Characteristics and Outcomes of Newly Diagnosed Multiple Myeloma Patients with and without Extramedullary Disease after Autologous Transplant and Maintenance Therapy: A Study from the Cmwp-EBMT

Abstract Patient selection becomes crucial for newly diagnosed multiple myeloma (NDMM), to identify those who may benefit the most from specific treatments. This is particularly important for patients for whom evidence of current treatment options remains very limited. One such subgroup is MM with extramedullary disease (EMD), especially those with organ manifestation. Maintenance therapy after autologous transplantation improves outcome for eligible NDMM patients, but randomized trials only included a small proportion of EMD patients, and to date, no adequate data exist on maintenance in this cohort. Here, we aimed to evaluate the characteristics and outcomes of NDMM with or without EMD after autologous transplant and maintenance therapy. Cohorts were identified from NDMM patients undergoing first autologous transplant between 2008 and 2018. Involvement had to be documented as absent or present. Maintenance treatment was defined as single-agent treatment within 6 months after first autologous transplant without relapse. Outcomes were calculated from the start of maintenance therapy. Primary end points were progression-free survival (PFS) and overall survival (OS). Secondary end point was cumulative incidence of relapse. In total, 830 NDMM patients with or without EMD were eligible, receiving either thalidomide (n=287), lenalidomide (n=446), bortezomib (n=75), or daratumumab (n=22; results for these patients will be presented at the meeting). 107 had EMD (n=83 paraskeletal and n=24 organ involvement). Maintenance drug distribution did not differ between NDMM with or without EMD (P=0.69) and is shown in Table 1. Fewer patients with organ involvement had IgA MM (23% vs 21% for no EMD and paraskeletal involvement, respectively). Patients with organ involvement more frequently were ISS stage III (50% vs 24% for no EMD and 15% for paraskeletal involvement). The median follow-up of the entire cohort was 44 months (95% CI, 40-48 months). According to involvement, 3-year PFS was 52% (48-57%) for patients without EMD, 56% (44-69%) for paraskeletal involvement, and 45% (22-68%) for organ involvement (P=0.15). Of note, early outcome after maintenance start appeared to be significantly worse for organ involvement, with 1-year PFS of 58% vs 81% for paraskeletal involvement and 82% for no EMD. 3-year OS was 81% (77-84%) for no EMD, 88% (80-96%) for paraskeletal involvement, and 68% (47-89%) for organ involvement (p=0.06). Survival curves are depicted in Figure 1. Regarding relapse, organ involvement showed worse early 1-year cumulative incidence, with 42% vs 19% for paraskeletal involvement and 16% for no EMD. In terms of maintenance therapy in patients without EMD, 3-year PFS was 45% (38-52%) for thalidomide, 59% (52-65%) for lenalidomide, 45% (31-59%) for bortezomib (P=0.005). 3-year OS was 79% (73-85%), 83% (78-88%), and 74% (61-87%; P=0.30). Relapse incidence was also significantly different showing lower relapse rates for lenalidomide (P=0.002). In terms of maintenance therapy in patients with EMD, 3-year PFS was 52% (36-67%) for thalidomide, 43% (27-60%) for lenalidomide, 65% (32-97%) for bortezomib (P=0.90). Overall survival was 81% (69-93%) for thalidomide, 86% (76-97%) for lenalidomide, and 89% (68-100%) for bortezomib (P=0.70). In multivariable analysis on PFS (including ISS, performance score, age, remission status) adjusting for early events at 1 year, organ involvement was significantly associated with worse early outcome (hazard ratio, 3.35; P=0.002) and showed no significant difference vs patients with no EMD after 1 year of follow-up. Paraskeletal involvement was not associated with different PFS. Lenalidomide was associated with significantly reduced risk for death or relapse/progression (hazard ratio, 0.69; P=0.003) vs thalidomide, and no difference was seen for bortezomib vs thalidomide. For OS, organ involvement appeared to be associated with worse outcome (hazard ratio 1.71; P=0.17), while no difference was seen for paraskeletal and no EMD. Lenalidomide (hazard ratio 0.72; P=0.05) and bortezomib (hazard ratio, 0.56; P=0.06) appeared to be associated with better OS. In conclusion, organ involvement was associated with worse early PFS, despite maintenance treatment. Different maintenance treatment did not seem to affect outcome in EMD. For patients without EMD, lenalidomide showed significantly higher PFS compared with thalidomide. Figure 1 Figure 1. Disclosures McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kobbe: Celgene: Research Funding. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Delforge: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thurner: Takeda: Honoraria; Abbvie: Other: Travel support; Janssen: Other: Travel support; EUSA-Pharma: Honoraria, Other: Travel Support; Astra-Zeneca: Honoraria; Merck: Honoraria. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Schönland: Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

