Upfront Autologous Hematopoietic Cell Transplantation Research Articles

Impact of Age on Outcome in Newly Diagnosed Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Cell Transplantation from the Worldwide Network for Blood and Marrow Transplantation Global Study

Background ： Induction therapy with proteasome inhibitors and immunomodulatory agents followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care in front line multiple myeloma (MM) treatment. Utilization of autologous HCT is increasing worldwide in younger and older patients in light of improvements in supportive care and infrastructure. However, global perspectives on patterns of patient age and the impact of age on outcomes in this population are scarce. In the current analysis of global registry data, we focused on the age distribution and the association of age with outcomes after HCT worldwide. Methods: Data were provided by the Worldwide Network for Blood and Marrow Transplantation through the European Society for Blood and Marrow Transplantation (EBMT), the Center for International Blood and Marrow Transplantation (CIBMTR), the Australia and New Zealand Transplant and Cellular Therapy Registry (ANZTCTR), the Asian Pacific Blood and Marrow Transplant Group (APBMT), the Eastern Mediterranean Blood and Marrow Transplant Group (EMBMT), the Latin American Bone Marrow Transplant group (LABMT), and the Ottawa hospital myeloma registry. The study included newly diagnosed MM patients transplanted between 2013 and 2017. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), incidence of relapse, and non-relapse mortality (NRM). The probability of OS and PFS was estimated based on the Kaplan-Meier method and differences were analyzed using the log-rank test. The incidences of relapse and NRM were modeled using the crude cumulative incidence estimator and compared between groups with Gray's test. Multivariate analyses were performed using Cox (cause-specific) proportional hazards models including a random effect for country. Age at HCT was modeled as a categorical variable (18-39, 40-64, 65-69, 70-74, and ≥75 years). Models further included patient sex, year of HCT, stage of disease at HCT, Karnofsky score, myeloma subclassification, conditioning dosage, interval between diagnosis and HCT, HCT comorbidity index, ISS at diagnosis, and cytogenetic risk score. Results: In total, 61,725 patients were included in this study; 37,459 (60.1%), 16,217 (26.3%), 3,164 (5.1%), 3,122 (5.1%), 543 (0.9%), 524 (0.8%), 339 (0.5%), 188 (0.3%), and 169 (0.3%) from EBMT, CIBMTR, ANZTCTR, Japan (APBMT), EMBMT, Taiwan (APBMT), LABMT, Ottawa, and Malaysia (APBMT), respectively. The median age at HCT was 60.8 (interquartile range: 54.6-65.8) years. The percentage of patients in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, varied considerably; 2%, 68.9%, 21.8%, 6.5%, and 0.8%, respectively (Table 1). The proportion of <40 years was higher in Malaysia, LABMT, and EMBMT (4-6%) compared to EBMT, CIBMTR, Japan, and ANZTCTR (2%). In contrast, the proportion of patients ≥65 years was higher in EBMT, CIBMTR, ANZTCTR, and Japan (>20%) compared to Malaysia, LABMT, and EMBMT (7-13%). The following patterns were observed in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, respectively. Melphalan 200 mg/m 2 for conditioning was used more frequently in younger patients (78.4%, 75.4%, 63.2%, 40.6%, and 28.3%, respectively). In 60.7% of the group ≥75 years, a lower dose of melphalan 140 mg/m 2 was chosen. OS was lower with older age (p<0.001) and was 86%, 83%, 81%, 78%, and 75% at 3 years, respectively (Figure and Table 1). PFS was similarly associated with older age (56%, 51%, 50%, 47%, and 45% at 3 years, respectively (p<0.001)). The cumulative incidence of relapse was not significantly different (15%, 16%, 15%, 16%, and 16% at 1 year, respectively (p=0.74)), but the cumulative incidence of NRM was higher with older age (p<0.001) and was 0%, 1%, 2%, 2%, and 4% at 1 year, respectively. On multivariate analysis, older age was associated with lower OS (overall p<0.0001), lower PFS (overall p=0.003), and higher NRM (overall p<0.0001), but not with the risk of relapse (overall p=0.79). Conclusions: There is considerable global variability in the age distribution of patients receiving HCT. Globally, 2% of patients receiving front line HCT for myeloma are aged <45 and 0.8% are >75 years. Advancing age was a significant risk factor for OS and PFS due to differences in NRM, but even in patients >75 years NRM was very low.

