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Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34 + cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 10 6  cells/kg) and high (>2.5 × 10 6  cells/kg) CD34 + dose groups. We included 2479 patients, 95 in the low CD34 + group and 2384 in the high CD34 + group. Patients in the low CD34 + group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% vs 35%, p < 0.001) and transplanted after 2009 (88% vs 80%, p = 0.047). Time to neutrophil and platelet recovery was longer in the low CD34 + group. Median PFS and OS were lower in the low CD34 + group (31.6 vs. 43.6 months, p = 0.011 and 76.4 vs. 108.2 months, p < 0.001, respectively). Evaluation of incrementally higher CD34 + dose did not show significant improvement in survival at thresholds >2.5 × 10 6  cells/kg. Multivariable analysis affirmed that CD34 + >2.5 × 10 6  cells/kg was associated with better PFS (HR 0.71, p = 0.008) and OS (0.59, p < 0.001). After propensity score matching, a CD34 + dose >2.5 × 10 6 cells/kg remained a predictor of better OS (0.42, p < 0.001). In conclusion, CD34 + dose >2.5 × 10 6 cells/kg was associated with improved survival, without any additional benefit at incrementally higher doses., (© 2024. The Author(s).)

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years., (© 2024. The Author(s).)

The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 and 24.8 months, (p < 0.001) and the median OS was 130.8, 128.5, 94.2 and 61.4 months (p < 0.001) for patients with R2-ISS stages I, II, III and IV respectively. On multivariable analysis (MVA) for PFS, using R2-ISS stage I as reference, R2-ISS stages III (hazard ratio [95% confidence interval], 1.55 [1.05-2.29]; p = 0.028) and IV (2.04 [1.24-3.36]; p = 0.005) were associated with significantly inferior PFS. In the MVA of OS, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS (2.43 [1.18-5.01]; p = 0.017). Overall, we found that R2-ISS is a reliable prognostic tool for NDMM patients undergoing up-front auto-HCT., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 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 therapy-related myelodysplastic syndrome (tMDS) had high-risk disease, per 2022 European LeukemiaNet and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed tMDS/AML were older at MM diagnosis (median 61 versus 59 years; P = .06), more often were male (73% versus 58%; P = .029), received more than 2 years of lenalidomide maintenance (57% versus 39%; P = .014), and experienced complete remission more frequently after Auto-HCT compared to those who did not develop t-MDS/AML (56% versus 40%; P = .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 transplantation (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 versus 11.1 months for Allo-HCT recipients versus nonrecipients, respectively (P = .25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% confidence interval]: 2.9 [1.3-6.3]; P = .009), age > 60 years (3.1 [1.2-8.2]; P = .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. T-MDS/AML after 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., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Multiple myeloma (MM) patients with high-risk cytogenetic abnormalities have inferior survival outcomes and are underrepresented in clinical trials. There is scarce data on MM patients with more than one high-risk cytogenetic aberration (ie, ultra- high-risk MM). This study was conducted to evaluate outcomes of newly diagnosed MM patients with ultra-high-risk MM who underwent autologous hematopoietic stem cell transplantation (autoHCT). We conducted a retrospective single-center chart review analysis of adult patients with ultra-high-risk MM who underwent autoHCT between 2008 and 2018 at MD Anderson Cancer Center. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), or 1q21 gain or amplification (1q+) by fluorescence in situ hybridization. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Seventy-nine patients with two or more high-risk cytogenetic abnormalities were included in our analysis. The median age of 61 years (range, 33.5 to 76.5 years), and 57% were female. Sixty-seven patients had two high-risk cytogenetic abnormalities, and 12 patients had three high-risk cytogenetic abnormalities. The most common combinations of high-risk 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 (48%) or carfilzomib, lenalidomide, and dexamethasone (16%) as induction therapy. Prior to autoHCT, 52 patients (66%) achieved a very good partial response or better (≥VGPR), whereas 23 patients (29%) achieved minimal residual disease (MRD)-negative ≥VGPR. Fifty-six patients (71%) received post-transplantation maintenance therapy. Thirty-six patients (46%) achieved MRD-negative ≥VGPR at day +100 after autoHCT, and 40 patients (51%) did so at best post-transplantation response. With a median follow-up in surviving patients of 38.3 months (range, 11.9 to 104.8 months), the median PFS and OS in the entire cohort were 22.9 months and 71.5 months, respectively. For the subset of patients with three HR abnormalities, the median PFS was 15.6 months and median OS was 28.0 months. In multivariate analysis, achieving MRD-negative ≥VGPR prior to autoHCT was associated with improved PFS (hazard ratio [HR], .42; P = .045), whereas male sex (HR, .15; P = .009) and achieving MRD-negative ≥VGPR post-autoHCT (HR, .27; P = .026) were associated with improved OS. In conclusion, 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 chimeric antigen receptor T cell therapy and bispecific antibodies., (Copyright © 2023. Published by Elsevier Inc.)