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Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Post-Transplant Myeloma Patients

Blood ◽

10.1182/blood-2021-151950 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4774-4774

Author(s):

Krina K. Patel ◽

Jatin J. Shah ◽

Lei Feng ◽

Hans C. Lee ◽

Elisabet E. Manasanch ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Clinical Trials ◽

Stem Cell ◽

Maintenance Therapy ◽

Cell Carcinoma ◽

Board Of Directors ◽

Research Funding ◽

Proteasome Inhibitors ◽

Advisory Board ◽

Advisory Committees

Abstract Backrground: Several randomized controlled clinical trials have demonstrated improved outcomes for newly diagnosed multiple myeloma (NDMM) patients who were treated with lenalidomide as maintenance therapy after autologous stem cell transplant (ASCT). Proteasome inhibitors have demonstrated clinical benefit in myeloma patients when used as part of induction and maintenance regimens, and the combination of proteasome inhibitors and lenalidomide in induction regimens has produced strong clinical responses. In this study, the addition of ixazomib to lenalidomide maintenance post-ASCT in NDMM patients was evaluated. Methods: Patients (n=64) were started on maintenance therapy with lenalidomide and ixazomib within 60-180 days of stem cell infusion. Each cycle was defined as 28 days with lenalidomide starting at 10 mg/day orally for 28 days with the option to increase the dose to 15 mg after 3 cycles. Ixazomib was provided at 3 mg (n=48 patients) or 4 mg (n=16 patients) orally on days 1, 8, and 15 of each 28-day cycle. However, ixazomib dose was reduced to 3 mg in all patients based on toxicity observed in other clinical trials of ixazomib at that time. The primary endpoint measured was progression-free survival (PFS), which was defined as the time between ASCT and disease progression or death, whichever occurred first. Results: A total of 64 patients were enrolled on this study between December 4, 2012, and May 13, 2015. Of these patients, 41 (64.06%) were 60 years of age or older and 42 (65.63%) were male. Fourteen patients had high-risk cytogenetic features (+1q21, Del17p, t(14:16), t(4:14)), 50 patients had standard cytogenetic risk features (t(11:14), t(6:14), hyperdiploidy, normal) and 9 patients had International Staging System stage 3 disease. Median PFS (mPFS) for all patients was 73.3 months and has not been reached for those with ISS stage 1 disease. mPFS for ISS Stage 3 disease and high-risk cytogenetic subgroups was 33.8 and 25.4 months, respectively. Twenty-two patients had progressive disease, while 21 patients continue to receive dual maintenance. Response rates deepened over time from baseline post-ASCT for 39 patients. The complete response (CR)/stringent CR rate was 42.9% and median overall survival was not reached with a median follow-up of 62 months (range 25.4 - 82.1 months). Thirty-one patients (48%) had improvement from their baseline response after maintenance therapy: 6 patients improved from PR to VGPR; 7 from PR to stringent CR (sCR)/CR; 16 from VGPR to sCR/CR; 1 from SD to CR; and 1 patient improved from SD to VGPR. The median time to response in the 31 patients with improved response to maintenance therapy was 10.9 months (range, 0.9 to 51.3 months). Minimal residual disease (MRD) was evaluated by multicolor flow cytometry (10^-5) in 21 patients by bone marrow biopsy; 8 patients were MRD-positive. The most common grade 3/4 adverse events (AEs) included neutropenia (46.9%), leukopenia (20.3%), thrombocytopenia (15.6%), lung infections (26.6%), diarrhea and maculopapular rash (12.5% each). Secondary primary malignancies occurred in 9 patients; these included squamous cell carcinoma of the skin (n=4), basal cell carcinoma of the skin (n=1), squamous cell carcinoma and basal cell carcinoma of the skin (n=1), hepatocellular carcinoma (n=1), melanoma (n=1) and leukemia (n=1). AEs led to dose reductions in ixazomib and lenalidomide in 20 and 31 patients, respectively. Discontinuation of ixazomib due to AEs occurred in 4 patients. Grade 1/2 neuropathy occurred in 22 patients and led to reduction or discontinuation of ixazomib in 2 patients. Conclusion: Addition of ixazomib to lenalidomide maintenance in myeloma patients demonstrated a better than expected PFS compared with what has been reported in studies of lenalidomide alone, and was both safe and tolerable. These results indicate a significant clinical benefit, especially for standard risk patients. Figure 1 Figure 1. Disclosures Patel: Oncopeptides: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lee: GlaxoSmithKline: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Regeneron: Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Oncopetides: Consultancy; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Genentech: Consultancy. Thomas: BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Ascentage Pharma: Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Qazilbash: NexImmune: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Biolline: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees.

