Autologous Hematopoietic Cell Transplantation For Multiple Myeloma Research Articles

Global characteristics and outcomes of autologous hematopoietic stem cell transplantation for newly diagnosed multiple myeloma: A study of the worldwide network for blood and marrow transplantation (WBMT).

Autologous hematopoietic cell transplantation (AHCT) is a commonly used treatment in multiple myeloma (MM). However, real-world global demographic and outcome data are scarce. We collected data on baseline characteristics and outcomes from 61 725 patients with newly diagnosed MM who underwent upfront AHCT between 2013 and 2017 from nine national/international registries. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), relapse incidence (RI) and non-relapse mortality (NRM). Median OS amounted to 90.2 months (95% CI 88.2-93.6) and median PFS 36.5 months (95% CI 36.1-37.0). At 24 months, cumulative RI was 33% (95% CI 32.5%-33.4%) and NRM was 2.5% (95% CI 2.3%-2.6%). In the multivariate analysis, superior outcomes were associated with younger age, IgG subtype, complete hematological response at auto-HCT, Karnofsky score of 100%, international staging scoring (ISS) stage 1, HCT-comorbidity index (CI) 0, standard cytogenetic risk, auto-HCT in recent years, and use of lenalidomide maintenance. There were differences in the baseline characteristics and outcomes between registries. While the NRM was 1%-3% at 12 months worldwide, the OS at 36 months was 69%-84%, RI at 12 months was 12%-24% and PFS at 36 months was 43%-63%. The variability in these outcomes is attributable to differences in patient and disease characteristics as well as the use of maintenance and macroeconomic factors. In conclusion, worldwide data indicate that AHCT in MM is a safe and effective therapy with an NRM of 1%-3% with considerable regional differences in OS, PFS, RI, and patient characteristics. Maintenance treatment post-AHCT had a beneficial effect on OS.

Similar Benefits of High-Dose Melphalan Based Conditioning Regimens Followed By Autologous Hematopoietic Cell Transplantation in Elderly Myeloma Population Compared to the Younger Group: Single Center Experience

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy and predominantly affects elderly population with a median age at onset around 70 years. High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) remains an important consolidative measures even in the era of novel agents including anti-CD38 antibodies. HCT in elderly patients is typically met with concerns for increased toxicity in this age group. Here, we evaluated our single center experience of autologous HCT in the elderly for the last decade. Methods: Clinical transplant data on MM patients who underwent HCT at Moffitt Cancer Center (MCC) were retrospectively reviewed. BMT Research Analysis Information Network (BRAIN) database was used for data query. The study population was limited to first autologous HCT for MM and receiving high-dose melphalan based conditioning regimens. Patients were divided into 3 groups based on their age at HCT: Age < 65 (n=1044), 65-69 (n=428), and 70+ (n=222). Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier method and compared with log-rank testing. Cumulative incidence function was compared with Gray's test. Results: There were 1694 MM patients who underwent autologous HCT with high-dose melphalan-based regimen at MCC from 2010 to 2021. Over 100 transplants per year were performed at our institution for MM since 2011 at both inpatient and outpatient settings. Median HCT-CI was 2, 3, and 3 for ages <65, 65-69, and 70+, respectively. Median serum creatinine (range) was 0.9 (0.5-10.1), 0.8 (0.4 - 11.9), and 0.9 (0.4 - 8.4) for ages <65, 65-69, and 70+, respectively. Reduced melphalan dosing (MEL140) was used in 5.6%, 10.1%, and 82.7% for ages <65, 65-69, and 70+, respectively. Univariate analysis showed that the 5-year OS for ages <65, 65-69, and 70+ was 71.1% (95% confidence interval (CI): 67.7-74.3), 69.6% (95%CI: 63.9-74.6), and 65.4% (95%CI: 56.4-73.0), respectively (Log rank, p=0.34, Figure). The 5-year PFS for ages <65, 65-69, and 70+ was 48.0% (95%CI: 44.3-51.5), 46.0% (95%CI: 40.0-51.8), and 46.0% (95%CI: 37.3-54.3), respectively (Log rank, p=0.64). The 5-year cumulative incidence of relapse for ages <65, 65-69, and 70+ was 44.9% (95%CI: 41.4-48.4), 44.4% (95%CI: 38.6-50.1), and 38.6% (95%CI: 31.1-46.0), respectively (Gray's test, p=0.2). The 3-moth, 1-year, and 5-year cumulative incidences of nonrelapse mortality (NRM) were 0.5% (95%CI: 0.2-1.2), 1.9% (95%CI: 1.2-2.9) and 7.0% (95%CI: 5.3-9.0) for age < 65, 0.7% (95%CI: 0.1-1.9), 0.9% (0.3-2.2%) and 9.4% (95%CI: 6.4-13.2) for ages 65-69, and 0.0% (95%CI: 0.0-0.0), 0.4% (95%CI: 0.0-2.4) and 15.2% (95%CI: 9.2-22.5) for age 70+, respectively, respectively (Gray's test, p=0.16). Additional multivariate analysis will be provided at the presentation. Conclusions: Overall, there were no differences in the MM HCT outcomes in different age groups at our center. Our data demonstrate the safe application of high-dose therapy in MM patients across the age group. Older MM patients appear to derive comparable survival benefits from HCT and should remain a standard consolidative measure. There is a suggestion that the NRM may be numerically higher in elderly population, and further analysis on long-term outcomes in elderly population is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Toxicity between Propylene Glycol (PG)-Free Melphalan with PG-Melphalan for Autologous Hematopoietic Cell Transplantation (AHCT) in Patients with Multiple Myeloma (MM)