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., (© 2023 Wiley Periodicals LLC.)

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., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

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., (© 2023. The Author(s).)

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 associated with inferior outcomes. Autologous hematopoietic stem cell transplantation (auto-HCT) is standard of care for patients with high-risk MM, yet there are scarce data on post-transplantation outcomes of patients with t(4;14) MM. The aim of the present study was to evaluate outcomes of MM patients with t(4;14) who underwent auto-HCT and received contemporary anti-myeloma agents for induction and post-transplantation maintenance. 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 and 2018 at MD Anderson Cancer Center. Primary endpoints were progression-free survival (PFS) and overall survival (OS), and secondary endpoints were hematologic response and minimal residual disease (MRD) status after auto-HCT. MRD status in the bone marrow biopsy was evaluated using 8-color next-generation flow cytometry with a sensitivity of 1/10 -5 cells. Seventy-nine patients were included (52% male), with a median age of 60 years (range, 32 to 78 years). Forty-four patients (56%) had an additional high-risk cytogenetic abnormality. Fifty patients (63%) achieved at least a very good partial response (≥VGPR) prior to auto-HCT and 20 (25%) had MRD-negative ≥VGPR. At the best post-transplantation evaluation, 90% had ≥VGPR and 63% had MRD-negative ≥VGPR. The median follow-up for survivors was 35.7 months (range, 7.7 to 111.6 months). For the entire cohort, median PFS and OS were 22.9 months and 60.4 months, respectively. Patients with MRD-negative ≥VGPR prior to transplantation had improved PFS and OS on both univariate analysis (UVA) and multivariate analysis (MVA) (hazard ratio [HR], .35 [95% confidence interval (CI), .16 to .76; P = .008] and .12 [95% CI, .03 to .44; P = .002], respectively). The presence of additional high-risk cytogenetic abnormalities was not associated with inferior PFS (P = .57) or OS (P = .70). Post-transplantation lenalidomide-based combinations were associated with improved OS in both UVA and MVA (HR, .14; 95% CI, .04 to .45; P = .001), while their impact on PFS was not statistically significant (P = .37). Our results consolidate t(4;14) as a high-risk abnormality associated with poor outcomes despite novel agent induction, auto-HCT, and post-transplantation maintenance. Despite some inherent study design limitations, including a relatively small cohort and heterogeneity in treatment, we observed that deeper pretransplantation response and post-transplantation 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)., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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 (allo-) hematopoietic cell transplantation (HCT) is a potentially curative option for a subgroup of patients with high-risk MM. This study assessed the long-term outcome of MM patients who underwent allo-HCT while in first remission as consolidation treatment. Thirty-three patients with newly diagnosed MM who underwent allo-HCT as part of consolidation therapy between 1994 and 2016 were reviewed retrospectively. Of these patients, 70% underwent autologous HCT before allo-HCT. All patients were chemosensitive and achieved at least partial response before proceeding to allo-HCT. Most received nonmyeloablative/reduced-intensity conditioning (88%) and a matched sibling donor graft (85%). Acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. The median duration of follow-up was 64.1 months (range, 1.4 to 199.2 months) for all patients and 164.4 months (range, 56.0 to 199.2 months) for survivors. The median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 to 73.0 months). The median time from treatment to progression was 73.0 months (95% CI, 30.6 months to not reached). The median overall survival (OS) was 131.9 months (95% CI, 38.4 months to not reached). Of all patients, 39% were alive for 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 years post-allo-HCT. The cumulative incidence of nonrelapse mortality was 3% at 100 days, 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 (hazard ratio [HR], 2.7; 95% CI, 1.01 to 7.21; P = .047) and OS (HR, 4.91; 95% CI, 1.48 to 16.27; P = .009). Achieving complete remission after allo-HCT also was associated with longer PFS (HR, 0.24; 95% CI, 0.09 to 0.64; P = .004) and OS (HR, .23; 95% CI, .07 to .72; P = .012). Allo-HCT may confer a survival advantage in a selected population of MM patients when performed early in the disease