Improved Stem Cell Transplant Related Mortality for AL Amyloidosis At a Single Transplant Center

Abstract Abstract 2016 The role of AHSCT in AL amyloidosis is controversial. There is evidence that AHSCT offers long term disease control with high organ response rates, however, the only randomized phase III trial comparing transplant with conventional melphalan and dexamethasone therapy deemed transplant inferior. Better understanding of risk stratification for SCT candidacy has resulted in TRM rates are as low as 5.6% in some series. The goal of the current study was to evaluate the TRM rate for all consecutive patients who have undergone AHSCT for AL amyloidosis at institution. Special attention in evaluation of any detectable differences in TRM over the time period of this review was a major goal of this project. Retrospective review was performed of all patients with primary AL amyloidosis who have undergone AHSCT at our institution. The database captured patients from December 2001 and our study includes patients through February 2012. Patients who were diagnosed with secondary amyloidosis by the stem cell transplant service and/or referring oncologist were excluded. TRM was defined as death from any cause within 100 days post stem cell infusion. We then evaluated data from the entire cohort and divided it into two different time periods: 2001–2006 and 2007–2012. Thirty-nine patients had an initial AHSCT during the study period. Nine patients were enrolled in the SWOG 0115 trial which comprised tandem autoSCT using 100 mg/m2 of melphalan conditioning 3–6 months apart. Of those, 6/9 (66%) had both transplants. For purposes of this abstract we report on the data resulting from first transplantation only for patients in the SWOG 0115 trial. The median age at transplant for the entire cohort was 57.6 years old (39–74). Males represent 64% of the patients. Most of the patients had symptomatic involvement of one organ (48.7%) with 23% having more than 2 organs involved. There were 14 patients transplanted in the 2001–2006 period and 25 patients in the 2007–2012 period. Overall TRM for 2001–2012 was 5.1%. During the 2001–2006 period TRM was 14% (2/14 patients). No TRM occurred for patients transplanted from 2007–2012. Overall survival (OS) improved when separately comparing the two study periods. Overall survival was 64% at 3 years in the 2001–2006 cohort and 92% at 3 years in the 2007–2012 cohort. Patients in the 2007–2012 cohort include all patients enrolled to SWOG 0115. Sixty percent of patients reported for that period received Univariate analysis of risk factors affecting improved OS identified year of transplant (>2006; p=0.03), number of treatments pre-transplant (>1; p=0.04), and time from diagnosis to transplant (>4mo; p=0.05) as factors associated with improved survival. Number of organs involved (>1; p=0.06) showed a trend towards worse survival. In conclusion, our single institution data demonstrates a reduction in TRM over the past 5 years. Reasons for improvement in TRM are under investigation and may include better risk stratification, better supportive care (including frequent hospitalization for cardiac monitoring in high-risk patients) and improvement in pre-AHSCT performance status for those patients receiving induction therapy with novel agents. Download : Download high-res image (19KB) Download : Download full-size image Figure: . Comparison of overall survival of patients with AL amyloidosis after autologous stem cell transplant based on year of transplant. Disclosures: Holmberg: Millenium: Research Funding; Otsuka: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Sanofi: Research Funding

Utilization of stored autologous PBSCs to support second autologous transplantation in multiple myeloma patients in the era of novel agent therapy.

Outcomes in multiple myeloma (MM) have improved significantly with novel agent therapy and autologous stem cell transplantation (ASCT). ASCTs are typically planned as either tandem or a single transplant with additional stored PBSCs available for a second salvage transplant. To accommodate these strategies, many centers routinely collect and store adequate PBSCs for two ASCTs. We analyzed the cost associated with this practice by determining the expenses of PBSC collection, cryopreservation and storage, and the ultimate use of additional cryopreserved PBSCs in patients who had undergone at least one ASCT. There were 889 MM patients transplanted between 1993 and 2011 at our center. Most (N=726) had residual PBSCs in storage after their first ASCT (ASCT1). Only 135 patients underwent a second ASCT within a median of 14 months after ASCT1. The percentage of patients receiving a second ASCT declined over time. The resources required to collect and store unused PBSCs added up to 336 extra patient days of apheresis and 41 587 extra patient months of cryopreservation, translating into an average extra cost per patient of US$4981.12. A reconsideration of conventional PBSC collection and storage practices would save significant cost for the majority of MM patients who never undergo a second ASCT

Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor (NCT03158688)

Introduction: The use of lenalidomide (LEN) and bortezomib (BTZ) in newly diagnosed multiple myeloma (MM) patients (pts), along with continuous or maintenance therapy paradigm have improved survival outcomes. However, many pts progress while on these agents or discontinue them due to toxicity. There is a need for novel, efficacious, and tolerable regimens that can treat MM pts who are exposed or refractory to LEN or BTZ. The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab have both been approved as single agents or as components of combination regimens for the treatment of RRMM. The combination of carfilzomib, dexamethasone, and daratumumab has been shown to be efficacious and safe in RRMM in the phase 1 study MMY1001 (Chari, Blood 2019). We present results from the primary analysis of CANDOR, a multicenter, phase 3, randomized study comparing carfilzomib, dexamethasone, and daratumumab (KdD) vs carfilzomib and dexamethasone (Kd) in RRMM pts. Methods: RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Pts were randomized 2:1 to KdD or Kd. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 wks for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (threshold, 10-5 cells), overall survival (OS), time to response, and safety. Results: 466 pts (KdD: 312; Kd: 154) from 102 sites worldwide were randomized. Baseline characteristics were balanced between the two arms. Median age was 64 years. Of the randomized pts, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively. 33% of pts were LEN-refractory. The primary endpoint of PFS was met after a median follow-up of 16.9 mo and 16.3 mo for the KdD and Kd arms, respectively. Median PFS was not reached for the KdD arm vs 15.8 mo for the Kd arm (HR, 0.63; 95% CI, 0.46-0.85; P=0.0014; Figure). PFS HRs favored KdD vs Kd across prespecified subgroups. Importantly, median PFS (KdD vs Kd) was not reached vs 12.1 mo in the LEN-exposed group (HR, 0.52; 95% CI, 0.34-0.80), and was not reached vs 11.1 mo in the LEN-refractory group (HR, 0.45; 95% CI, 0.28-0.74). Median time to first response was 1 mo in the KdD and Kd arms. ORR was 84.3% vs 74.7% (P=0.0040), and the rate of complete response or better was 28.5% vs 10.4%. MRD-negative complete response rate at 12 mo was 12.5% for KdD vs 1.3% for Kd (P<0.0001). Median OS was not reached in either arm at a median follow-up time of 17 mo (HR, 0.75; 95% CI, 0.49-1.13; P=0.08). Median treatment duration was longer in the KdD than Kd arm (70.1 vs 40.3 wks). The incidence of grade ≥3 AEs was 82.1% and 73.9% in the KdD and Kd arms, respectively. Serious AEs occurred in 56.2% (KdD) and 45.8% (Kd). The rate of treatment discontinuation due to AEs was similar in both arms (KdD, 22.4%; Kd, 24.8%). The frequency of grade ≥3 cardiac failure was 3.9% (KdD) and 8.5% (Kd); rate of cardiac failure event leading to K discontinuation was similar in the arms (3.9% and 4.6%). 5 deaths were reported as treatment-related, all in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest [n=1 each]). Additional efficacy endpoints, including key subgroup analyses will be presented. Conclusion: KdD resulted in a significant PFS benefit over Kd, with a 37% reduction in the risk of progression or death. Pts treated with KdD achieved deeper responses, with a nearly 10-times higher MRD negative-complete response rate vs Kd-treated pts. The PFS benefit of KdD was maintained across prespecified clinically important subgroups, particularly among LEN-exposed and LEN-refractory pts. AEs were generally manageable and the incidence of AEs leading to treatment discontinuation was similar in the arms. Overall, KdD was associated with a favorable benefit-risk profile and represents an efficacious new regimen for RRMM, including for LEN-exposed and/or LEN-refractory pts. Figure Disclosures Usmani: AbbVie: Other: Personal fees; SkylineDx: Consultancy, Other: Grant, Personal fees, Research Funding; GSK: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Grant, Personal fees, Research Funding; MundiPharma: Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Sanofi: Other: Grant, Personal fees, Research Funding, Speakers Bureau; Pharmacyclics: Other: Grant, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Grant, Research Funding; Array Biopharma: Grant, Personal fees, Research Funding; Amgen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau. Quach:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: Free drug for investigator-initiated study, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Glicomimetics: Other: Personal fees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Landgren:Takeda: Other: Grants, Independent Data Monitoring Committee (IDMC); Rising Tides Foundation: Other: Grants; Amgen: Other: Grant, Personal fees; Seattle Genetics: Other: Grants; NIH: Other: Grants; FDA: Other: Personal fees; Glenmark: Other: Grants; MMRF: Other: Independent Data Monitoring Committee (IDMC); IMF: Other: Grants; LLS: Other: Grants; Perelman Family Foundation: Other: Grants; Karyopharm: Other: Grants; Adaptive: Other: Personal fees; Binding Site: Other: Personal fees; Celgene: Other: Grant, Personal fees; BMS: Other: Personal fees; Cellectis: Other: Personal fees; Juno: Other: Personal fees; Pfizer: Other: Personal fees; Merck: Other: Independent Data Monitoring Committee (IDMC); Janssen: Other: Grants, Personal fees, Independent Data Monitoring Committee (IDMC). Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; GSK: Honoraria; AbbVie: Honoraria. Siegel:Novartis: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; GSK: Honoraria. Yang:Amgen: Employment, Equity Ownership. Klippel:Amgen: Employment, Equity Ownership. Zahlten-Kumeli:Amgen: Employment, Equity Ownership. Dimopoulos:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi Oncology: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis Pharma: Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: carfilzomib dexamethasone, and daratumumab triplet for relapsed or refractory multiple myelom