A retrospective analysis of 124 patients with multiple myeloma who received up-front autologous hematopoietic cell transplantation following triplet induction therapy

The IFM/DFCI group reported that VRD induction followed by up-front autologous peripheral blood stem cell transplantation (ASCT) and maintenance therapy led to median PFS of 50 months, which established up-front ASCT as the standard of care even in the era of novel agents. We conducted a retrospective analysis on outcomes of patients who received triplet induction therapy followed by up-front ASCT at our institution. A total of 124 patients received ASCT between November 2016 and December 2021 at Japanese Red Cross Medical Center. Patient characteristics, treatment response before and after ASCT, and PFS and OS were retrospectively analyzed. VRD-based induction therapy was used for 94%. Among 118 evaluable patients, 116 (98%) received either consolidation and/or maintenance therapy. Best responses were ≥CR 77% and ≥VGPR 94%, respectively. Sixty-eight out of 104 patients achieved MRD-negativity by multiparameter FCM (<10-5). Five-year estimated PFS and OS were 54.7% and 80.2%, respectively. Age ≥65, high-risk cytogenetic abnormalities, and <VGPR before ASCT were identified as worse prognostic factors for PFS. Patients who achieved MRD negativity had significantly PFS (p=0.0048, 4-yr PFS 86.4% vs. 49.8%). The negative impact on PFS in the high-risk group can be overcome by achieving MRD-negativity. Prospective research is warranted to evaluate the effectiveness of consolidation therapy.

Outcomes of upfront autologous hematopoietic cell transplantation in patients with multiple myeloma who are 75 years old or older.

Consolidative autologous hematopoietic stem cell transplantation (AHCT) is commonly used for patients with multiple myeloma (MM). We studied AHCT use and outcomes in patients with MM ≥75 years old. Patients with MM ≥75 years old receiving AHCT between 2013 and 2017 in the United States were identified using the Center for International Blood and Marrow Transplant Research database. Relapse and/or progression (REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models. Covariates used were age, sex, Karnofsky performance score (KPS), HCT-comorbidity index (HCT-CI), International Staging System and/or Durie-Salmon stage, high-risk cytogenetics, melphalan dose, and disease status at and 1 year after transplant. AHCT utilization rate using the Surveillance, Epidemiology, and End Results database was used to estimate specific incidence among ≥75 years old by race and gender. Of 360 patients, 63% were male, 84% were White, 56% had KPS <90, and 57% had HCT-CI ≥3. The 100-day transplant-related mortality was 1% (0%-2%) with a 2-year REL rate of 27% (95% confidence interval [CI], 22%-33%), PFS of 66% (95% CI, 60%-72%), and OS of 83% (95% CI, 78%-87%). On multivariate analysis, only high-risk cytogenetics was associated with REL risk and decreased PFS. In White males, transplant utilization rate was 5.2%-5.8% compared to 3.5%-4.0% in African American males (P = .02). There was 3.37-3.79% transplant utilization in White females compared to 1.88-2.12% in African American females (P < .01). The use of AHCT was associated with excellent 2-year outcomes in this selected MM population ≥75 years old. Transplant utilization for patients ≥75 years old remains low with significant racial and gender disparities.