course; additional data on identifying the patients who will benefit the most are needed., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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 (HRMMs) may need a more intense regimen. We hypothesized that adding another antimyeloma drug to Len maintenance would lead to improved outcomes. We conducted this retrospective single-center chart review analysis of adult HRMM patients who underwent autoHCT between 2008 and 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. We divided patients into those who received either single-agent Len maintenance (Len-only) or Len-based combinations (Len-combo). We compared nonrelapse mortality, day 100 and best post-transplantation responses, minimal residual disease status, PFS, and overall survival (OS) between the 2 groups. We also performed sensitivity analyses using inverse probability weights to correct for potential bias owing to nonrandomization of the 2 groups. A total of 231 patients with HRMM were included in our analysis, with a median age of 62.4 years (range, 33.5 to 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 with the Len-only group (32% versus 12%: P < .001). The median duration of follow-up was 40.7 months in the Len-only group and 37.0 months in the Len-combo group. For all patients, the median PFS was 25.5 months, and the median OS was 82.6 months. There was no significant between-group difference in PFS (hazard ratio [HR] 1.01; 95% confidence interval [CI], .71-1.44; P = .94) or OS (HR, .84; 95% CI, .49 to 1.43; P = .52). However, for patients with high-risk cytogenetic abnormalities other than 1q+, there was a trend toward better PFS in the Len-combo group (HR, .59; 95% CI, .32 to 1.09; P = .09), but no difference in OS (HR, .79; 95% CI, .37 to 1.65; P = .53). In this single-center retrospective analysis, the use of Len-based combinations for post-transplantation maintenance was not associated with improved outcomes in HRMM patients; however, there was a trend toward improved PFS in patients with high-risk abnormalities other than 1q+., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of the CDKN2C gene at chromosome region 1p32 (1p-), which is also associated with inferior outcomes. In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p- after high-dose therapy and autologous hematopoietic cell transplantation (auto-HCT). From January 2006 to December 2015, 1491 newly diagnosed patients with MM underwent upfront high-dose therapy and auto-HCT at our institution. Of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p- by FISH from the cohort of 899 patients. A control group (n = 287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above 2 cohorts, using a propensity score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p-. Patients were matched for age at auto-HCT, sex, International Staging System stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen, and maintenance therapy. Sixty-seven (79%), 4 (5%), and 14 (16%) patients had 1q+, 1p-, or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p- and the control group. The median follow-up time for all patients was 29.2 months (range, 0.29 to 84.96). The cumulative incidence of 100-day nonrelapse mortality was 1.2% and 0% for the 1q+/1p- and the control group, respectively. Forty-two patients (50%) in the 1q+/1p- group achieved complete response compared with 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 41% and 79% for the 1q+/1p- group and 56% and 86% for the control group. Patients in the 1q+/1p- group were at significantly increased risk of progression or death compared to the control group (hazard ratio [HR], 2.21; confidence interval [CI], 1.18 to 4.16; P = .014). No significant association between OS in the 2 groups was observed. The outcome of the 1q+/1p- alone (with no additional high-risk cytogenetics) and the propensity score matched control groups was also compared. Median PFS for the 1q+/1p- alone subgroup was 26.6 months, compared with 38.8 months for the control group (HR, 1.9; CI, 0.9 to 4.08; P = .09). The median OS had not been reached for the 1q+/1p- alone subgroup and was 81.1 months for the control group (HR, 1.25; CI, 0.3 to 4.6; P= .73). 1q+/1p- abnormalities with amplification of CKS1B and deletion ofCDKN2Cgenes were associated with shorter PFS compared with a propensity score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+/1p- patients with MM have improved with the use of more effective induction, conditioning, and maintenance therapy compared with historical controls, but we still need more effective therapeutic approaches to fully overcome the negative impact of 1q+/1p-., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