Introduction High-dose melphalan (Mel) conditioning before AHCT has been standard in MM. The lyophilized Mel formulation has inadequate solubility and stability after reconstitution, and propylene glycol (PG) which is used to improve solubility, is associated with toxicity. A PG-free Mel preparation, Evomela, uses captisol as a solubilizing agent and in a phase IIb study showed acceptable safety profile, comparable efficacy and was FDA approved as a conditioning regimen for AHCT. There is limited evidence directly comparing toxicity and outcomes between the two Mel formulations used as conditioning for AHCT in MM. Objective Compare early post-AHCT toxicity and outcomes in MM patients receiving conditioning with PG-Mel vs. PG-free Mel. Methods This is a single-center retrospective study analyzing outcomes in a cohort of consecutive MM patients receiving AHCT using Mel conditioning between 01/2015 and 01/2018. Our center switched from using PG-Mel to PG-free Mel in 11/2016. The cohort was divided into 2 groups based on Mel formulation (PG-Mel vs. PG-free Mel); patients enrolled immediately prior to this date and immediately after formed 2 groups. The primary endpoint was toxicities in 30 days of AHCT. Secondary endpoints included engraftment, early infections, day 100 responses and mortality. Covariate balancing weights were computed using inverse propensity scores based on age, KPS, ISS, HCT-CI, cytogenetic risk, lines of therapy pre-AHCT and Mel dose. Weighted analysis was performed to estimate the average treatment effect of PG-Mel vs. PG-free Mel on outcomes. Results Of 294 AHCT patients, 162 received PG-Mel and 132 received PG-free Mel conditioning. PG-free Mel patients were older and had lower KPS (Figure 1). In univariate analysis, PG-free Mel was associated with faster neutrophil recovery (12 vs. 13 days, p Conclusion Preliminary analysis suggests PG-free Mel conditioning allows modest improvement in time to engraftment and risk of severe infections, compared to PG-Mel. Organ toxicity profile and 100-day mortality are comparable.

Efficacy of Proteasome Inhibitor-Based Maintenance Post Autologous Hematopoietic Cell Transplant in Multiple Myeloma: A Systematic Review and Meta-Analysis

Background Autologous hematopoietic cell transplantation (AHCT) followed by maintenance therapy is the current standard of care in the treatment of multiple myeloma (MM). Lenalidomide (Len) is most commonly utilized as maintenance therapy as it has been shown to improve both progression free survival (PFS) and overall survival (OS). However, long-term maintenance therapy with Len is associated with development of secondary primary malignancies (SPM). Proteasome-inhibitor (PI)-based maintenance strategies have been evaluated in several phase III trials and also appear to yield survival benefits in MM. Methods We performed a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019. We extracted data on clinical outcomes related to benefits (OS, PFS and deepening of hematologic response [DOHR]) and harms (SPM), independently by two authors. Our search strategy identified total of 2144 references. Three studies (5 manuscripts) were included in this systematic review (Figure 1). Results Median age for patients receiving PI maintenance after AHCT ranged from 25 to 65 years. All patients underwent an AHCT with melphalan 200mg/m2 prior to initiation of PI maintenance. Also, 70% of patients received a PI-containing induction regimen. 513 patients received bortezomib maintenance and 395 patients received ixazomib. The control arm in these studies was either placebo (n=261) or thalidomide (n=597). PI maintenance did not improve OS (n=2 studies, 1012 patients, hazard ratio [HR] 0.88, 95% CI 0.73-0.105, p=0.15) but improved PFS (HR 0.75, 95% CI 0.67-0.85, p= Conclusions The results of our systematic review show that PI-based maintenance following AHCT in MM leads to significant improvement in PFS and DOHR without an increase in development of SPM compared to placebo/non-PI maintenance. Prospective randomized phase III trials comparing Len to PI-based maintenance is an interesting question that remains unanswered.