The Role of Upfront Autologous Hematopoietic Cell Transplantation in the Treatment of Mantle Cell Lymphoma, a Population Based Study Using the National Cancer Data Base (NCDB)

Introduction: There are no prospective randomized data supporting the use of upfront consolidative autologous stem cell transplant (ASCT) in newly diagnosed mantle cell lymphoma (MCL) patients (pts). The aim of this population-based study in MCL pts is to better define the impact of frontline ASCT on overall survival (OS), and to identify factors influencing treatment selection.Methods: Using the National Cancer Data Base (NCDB), we identified pts with newly diagnosed MCL treated from 2004-2012 with multi-agent chemo alone or in combination with consolidative ASCT as part of first line treatment. Univariable and multivariable Cox proportional hazards regression analyses were used to identify predictors for treatment selection and OS, including age, gender, race, stage, Charlson-Deyo comorbidity index (CDCI), income, education, insurance, treatment facility type, distance to treatment facility and year of diagnosis. Income was recorded as quartiles of median annual household income and education as percentage of persons with less than high school education in pts' residence census. Including these same factors, a propensity score matched analysis (PSMA) was performed to further account for confounding variables.Results: We identified 16,035 MCL pts with known survival times. The following groups were excluded: no chemo (n=3,193), chemo status/type unknown (n=1,056), chemo contraindicated (n=199), single-agent chemo (n=983), received allogeneic SCT (n=79) or ASCT data missing (n=235). The final analysis included 10,290 pts. Median age was 65 years (range 20-90); 66% were > 60 years, 73% male, 93% Caucasian, and 78% had stage III-IV. CDCI was 0 in 79%, 1 in 16% and ≥2 in 5%. Forty percent of pts were treated at academic institutions and 49% travelled >11.5 miles to receive treatment. Medicare was the most common insurance type (48%), followed by private (43%) and Medicaid (4%). Median follow up was 34 months (interquartile range (IQR) 16-60). Median OS for the entire cohort was 64 months; 5- and 10-year OS rates were 52% and 33%, respectively. Seventeen percent of the pts (n=1774) underwent upfront ASCT, and there was a trend of increased use from 2004-2012 (11.9% in 2004 and 21.2% in 2012) that resulted in an annual increase of 1.2% (p<0.001). 31% of pts ≤60 and 25% of pts ≤70 years received ASCT. For the ASCT group, median age was 58 years (IQR 52-64; range 23-77); 89 pts (5%) were ≥70 years of age. Predictors for ASCT use included (p<0.001 for each): stage III-IV (odds ratio (OR) 2.4), having private insurance (OR 2.71), higher education (OR 2.1), no transition of care (diagnosis and treatment done at the same facility) (OR 3.15), longer distance (> 11.5 miles) to treatment facility (OR 1.73) and year of diagnosis ≥2009 (OR 1.62) (Figure 1). Median follow up was 44 months (IQR 28-69) for ASCT group and 31 months (IQR 14-58) for chemo only group. Five and 10-year OS rates for ASCT and chemo group were 77%, 57%, 47% and 28%, respectively. After adjusting for other covariates, the use of ASCT was associated with superior OS (HR: 0.46; 95% CI 0.41-0.52; p<0.001). Other factors associated with superior OS were: female gender (HR 0.92, p=0.01), income (HR 0.92, p<0.001), private insurance (HR 0.71, p<0.001), no transition of care (HR 0.82, p<0.001) and diagnosis year ≥2009 (HR 0.91, p=0.005). Predictors for inferior OS were: age >60 (HR 1.62, p<0.001), African American race (HR 1.23, p=0.009), stage III-IV (HR 1.58, p<0.001) and CDCI ≥2 (HR 2.0, p<0.001). Using a subset of 1582 pts treated with ASCT and 1582 matched controls treated with chemo only, PSMA confirmed the OS benefit associated with ASCT (HR 0.5; CI 0.44-0.57, p<0.001). This OS benefit was observed in both younger (≤60 years: HR 0.44, CI 0.37-0.53, p<0.001) and older pts (>60 years: HR 0.59, CI 0.46-0.68; p<0.001) (Figure 2).Conclusion: In this large MCL cohort, the use of upfront consolidative ASCT was associated with superior OS when compared to chemo alone. Less than one third of young MCL pts treated with multi-agent chemo received consolidative ASCT, and this was influenced by sociodemographic factors with patterns favoring pts with higher education and private insurance. While one caveat in interpreting this retrospective study is that ASCT may have been preferentially applied to pts who responded to induction therapy, these data suggest clinical efficacy of ASCT in MCL. Prospective randomized trials are needed for further validation. [Display omitted] DisclosuresMajhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Revised-International Staging System (R-ISS) Is Independently Predictive and Prognostic for Early Relapse (