There is limited data on the outcomes of autologous hematopoietic cell transplantation (auto-HCT) in myeloma patients, 75 or older. We retrospectively analyzed all myeloma patients ( n  = 72), aged ≥75, who underwent auto-HCT at our center between January 1, 2000, and December 31, 2015. All patients received melphalan ≥140 mg m -2 conditioning. At day-100, the cumulative incidence of non-relapse mortality was 1%. The overall response rate was 91% with 29% achieving complete/stringent complete remission. The median progression-free survival (PFS) was 31.4 months, and median overall survival (OS) was 72.8 months. The presence of high-risk cytogenetic abnormalities was associated with inferior PFS ( p  = 0.005) and OS ( p  = 0.005), while international staging system stage III was identified as a negative prognostic factor for OS ( p =  0.002 vs. stage II). We conclude that auto-HCT can be safely performed in myeloma patients 75 and older and is associated with encouraging response rates.

Purpose: Patients with multiple myeloma with t(11;14) have been considered to have standard-risk disease. However, several recent reports have shown contradictory results. We identified 95 patients with multiple myeloma with t(11;14) on 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 patients with multiple myeloma 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. Patients in the 2 groups were matched for age, International staging system stage at diagnosis, serum creatinine at presentation, disease status at auto-HCT, type of preparative regimens, dose of melphalan used for conditioning, and induction and maintenance regimens., Results: Patients in t(11;14) group had a post auto-HCT overall response rate (ORR) of 97.5% (78/80), compared with 100% (80/80) in the standard-risk control group ( P = 0.50). Complete response rate in the t(11;14) group was 35% (28/80), compared with 45% (36/80) in the standard-risk control group ( P = 0.26). The 4-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 4-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 with a propensity matched standard-risk control group., Conclusions: Our study confirms that t(11;14) multiple myeloma undergoing upfront autologous transplantation had similar outcomes as patients with multiple myeloma with normal cytogenetic and FISH studies. Existence of additional genomic aberrations by CC or FISH was associated with a worse outcome., (©2019 American Association for Cancer Research.)

Background: Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial., Methods: The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m 2 followed by pharmacokinetically adjusted doses on days -7, -6, -5, and -4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m 2 per day on days -2 and -1 (total melphalan dose 140 mg/m 2 ), or a melphalan dose of 200 mg/m 2 on day -2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov, number NCT01413178., Findings: Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2-47·1) and 20·2 months (IQR 8·8-46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9-64·7) with busulfan plus melphalan versus 43·5 months (19·9-not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30-0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2-3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group., Interpretation: These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma., Funding: This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant (CA016672)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of our study was to determine the impact of high-risk disease (HRD) and MRD on outcomes in myeloma patients receiving bortezomib-based induction followed by autologous hematopoietic stem cell transplant (auto-HSCT). HRD included t(4:14), t(14;16), del 17p, del 1p and/or amplification 1q by cytogenetics/FISH; all others were standard-risk disease (SRD). A subset of 165 newly diagnosed myeloma patients in a 2:1 ratio of HRD:SRD was generated using propensity score based nearest neighbor matching. Multiparametric flow cytometry (MFC) was used to detect MRD after auto-HSCT in select patients. MRD+ status at 3 months post auto-HSCT (hazard ratio (HR = 4.23, p = .028) and HRD (HR = 1.72, p = .026) were associated with a shorter PFS. Similarly, MRD+ 3 months post auto-HSCT (HR = 6.93, p = .08) and HRD (HR = 3.54, p < .001) and were associated with a shorter OS. Despite bortezomib-based induction, upfront auto-HSCT, and use of maintenance therapy, PFS and OS remained worse in MRD+ and HRD patients.