Cost and Utilization Of Stored Autologous PBSC To Support Tandem ASCT In MM Patients In The Era Of Novel Agent Therapy

Introduction Historically, autologous stem cell transplantation (ASCT) for multiple myeloma (MM) improves overall survival (OS) compared to conventional chemotherapy alone. Before the introduction of novel agent therapy, tandem ASCT, defined as a second ASCT within 180 days of the first, was an important option for suboptimal responses after an initial ASCT and thus collecting adequate peripheral blood stem cells (PBSCs) for 2 transplants has been considered standard of care. However, the role of tandem transplants is being challenged by novel agent maintenance strategies. Considering this changing landscape of MM therapy, we sought to evaluate the current PBSC collection and storage practices that set the CD34+ cell dose goal to be sufficient for 2 transplants. Methods We obtained clinical, PBSC collection and storage data on MM patients who underwent ASCT from 1993 to 2011 from the Autologous Transplant and Cellular Therapy Laboratory databases at the Fred Hutchinson Cancer Research Center. We determined frequencies and trends of all second ASCTs, including tandem, costs involved in PBSC collection, storage, and utilization of the product that remained cryopreserved for a second ASCT. Cell dose target at our center is 5 x 106 CD34+ cells/kg/transplant. To analyze trends over time, we divided the sample into groups of 3 or 4 year periods. Collection and cryopreservation costs for second ASCT were calculated by first determining the number of days required to collect sufficient PBSC for one ASCT, then the number of additional days to complete the actual collection, and the cumulative costs of long-term storage in our facility. Cost was estimated per July 2012 charges: 1 day PBSC collection $3,016, 1 day processing for cryopreservation$5,955, 1 year storage fees $408 ($34/month). The cost of mobilization chemotherapy and growth factors were not included. Results From May 1993 to June 2011, 889 MM patients underwent PBSC collection and ASCT (111 of 1000 excluded due to incomplete records). Median total PBSC collection days was 2 (range 1 – 10) with median yield of 13.18 x 106/kg CD34+ cells. Median days to collect sufficient cells for one ASCT was 1 day (1 – 9) and 383 patients collected adequate cells for 2 ASCTs after 1 apheresis procedure. Of 889 patients, 135 underwent a second ASCT within a median 14 months (2.5 – 113) of the first. Number of second ASCTs per time period: 1993 to 1995 – 9 of 39 MM patients undergoing ASCT (23%), 1996 to 1999 – 18 of 100 (18%), 2000 to 2003 – 15 of 162 (9%), 2004 to 2007 – 62 of 251 (25%), 2008 to 2011 – 31 of 337 (9%). Fifty patients underwent tandem ASCTs and these accounted for 89%, 72%, 7%, 24%, and 42% of all second ASCTs during the respective periods; the other 85 occurred > 6 months after the first. Number of additional days and associated costs to collect and store PBSC for a second ASCT: 5 days ($44,855), n=1 patient; 4 days ($35,844), n=2; 3 days ($26,913), n=10; 2 days ($17,942), n=41; and 1 day ($8,971), n=211. 