Background: R-ISS, which includes ISS combined with presence of t(4;14), 17pdel or t(14;16) and/or elevated serum LDH has been proposed and validated in Europe. Early relapse (<24 months) is a strong predictor of worse MM outcomes after AHCT. We hypothesized that R-ISS at diagnosis will predict early relapse and remain prognostically important among early relapsers. We analyzed post-relapse overall survival (OS) by R-ISS among early post-AHCT MM relapsers.Patients and Methods: Using the Center for International Blood and Marrow Transplant Research database, we identified MM patients receiving first AHCT in 2008-2014 with melphalan conditioning after novel therapy induction, within 18 months of diagnosis, and available diagnostic LDH and molecular studies (n= 628). Relative risk of relapse/progression, progression-free survival (PFS) and OS was calculated using the Cox proportional hazards regression with R-ISS group as predictor. A landmark analysis was conducted at 24 months to identify patients who relapsed within 24 months. Post-early relapse survival was tested in multivariate analysis to identify factors affecting post-relapse OS.Results: The number of patients were: R-ISS stage I, N=199; II, N=360 and III, N=69. Baseline characteristics are shown in table 1. R-ISS II had 13% ISS I, 59% ISS II and 28% ISS III patients. More patients in R-ISS III had received more than 1 line of chemotherapy (29% compared to 20% for R-ISS II and 15% for R-ISS I). Disease status at AHCT was similar in all 3 groups. Worse relapse/progression, progression-free and overall survival was seen with higher R-ISS (table 2). The cumulative incidence of early relapse was 23% (R-ISS I), 39% (R-ISS II) and 50% (R-ISS III) groups (p <0.001). Multivariate analysis of post- relapse OS among early relapsers showed that R-ISS III at diagnosis was independently prognostic (table 3). Figure 1 shows post-relapse survival by R-ISS groups.Conclusions: We conclude that R-ISS at diagnosis is predictive of early relapse after upfront autoHCT and R-ISS is independently prognostic of post-relapse survival among early relapsers after AHCT. Among patients who relapse early, HCT-CI≥3, use of >1 line of induction chemotherapy and melphalan dose are independently associated with worse post-relapse survival. [Display omitted] DisclosuresD'Souza:Celgene: Consultancy; Prothena: Research Funding; Merck: Research Funding. Gasparetto:Janssen, BMS, Celgene: Consultancy; Celgene: Research Funding; Janssen, BMS, Celgene: Other: Travel, accommodations, or other expenses paid or reimbursed; Janssen, BMS, Celgene, Takeda: Honoraria. Kumar:Skyline: Honoraria; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding.

Novel prognostic scoring system for autologous hematopoietic cell transplantation in multiple myeloma.

We studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008-2017 to develop a prognostic model to predict outcomes. High-risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high-risk cytogenetics [hazard ratio, (HR) 1·68 (1·3-2·17)] and pre-AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33-2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07-1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three-category system with low risk (0-3), intermediate risk (4-8) and high risk (9-10) showed 3-year progression-free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52-63) vs. 49% (95% CI: 43-56) vs. 31% (95% CI: 12-51), P < 0.001 respectively, and 3-year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84-91) vs. 81% (95% CI: 76-86) vs. 64% (95% CI: 39-80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma

Breaking the Glass Ceiling of Age in Transplant in Multiple Myeloma

Revised International Staging System Is Predictive and Prognostic for Early Relapse (

The revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on postrelapse survival after an early relapse. Using the Center for International Blood and Marrow Transplant Research database we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n = 628). Relative risks of relapse/progression, progression-free survival (PFS), and OS were calculated with the R-ISS group as a predictor in multivariate analysis. Among early relapsers, postrelapse survival was tested to identify factors affecting postrelapse OS. The cumulative incidence of early relapse was 23%, 39%, and 50% for R-ISS I, R-ISS II, and R-ISS III, respectively (P < .001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior postrelapse OS among early relapsers, as was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects postrelapse survival among early relapsers.