Background: Despite the introduction of effective, novel agents, the outcome of patients with refractory multiple myeloma remains poor, particularly those who are refractory to both proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). Limited data are available on the role of autologous hematopoietic stem cell transplantation in this population., Methods: Patients with refractory myeloma who underwent first autologous hematopoietic stem cell transplantation (auto-HCT) between March 2000 and October 2015 were retrospectively analyzed. Those who had primary refractory disease and those with relapsed and refractory disease were included. Disease that was refractory to at least 1 PI and at least 1 IMiD was classified as double-refractory multiple myeloma (DR-MM)., Results: In total, 233 patients were identified, including 105 (45%) classified with DR-MM and 128 (55%) classified with nondouble-refractory myeloma (NDR-MM). At a median follow-up of 42 months for surviving patients, at least a partial response was observed in 188 patients (81%; 83 patients in the DR-MM group [79%] and 105 patients in the NDR-MM [82%]; P = .77). A near complete response or better was observed in 52 patients (22%; 25 patients in the DR-MM group [24%] and 27 patients in the NDR-MM group [21%]; P = .77). The median progression-free survival was 17.6 months (14.4 months in the DR-MM group and 18.2 months in the NDR-MM group), and the 2-year progression-free survival rate was 38% (35% in the DR-MM group and 40% in the NDR-MM group; P = .40). The median overall survival was 48 months (38.9 months in the DR-MM group and 56.6 months in the NDR-MM group), and the 2-year overall survival rate was 74% (71% in the DR-MM group and 76% in the NDR-MM group; P = .27)., Conclusions: The current findings indicate that auto-HCT is an effective and safe therapy in patients with refractory multiple myeloma, including those who are refractory to IMiDs and PIs. Cancer 2017;123:3568-75. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Although lenalidomide maintenance therapy has demonstrated improved outcomes after autologous hematopoietic stem cell transplantation (auto-HCT) for patients with multiple myeloma (MM), the impact of the duration of this therapy is not clearly known., Methods: This study retrospectively analyzed all MM patients who were placed on maintenance lenalidomide after auto-HCT between January 2007 and December 2013. Progression-free survival (PFS) and overall survival (OS) were analyzed in multivariate Cox proportional hazards regression models that included the duration of maintenance as a time-dependent covariate., Results: Of the 464 patients identified, 46% initiated therapy early (<4 months after auto-HCT). The median PFS and OS were 38 and 78 months, respectively. Improvements in PFS (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.04-0.38; P < .001) and OS (HR, 0.09; 95% CI, 0.03-0.26; P < .001) were seen for those on maintenance for >2 years versus those on maintenance for ≤2 years. For those on maintenance for >3 versus those on maintenance for ≤3 years, this trend continued with improvements seen in PFS (HR, 0.02; 95% CI, 0.00-0.44; P = .012) and OS (HR, 0.05; 95% CI, 0.00-0.83; P = .037). The incidence of second primary malignancies (SPMs) in the entire cohort was 3%. No differences were seen in survival between early and late initiators of maintenance lenalidomide., Conclusions: A longer duration of maintenance therapy was associated with longer survival. The incidence of SPMs was low, and they were not associated with the duration of maintenance. The timing of the initiation of maintenance had no effect on survival. Cancer 2016;122:3831-3837. © 2016 American Cancer Society., (© 2016 American Cancer Society.)