637 patients had unused PBSC that remained in storage for ≥ 1 year, with a rising trend over time: 1993 to 1995 – 7 (1From January 2009, some patients received plerixafor to achieve the collection goal for 1 ASCT. Its cost was not considered additional. Estimated average cost for PBSC collection, cryopreservation and storage was at least$20,065.96/person and at least $6718.11/person was spent to collect and store PBSC for a tandem ASCT that was never performed. Conclusions Approximately 70% of patients had PBSC products that remained unused and in prolonged cryopreservation after the first ASCT. Estimated cost for collection and storage of PBSC beyond that needed for a single ASCT accounted for roughly 1/3 of total costs. This conventional practice should be reconsidered in view of rising treatment costs, the evolving role of novel agents in maintenance therapy, and the deeper responses achievable with novel agents prior to first ASCT, thus reducing the need for tandem ASCT. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Pre-transplantation novel agent induction predicts progression-free survival for patients with immunoglobulin light-chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation

INTRODUCTION: High-dose melphalan and autologous stem cell transplant (HDM/SCT) is an effective treatment modality for immunoglobulin light-chain (AL) amyloidosis, however, its application remains restricted to patients with good performance status and limited organ involvement. In recent years, the paradigm for AL amyloidosis has changed with the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). We hypothesized that use of novel agent induction regimens has improved outcomes for patients with AL amyloidosis undergoing HDM/SCT at our center. METHODS: All patients with AL amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were included in this study. Any regimen administered within 6 months prior to HDM/SCT including an IMiD or a PI was considered a novel induction regimen. Use of induction regimen was evaluated in a Cox proportional hazard model for association with progression-free (PFS) and overall survival (OS). RESULTS: Forty-five patients with AL amyloidosis underwent HDM/SCT. The median age was 57.2 years (range, 39 – 74.4), 15 (33.3%) were women. The median number of organs involved was 2 (range 1 – 5), with 20 patients having only 1 (44.4%), 10 patients having 2 (22.2%), and 15 patients (33.3%) having ≥ 3 organs involved. Novel agent induction regimens were used prior to HDM/SCT in 21 patients (46.7%); these comprised PI in 13/21 (57.1%), IMiD alone in 6/21 (28.6%), PI and cyclophosphamide (CyBorD) in 3/21 (14.3%), and IMiD and PI in 3/21 (14.3%). Use of a novel agent induction regimen was associated with improved progressive-free survival (PFS), but not overall survival (OS). The 3-year PFS for patients who received a novel agent induction was 79%, while for those who did not was 53% (Hazard ratio [HR] = 0.317, p = 0.048). The 3-year OS for patients who received novel agent induction regimens was 95%, while for those who did not was 71% (HR = 0.454, p = 0.247). DISCUSSION: Our data suggest that use of a novel agent induction regimen including an IMiD or PI prior to HDM/SCT for patients with AL amyloidosis could improve outcomes, with improvement in PFS. Although these results are limited by sample size and lack of randomization, these results support possible further investigation of novel agent induction regimens in the context of a prospective clinical trial