The Result of a Phase 1 Study of Selinexor in Combination with High-Dose Melphalan and Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: High-dose melphalan and autologous hematopoietic cell transplantation (HCT) remains a crucial treatment modality for patients with multiple myeloma (MM). Strategies to improve the conditioning regimen have been explored with addition of novel targeted therapies previously with limited success. Selinexor, an orally available selective inhibitor of nuclear export (SINE), targeting Exportin-1 (XPO-1), was recently approved by the Food and Drug Administration (FDA) for relapsed/refractory MM. Our pre-clinical data show synergy between selinexor and bifunctional alkylating agents in several MM models. Therefore, we hypothesized that the addition of selinexor to high-dose melaphalan would be safe and improve outcomes of autologous HCT in MM. Methods: We designed a single institution, standard 3+3 dose escalation phase 1 study to evaluate the combination of selinexor (given at 40 mg po (dose level 1); 60 mg (dose level 2); and 80 mg (dose level 3) on days -3 and -2 before melphalan) and high-dose melphalan (100 mg/m2 IV on days -3 and -2) as a conditioning regimen for autologous HCT in patients with MM achieving either partial response (PR) or very good partial response (VGPR) after less than 4 lines of systemic anti-myeloma chemotherapy (NCT02780609). The primary objective was to establish a maximum tolerated dose (MTD) and identify a recommended phase 2 dose (RP2D). Results: From 08/2017 to 03/2019, a total of 12 MM patients (pts) received autologous HCT under the phase 1 protocol at Moffitt Cancer Center. Baseline characteristics included: a median age of 57 (range, 43-69); M:F = 7:5; IgG subtype=9, light chain type=2, IgD subtype=1; 92% with Durie-Salmon stage 3; 22% with high-risk disease based on del17p/t(4;14) (2/9, n=3 with unknown risk); a median number of induction=1 (range, 1-2); all received bortezomib-based induction, 83% received immunomodulatory agent, 17% received daratumumab. Pre-HCT responses were PR=4; VGPR=8. Pts received a median of 4.16 (range, 2.16-5.73) million CD34+ cells/kg. Neutrophil engraftment occurred with a median of 11 (range 11-12) days, and a platelet engraftment with a median of 15 (range, 10-36) days. Three pts each entered in dose level 1 and 2; and 6 pts at dose level 3. One pt in dose level 2 did not receive dexamethasone on day -1 due to grade (G) 3 hyperglycemia. One pt in dose level 3 (80 mg selinexor) did not receive day -2 dose of selinexor due to liver function test (LFT) abnormality (ALT &gt; 2x ULN) which was considered as dose-limiting toxicity (DLT) as second dose of selinexor was not given. LFTs normalized after HCT. Dose level 3 was expanded to 3 additional pts and no additional DLTs were observed. Treatment-related serious adverse events (SAEs) included: G3 febrile neutropenia=3, G3 diarrhea=1, G3 nausea=1, G3 small bowel obstruction=1, G3 acute kidney injury=1, G3 lung infection=1. Post-HCT responses at day +90 were complete response (CR)=2, VGPR=6, PR=3, and progression=1. CR conversion rate was 16.7% though phase 1 portion of the study was not powered to evaluate the CR rate. Therefore, RP2D was established as selinexor 80 mg on days -3 and -2. The study is proceeding to the phase 2 portion to assess the efficacy of this combination. Conclusions: The combination with selinexor 80 mg po with high-dose melphalan at 100 mg/m2 on days -3 and -2 (dose level 3) was well tolerated and engraftment kinetics were not altered. A phase 2 study of selinexor 80 mg with high-dose melphalan and autologous HCT is ongoing (NCT02780609). Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Alsina:Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau. Baz:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding. Shain:Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Sullivan:Karyopharm: Research Funding. OffLabel Disclosure: Selinexor in combination with high-dose melphalan

