., Bashir, Q., Shpall, E. J., et al
Transplantation and cellular therapy. 2023;29(1):37.e1-37.e7
Abstract
Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplantation (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. In this study, we retrospectively examined the possible effect of RT on PBPC collection. We reviewed the charts of 732 patients with MM treated with RT at our institution from 1999 to 2017, including patients who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM RT) were reviewed to estimate the percentage of bone marrow (BM) treated using published estimates of skeletal BM distribution. Statistics were performed using Pearson correlation and the t-test. The 732 MM patients included 485 planned for ASCT; of these, 223 received RT prior to PBPC collection and were included in the final cohort. The median age at PBPC collection was 59 years (range, 33 to 80 years). For SIT, patients received combination regimens including the following agents: bortezomib (142 patients; 64%), lenalidomide (111 patients; 50%), and alkylators (46 patients; 21%). Nine patients (4%) received dexamethasone alone. The median cumulative %BM treated per patient was 6.7 (range .0 to 47.4). The median RT dose was 24 Gy (range, 10.0 to 75.6 Gy). Mobilization was performed using granulocyte-colony stimulating factor (G-CSF) alone (189 patients; 85%), G-CSF with plerixafor (15 patients; 7%), or chemotherapy (19 patients; 9%). A median of 7.8 × 10(6) CD34(+)/kg PBPCs (range, .5 to 54.8× 10(6) CD34(+)/kg) were collected in a median of 3 (range, 1 to 9) apheresis procedures. One hundred ninety-six patients (99%) collected ≥2.0 × 10(6) CD34(+)/kg PBPCs, and 166 (83%) collected >5.0 × 10(6) CD34(+)/kg PBPCs. The number of PBPCs collected was not associated with %BM treated (P = .15) or RT dose (P = .56). The number of apheresis procedures performed was not associated with %BM treated (P = .54) or RT dose (P = .85). The amount of PBPCs collected did not differ significantly between patients receiving RT to the pelvis/sacrum (P = .20) and those receiving RT to the spine (P = .13). The time to platelet engraftment was longer for patients with higher %BM treated (P = .02). Eleven patients did not undergo a confirmed ASCT, owing to patient preference (3 patients), trial therapy (1 patient), comorbidities (1 patient), election for hospice (1 patient), inadequate collection (4 patients), or inadequate follow-up (1 patient). In our study cohort, RT prior to ASCT did not impair successful ASCT. RT must be carefully planned and delivered to ensure safe incorporation into pre-ASCT treatment regimens.
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Efficacy, safety, and cost of mobilization strategies in multiple myeloma: a prospective, observational study
Dhakal, B., Zhang, M. J., Burns, L. J., Tang, X., Meyer, C., Mau, L. W., Nooka, A. K., Stadtmauer, E., Micallef, I. N., McGuirk, J., et al
Haematologica. 2023;108(8):2249-2254
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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 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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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
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10.
KRD vs. VRD as induction before autologous hematopoietic progenitor cell transplantation for high-risk multiple myeloma
Gaballa, M. R., Ma, J., Rauf, M., Bassett, R., Pasvolsky, O., Tanner, M. R., Bashir, Q., Srour, S. A., Saini, N., Ramdial, J., et al
Bone marrow transplantation. 2022
Abstract
Bortezomib, lenalidomide, and dexamethasone (VRD) induction is standard prior to autologous hematopoietic cell transplantation (auto-HCT) in newly diagnosed, high-risk multiple myeloma (ND-HRMM). Carfilzomib (K) is another proteasome inhibitor approved for MM. In this single-center, retrospective analysis, we compared outcomes in ND-HRMM with pre-transplant KRD or VRD induction. High-risk was defined by t(4:14), t(14:16), 1q21 gain/amplification, or del(17p). Primary endpoints were progression-free (PFS) and overall survival (OS). Of 121 ND-HRMM patients, 63 received KRD, and 58 received VRD. Post-induction, complete (CR), very good partial (VGPR), partial response (PR), and overall response (ORR) rates were 23.8%/49.2%/25.4%/98.4% with KRD, and 19%/46.6%/27.6%/93.1% with VRD. At day 100 post-auto-HCT, these were 38.1%/42.9%/19%/100% with KRD, versus 35.1%/49.1%/12.3%/94.8% with VRD. Pre-auto-HCT, 11 (18.3%) KRD and 7 (12.5%) VRD patients had minimal residual disease (MRD)-negative CR (p = 0.45). Post-auto-HCT, 14 (41.2%) and 13 (43.3%) patients had MRD-negative CR (p = 1.000). Median PFS was 38.2 (95%CI 28.7-NA) and 45.9 months (95%CI 43.2-NA) for KRD and VRD, respectively (p = 0.25). Respective 3-year PFS and OS were 53.5% (95%CI 41.1-69.6) and 95.2% (95%CI 90-100) for KRD and 64% (95%CI 51.6-79.5) and 84.2% (95%CI 73.5-96.3, p = 0.30) for VRD. Overall, KRD induction pre-auto-HCT does not improve outcomes. Prospective, randomized studies are needed to confirm these findings.