Staging Systems for Newly Diagnosed Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation: The Revised International Staging System Shows the Most Differentiation between Groups

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.

Trends in Pre- and Post-Transplant Therapies Prior to First Autologous Hematopoietic Cell Transplantation Among Patients with Multiple Myeloma in the United States, 2004-2014

Background: Novel therapies and novel treatment paradigms such as post-transplant consolidation and/or maintenance therapies within the last decade have led to remarkable improvement in the survival of multiple myeloma (MM), the second most common hematologic malignancy seen in adults. Upfront autologous hematopoietic cell transplantation (AHCT) remains the standard of care in transplant-eligible patients. We analyzed trends in pre- and post-transplant therapies among patients undergoing AHCT for MM in the United States (US) using the Center for International Blood and Marrow Transplant Research (CIBMTR) database.Methods: All first AHCT in the US (n=37705) using high dose melphalan for MM reported to the CIBMTR between 2004 and 2014 were included and a representative subset (n=5077) were included in subanalyses. During this period, the CIBMTR captured 60-80% of AHCT activity for MM in the US. Demographic, disease-related and treatment-related data were analyzed for trends. Data on use of individual chemotherapies for induction and post-transplant consolidation/maintenance were obtained (thalidomide, T; lenalidomide, R; bortezomib, V; cyclophosphamide, C; dexamethasone, D). Post-transplant therapies were available in the 2008-2014 cohort. Kaplan-Meier method was used to conduct survival analysis; PFS and OS analysis were compared 2004/05, 2006/07, 2008/09, 2010/11 and 2012/13 so that at least 3 years of actual follow up was available for all patients.Results: The baseline demographic data for the 5077 patients (2004/05, N =1062, 2006/07, N=972, 2008/09, N=1156, 2010/11, N=566, 2012/14, N=1321) showed a median (range) age was 59 (20-82) years, with 58% males, 23% African Americans, 42% KPS <90%. International Staging System, ISS stage III was seen in 33%. 76% of patients underwent first AHCT in <12 months from diagnosis. 88% had chemosensitive disease (i.e. pre-AHCT response partial response or better), 85% of patients had melphalan dose 200 mg/m2. 27% had AHCT in <6 months of diagnosis, 49% 6-12 months, 14% 12-24 months and 9% >24 months. The median follow up of survivors was 68 months (1-135). Figure 1A shows the various induction regimen trends over the period. RVD is the most frequent pre-transplant induction regimen and used in 44% of induction regimens since 2010, followed by VD, CVD and RD. Planned post-transplant treatments (consolidation or maintenance) at day 100 were more frequent after 2010 (Figure 1B) with R being the most frequent maintenance agent. The frequency of maintenance utilization did not go up significantly from 2010 to 2014, and 51% of patients received post-transplant therapies during this period. Among the patients who died, myeloma remained the most common cause of death: 2004-2005, 70%; 2006-2007, 74%; 2008-2009, 76%; 2010-2011, 79% and 2012-2014, 75%. Survival data showed improvement in PFS over the study period with 3-year median PFS improving from 29 (26-32) months in 2004/05 to 32 (29-35) months in 2006/07 to 38 (35-41) months in 2008/09 to 52 (48-56) months in 2010/11 to 56 (50-61) months in 2012/13 (p-value <0.001) (Figure 2). Similarly, 3 year median OS also showed improvement in successive time periods; 74 (72-77) months in 2004/05 to 77 (74-79) months in 2006/07, 77 (74-79) months in 2008/09, 78 (74-81) months in 2010/11 to 83 (79-87) months in 2012/13 (p-value <0.001) (Figure 3).Conclusions: This analysis shows that outcomes of upfront AHCT recipients for MM have improved in the last 10 years at a steady pace with a substantial improvement in the most recent cohort (Fig 3). RVD is currently the most common pre-transplant induction regimen since 2010. Approximately half of patients are placed on maintenance treatment after AHCT, with R as the most frequently used maintenance agent. Despite these impressive gains in the field, progression of MM remains the most frequent cause of death. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma

Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving “upfront” AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.

Post-Transplant Outcomes in High-Risk Compared with Non–High-Risk Multiple Myeloma: A CIBMTR Analysis

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Post-Transplant Therapy Is More Important Than Induction Regimen Choice in Autologous Hematopoietic Cell Transplantation (AHCT) Recipients for Multiple Myeloma (MM)

Background:Modern therapies incorporating bortezomib (V), lenalidomide (R), cyclophosphamide (C) and dexamethasone (D) constitute the most common doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens for transplant eligible MM in the US. These regimens produce an overall response rate of >80% but their impact on longer term post-AHCT outcomes are largely unknown.Patient and Methods: We evaluated the relative impact of pre- and post-AHCT treatment on 693 patients receiving upfront AHCT after induction with RD (178), VD (161), CVD (84) or VRD (270) using data prospectively reported to the CIBMTR from 2008-2013. Analysis was limited to those receiving one line of induction chemotherapy and a single transplant with 200 mg/m2 melphalan as conditioning regimen no later than 12 months from treatment initiation. Survival endpoints were evaluated from time of AHCT and the planned use of post-AHCT maintenance incorporating R or V was also considered.Results: The table shows patient characteristics. Median number of induction cycles were 4 (range, 2 to 16) and median time to transplant was 6.5 months. Median follow up was 36 months (3 to 82) from time of transplant. Age, disease stage, disease status at transplant and cytogenetic risk were similar between the 4 cohorts. Fourteen percent had high-risk chromosomal abnormalities [17pdel, t(4;14), t(14;16), chromosome 1 abnormalities and hypodiploidy]. CVD and VD were used more frequently in patients with renal failure. Doublet use was more common before 2010 (55%) and triplets after 2010 (85%). Use of R or V post-AHCT chemotherapy was higher in with VRD (79%) and CVD (81%) cohorts vs. RD (53%) and VD (67%).No differences in pre- or post-AHCT responses were seen with regard to choice of induction agents. Pre-AHCT responses ≥VGPR were 57% for VRD vs. 45/42/51% for CVD/RD/VD respectively. Corresponding post AHCT responses at day 100 were 65% for VRD and 58/63/65% respectively.In multivariate analysis of relapse, progression free (PFS) and overall survival (OS), there was no overall difference in these outcomes based on induction regimen. High risk cytogenetics (HR = 0.57, p=0.0004 for non-high risk) and absence of planned maintenance (HR=1.55, p=0.0008) were associated with higher risk of relapse. VRD was associated with a marginal benefit in relapse risk vs. CVD (HR=0.68, p=0.04). Non-relapse mortality was similar across cohorts. Those not receiving planned post-AHCT maintenance (HR 1.69, p<0.001) and high-risk MM had higher risk of progression/death (HR in non-high risk 0.58, p<0.001); OS was lower in those with low stage (DSS or ISS I/II) vs. stage III (HR 0.6, p=0.006) and with non-high risk cytogenetics (HR 0.5, p=0.001).Patients receiving planned post-AHCT therapy had significantly improved 3-year PFS vs. no post-AHCT therapy (55% vs. 39%, log-rank p=0.0001) (figure).Conclusions:Modern induction doublets and triplets induce similar response rates and post AHCT outcomes at a median follow-up of 36 mo. Although there is an increase in use of triplets after 2010 in transplant eligible patients, our analysis suggests that the choice of induction regimen is less important than the decision to use vs. not use planned post-AHCT maintenance therapy. [Display omitted] [Display omitted] DisclosuresKrishnan:Janssen: Consultancy; BMS: Consultancy; Jazz: Consultancy; Millenium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy.