Toxicity Analysis of Propylene Glycol-Free Melphalan (Evomela®) Compared to Propylene Glycol-Based Melphalan Hydrochloride in Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background High-dose melphalan is the most common conditioning regimen for patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (AHCT). Historically, melphalan had limited solubility and required propylene glycol (PG) as a co-solvent, which can be associated with toxicities such as metabolic acidosis, renal dysfunction, and arrhythmias. Additionally, PG-melphalan requires administration within 1 hour of reconstitution due to poor stability. Evomela® is a PG-free formulation of melphalan that uses Captisol, a cyclodextrin derivative, to enhance solubility and stability. This novel formulation was found to be bioequivalent, safe and effective, compared to PG-melphalan when given as 100 mg/m2/day on two consecutive days prior to AHCT. Recently, considerable pharmacokinetic variability was shown after a single dose of Evomela® prior to AHCT, resulting in a trend towards increased grade 3-4 toxicities. In late 2016, our institution replaced PG-melphalan with Evomela®. We sought to compare hematologic and non-hematologic toxicities of PG-melphalan vs. Evomela® in patients undergoing AHCT for MM. Methods This is a single center, retrospective analysis of adult patients who received high-dose melphalan prior to AHCT for MM from January 2015 through June 2018. Baseline characteristics and outcomes were compared using either Wilcoxon Rank Sum test or Fisher's Exact test. Results Baseline characteristics between groups were comparable (Figure 1). Figure 2 summarizes hematologic and selected non-hematologic outcomes. Time to absolute neutrophil count (ANC) and platelet recovery were similar between groups. However, patients who received Evomela® required more frequent platelet transfusions through day +30 than those who received PG-melphalan (2 vs 1, P = 0.021). Patients in the Evomela® group also required significantly more anti-emetic rescue doses through day +30 (12 vs 1, P = Conclusion Evomela® led to similar engraftment kinetics compared to PG-melphalan, but Evomela® patients required more platelets transfusions. Evomela® was associated with more nausea/vomiting based on anti-emetic rescue use. We plan to evaluate the documented grades of diarrhea, nausea/vomiting, mucositis, and renal toxicity to further characterize the differential toxicity profile of PG-melphalan and Evomela®.

Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation

BackgroundRepurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response.MethodsWe conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18–75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention.ResultsOne hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%.ConclusionsFindings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations.Trial registrationThis randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008-2013 were identified (N =1492) and grouped as normal/mild (≥60 ml/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on MDRD. Multivariate analysis of non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) was performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)% respectively, (p=0·42); 5-year OS for normal, mod and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)% respectively, (p=0·69). With moderate RI, 5-year PFS for HDM 140 mg/m2 was 18 (6-35)% and for Mel200 was 46 (36-57)% (p=0·009). With severe RI, 5-year PFS Mel140 was 25 (11-41) % and for Mel200 was 32 (11-58)% (p=0·37). We conclude that AHCT is safe and effective in patients with MM with RI.

Analysis of hematopoietic recovery after autologous transplantation as method of quality control for long-term progenitor cell cryopreservation.

Hematopoietic precursor cells (HPC) are able to restore hematopoiesis after high-dose chemotherapy and their cryopreservation is routinely employed prior to the autologous hematopoietic cell transplantation (AHCT). Although previous studies showed feasibility of long-term HPC storage, concerns remain about possible negative effects on their potency. To study the effects of long-term cryopreservation, we compared time to neutrophil and platelet recovery in 50 patients receiving two AHCT for multiple myeloma at least 2 years apart between 2006 and 2016, using HPC obtained from one mobilization and collection attempt before the first transplant. This product was divided into equivalent fractions allowing a minimum of 2 × 106 CD34+ cells/kg recipient's weight. One fraction was used for the first transplant after median storage of 60 days (range, 17-165) and another fraction was used after median storage of 1448 days (range, 849-3510) at the second AHCT. Neutrophil recovery occurred at 14 days (median; range, 11-21) after the first and 13 days (10-20) after the second AHCT. Platelets recovered at a median of 16 days after both procedures. Considering other factors, such as disease status, conditioning and HPC dose, this single institution data demonstrated no reduction in the potency of HPC after long-term storage.

Hispanics have the lowest stem cell transplant utilization rate for autologous hematopoietic cell transplantation for multiple myeloma in the United States: A CIBMTR report.

Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States. The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102). The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non-Hispanic blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P < .001). More Hispanics (57%) versus non-Hispanic blacks (54%) and non-Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non-Hispanic blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes. Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society.

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.

Time to Insurance Approval in Private and Public Payers Does Not Influence Survival in Patients Who Undergo Hematopoietic Cell Transplantation

In the United States, insurance status has been implicated as a barrier to obtaining timely treatment. In this retrospective cohort study of 521 patients who underwent first hematopoietic cell transplantation (HCT), we investigated the association between timeliness of HCT and overall survival. Timeliness was operationally defined in the following 3 ways: (1) payer approval, from request for approval to actual payer approval; (2) transplantation speed, from payer approval to time of actual HCT; and (3) total time, from request for approval to HCT. Patients with private insurance had longer time to payer approval (P < .0001) than those with public payers but shorter time from approval to actual HCT (P < .0001) and total time to HCT (P < .0001). Multivariate Cox regression showed no significant differences in risk of death between slow and fast times in the 3 indices of timeliness in the models that used all patients (n = 509), autologous HCT in lymphoma (n = 278), and autologous HCT in multiple myeloma (n = 121). Additional studies to evaluate the effect of insurance timeliness on all patients for whom HCT is recommended, not just those who undergo HCT, should be conducted.

Transplantation Related Toxicity and Mortality in Older Autologous Hematopoietic Cell Transplantation Recipients

High dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT) is the standard of care for patients with relapsed aggressive Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and after initial treatment of multiple myeloma (MM). With advances in supportive care, AHCT is increasingly being performed for patients older than 60 years of age. However, prior studies evaluating outcomes of transplant in older AHCT recipients are inconsistent, with conflicting data on risk of complications and major outcomes of non-relapse mortality (NRM), overall survival (OS) and progression free survival (PFS). Data from registry studies report lower NRM in young and old patients, in recent years, likely due to improvement in supportive care. We analyzed patients receiving an AHCT for MM or lymphoma in a contemporary cohort (2010-2012) receiving consistent treatment and supportive care. We hypothesized that with improved supportive care, there would be little or no difference in outcomes of younger (40-59 years) versus older (> 60 years) AHCT recipients, examining engraftment, OS, PFS, NRM and non-hematologic grade 3-5 toxicities within one year post AHCT.Study cohort and Methods: All patients > 40 years (n=144) who underwent an AHCT for lymphoma (NHL, n = 56; HL, n = 11) or MM (n = 77) from 2010 -2012 at University of Minnesota were included. Engraftment, OS, PFS, NRM and non-hematologic grade 3-5 toxicities within the first year post AHCT were compared between the two cohorts (age 40-59 years, > 60 years).Results. The median age at transplant was 54 years (range 40-59 years) in the younger cohort (n= 77) and 65 years (range 60-76 years) in the older cohort (n=67). Older recipients more often had MM and were less often in complete remission. Over 95% of patients in both groups had a Karnofsky performance status (KPS) of > 80% (p=0.46) while 27% in the older group versus 22% in the younger group had a HCT-CI comorbidity score of > 3 (p= 0.72). We examined 17 categories of non-hematologic grade 3-5 toxicities. The frequency of infections during neutropenia was significantly higher in the older group (64% vs. 44%; 0=0.02). The proportion of patients with any grade 3-5 toxicity was also higher in the older group (84% vs. 67%, p= 0.03). In multivariate analysis, after adjustment for gender and disease, older age (> 60) was significantly associated with higher odds ratio (OR: 2.57, 95% CI: [1.09-6.05]) of grade 3-5 toxicity (Table 1). Based on the high-risk variables shown in Table 1, the predicted probability of grade 3-5 toxicities within one year (adjusted for age, gender and disease) was highest (94%) in females > 60 years with NHL and lowest in males age 40-59 years with HL (47%). There was no difference in time to neutrophil and platelet engraftment (Table 2). Two older recipients (cumulative incidence of NRM: 3%) and no younger recipients had NRM within one year. After a median follow up of two years, the probability of OS at two years was lower in the older group (76% vs. 90%, P=0.04) but no difference was noted in disease relapse or PFS.Conclusion: AHCT can be performed safely in older recipients. However, the higher toxicity and slightly higher NRM in this population needs attention. Studies focusing on risk-stratification in older patients (including geriatric assessments) would further help predict toxicity. Further studies addressing enhanced supportive care needs for older patients who are most likely to benefit are indicated.Table 1:Risk factors for grade 3-5 toxicitiesFactorOR95% CIPAge 40-591.00Age 60-762.571.09 – 6.05.03Male1.00Female2.240.96 – 5.24.06Multiple myeloma1.00Hodgkin lymphoma0.820.21 – 3.18.77Non-Hodgkin lymphoma2.671.07 – 6.68.04Table 2:Outcomes by ageAge 40-59Age 60+PDays to ANC recovery median (IQR)10 (10-11)11 (10-11)0.15Days to Platelet > 20K median (IQR)19 (17-21)18 (17-21)0.861 year NRM (95% CI)03 (1-7)0.052 year relapse (95% CI)47 (34-60)39 (27-51)0.442 year OS (95% CI)90 (82-98)76 (65-87)0.042 year PFS (95% CI)53 (41-65)55 (43-67)0.80 DisclosuresBachanova:Seattle Genetics, Inc.: Consultancy, Research Funding.