Is hematopoietic cell transplantation still a valid option for mantle cell lymphoma in first remission in the chemoimmunotherapy-era?

Modern chemoimmunotherapies have produced higher response rates and improved survival in mantle cell lymphoma (MCL); however, disease relapse remains a challenge. The availability of various post-remission maintenance or consolidation strategies, have led some to question the role of upfront autologous hematopoietic cell transplantation (auto-HCT) consolidation for MCL, in the chemoimmunotherapy-era. A one size fits all approach is no longer appropriate for MCL in first remission, and the choice of preferred post-remission (observation, maintenance or consolidation) strategy is increasingly becoming a factor of patient age, comorbidities and disease risk stratification. In select low-risk patients (based on Mantle cell lymphoma International Prognostic Index (MIPI)), observation following rituximab plus Hyper-CVAD-like inductions seems appropriate. Rituximab maintenance after anthracycline-based chemoimmunotherapies in elderly transplant ineligible patients has shown survival benefit and should be considered a valid option. Limited studies suggest feasibility of radioimmunotherapy consolidation in first remission; however, in the absence of randomized data, this modality remains investigational. In younger, transplant-eligible patients receiving cytarabine-containing inductions, upfront consolidation with auto-HCT has shown survival benefit, and remains a standard-of-care option in the modern-era. Hyper-CVAD associated stem cell mobilization failure is an increasingly recognized problem, underscoring the need for alternative inductions, or consideration for early stem cell collection, when this induction regimen is used. Outcomes of high-risk MIPI patients remain suboptimal with currently available induction and post-remission strategies and represents an area where adoptive immunotherapy in the form of allogeneic-HCT warrants investigation. Incorporation of novel MoAbs and targeted agents (PI3K inhibitors, mTOR inhibitors, BTK inhibitors and so on.) in maintenance and consolidation strategies will build on the significant therapeutic gains of last decade, in coming years.

Salvage autologous stem cell transplantation for multiple myeloma relapsing or progressing after up-front autologous transplantation

Progression or relapse occurs in the vast majority of patients with multiple myeloma (MM) who undergo up-front autologous hematopoietic cell transplantation (AHCT1), which remains a cornerstone of treatment in the era of novel agents. Limited data are available regarding the value of salvage therapy with a second AHCT (AHCT2) in patients who relapse/progress after AHCT1. We analyzed the outcome of 83 patients who underwent salvage AHCT2 between 1994 and 2011. Most patients (77%) had received treatment with novel agents between AHCT1 and AHCT2, and 28% of patients were from ethnic minority groups. Median overall survival (OS) from AHCT2 was 31.5 months (95% confidence interval [CI]: 22–41), and median progression-free survival (PFS) was 15.5 months (95% CI: 11–20). In multivariate analysis, only disease status (≥ PR) at AHCT2 was associated with better OS. The 3-year OS rates for patients receiving AHCT2 in > PR and PR were 85.9% (95% CI: 61–96) and 51.3% (95% CI: 34–68), respectively. Disease status at AHCT2 and time to progression/relapse after AHCT1 were associated with PFS in multivariate analysis. In summary, salvage AHCT2 is an effective treatment option in patients with chemosensitive relapse/progression and prolonged remission after a prior autograft.

Trends in Utilization and Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) in the Upfront Management of Patients with Multiple Myeloma: A Cibmtr Analysis

AbstractAbstract ▪596▪This icon denotes a clinically relevant abstract BackgroundLarge population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. MethodsWe retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. ResultsAcross the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. ConclusionsUtilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. [Display omitted] Disclosures:No relevant conflicts of interest to declare.