Multiple Myeloma: Future Directions in Autologous Transplantation and Novel Agents

INTRODUCTION induction regimen even in the novel era. Therefore, the most Autologous hematopoietic cell transplantation (AHCT) in the 1990s and the advent of “novel” therapy, such as immune modulators and proteasome inhibitors, in the 2000s have led to impressive gains in the treatment of multiple myeloma (MM) [1,2]. In the prenovel drug era, the therapy paradigm composed of induction followed by planned AHCT in eligible patients, denoted as “upfront” or early AHCT, aimed at achieving a deeper disease response and longer survival. With modern induction therapies incorporating novel drugs, the timing and need for AHCT is increasingly debated because an additional survival benefit for early AHCT has not been established with modern induction regimens. Routine post-transplant consolidation and maintenance are new trends in AHCT-based treatment of MM. Second-generation immune modulators and proteasome inhibitors, sensitive prognostic schema, and disease-monitoring techniques are also changing the treatment landscape. This session at the tandem BMT meetings explores the relevance and future of early AHCT in MM, the role of consolidation/maintenance post-transplant, and new drug development.

Outcomes Following Syngeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Matched Comparison to Autologous Transplantation.

Relapse is the main cause of treatment failure following autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM). Syngeneic HCT offers the advantage of a myeloma-free-graft. However, a potential disadvantage is the lack of a graft versus myeloma effect (GVM). We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after syngeneic versus autologous HCT for MM done between 1988 and 2003. Median follow up was >70 months in both groups. 43 syngeneic HCT recipients were matched to 170 autologous HCT recipients using a propensity score. A numerical propensity score for each syngeneic HCT recipient was calculated using the variables of age, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to HCT and year of HCT. Propensity scores ranged from 0.004–0.286. Syngeneic HCT recipients (cases) were matched in random order to autologous transplant (control) recipients with similar propensity scores. Patients who underwent tandem transplants were excluded. Median age (range) was 53 and 52 years in cases and controls. Most patients in both groups (60% of cases, 64% of controls) were transplanted within 12 months of diagnosis. Except for a higher proportion of patients with IgG myeloma (59% vs. 39%, p<0.01) and PBSC grafts (92% vs. 51%, p<0.01) in the control group there were no statistically significant differences in baseline characteristics of the two groups. 5-year outcomes are summarized in the table.5-year outcome, probability (95% CI)SyngeneicAutologousTreatment-related mortatlity14 (5–26)10 (6–15)Disease progression42 (26–58)71 (64–78)Progression-free survival44 (28–60)19 (13–26)Overall survival59 (43–74)40 (32–48)Medican follow up survivors, months71 (23–161)85 (3–145)In multivariate analysis, risks of progression and treatment failure were significantly lower after syngeneic than autologous HCT [disease progression RR= 0.43 (95%CI, 0.23–0.78, p=0.004); treatment failure RR= 0.59 (95%CI 0.35–0.98, p=0.04)]. TRM at 1 year was 14% (5–26) in the syngeneic group and 9% (5–13%) in controls (p=0.33). The 5-year risk of mortality was lower in the syngeneic group but the difference was not statistically significant (RR= 0.61, 95%CI 0.36–1.05, p=0.07). Disease recurrence accounted for 79% of deaths in the autologous and 47% in the syngeneic cohort. We conclude that syngeneic HCT for MM results in superior PFS and lower progression rates compared to autologous HCT, confirming previous smaller analyses and emphasizing the importance of a disease-free graft. Interestingly, these data suggest that relapse rates similar to those observed after nonmyeloablative allogeneic transplantation – another source of tumor free grafts – can occur in the absence of clinical graft versus host disease.