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Validating a Machine Learning Grading System for Acute Gvhd. a Study on Behalf of the EBMT Transplant Complications Working Party

Blood ◽

10.1182/blood-2021-147724 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1809-1809

Author(s):

Amin T. Turki ◽

Christophe Peczynski ◽

Olaf Penack ◽

Helene Schoemans ◽

Gerard Socie ◽

...

Keyword(s):

Clinical Outcome ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Data Safety Monitoring Board ◽

Data Driven ◽

Organ Involvement ◽

Grading System ◽

Advisory Committees ◽

Grading Systems

Abstract Despite significantly improved preventive measures, acute graft-versus-host disease (aGVHD) remains as one of the most frequent complications after allogeneic hematopoietic stem cell transplantation (HCT). Its clinical grading is determined by the evaluation of its primarily affected organs, namely skin, liver and the gastro-intestinal tract. A number of existing grading systems, of which the 'Keystone Consensus' (Przepiorka D et al. BMT 1994) and MAGIC grading systems (Harris AC et al. BBMT 2016) are the most customary, have been proposed over the years to evaluate aGVHD severity based on the extent of aGVHD organ involvement. However, limitations remain regarding its association with clinical outcome. In the current era, particularly consensus grades I and II aGVHD are hardly distinguishable with respect to overall survival (OS). Given the discrepancies in aGVHD grading, we hypothesized that a data-driven approach would support the understanding and classification of aGVHD with respect to organ involvement, clinical outcome and risk cohorts. Here, we validated on a large, multi-national EBMT cohort a novel data-driven grading system for aGVHD that was previously developed by unsupervised learning applying principal component analysis on aGVHD organ stages (Turki AT et al. EHA 2020). The resulting Machine Learning (ML) aGVHD grading had 12 stages that were divided into 4 balanced ML-aGVHD grades to assess the severity of aGVHD, different from conventional grading. Our study included 19,617 adult patients with first HCT for hematologic malignancies between 2009 and 2018 and evidence of aGVHD. All donors except cord blood HCT were included. Detailed aGVHD organ involvement were required for the calculation of the ML-aGVHD score. Exclusion criteria were missing information on aGVHD organ involvement or follow up and very late onset aGVHD (> d+180). The baseline characteristics of this cohort reflect current HCT practice, with acute myeloid leukemia (55.3%) as predominant disease and a majority of unrelated donor HCT recipients (63.7%). Myeloablative conditioning was used in 46.7% of patients. In addition to baseline calcineurin inhibitors, 60.6% of patients received in-vivo T cell depletion with ATG or Campath. The ML-aGVHD grading distinguished 12 ML stages with significantly different clinical outcomes for OS (Figure 1a), non-relapse mortality (NRM) and relapse. The 4 ML-aGVHD grades (ML-I, stages 1-3; ML-II stages 4-6; ML-III, stages 7-9; ML-IV stages 10-12) revealed highly significant and clinically relevant differences for OS and NRM (p<0.0001). Utilizing the ML-aGVHD grading, 71.3% of patients were categorized ML-I, 18.3% ML-II, 7.98% ML-III and 2.38% ML-IV. The 6-month and 12-month OS probability from the diagnosis of aGVHD were 85.4% and 75.3% for ML-I, 72,7% and 61.5% for ML-II, 41.5% and 31% for ML-III and 14.8% and 9.1% for ML-IV, respectively (Figure 1b). We also analyzed the impact of covariates from the EBMT database on clinical outcome by Cox regression. All significant variables from univariate Cox regression were integrated into multivariate models for OS and NRM. Confounding factors for multivariate analysis for OS included patient age, gender, performance status, remission at HCT, HCT period, donor constellation and CMV status. The analysis confirmed the significant differences for OS as revealed by the ML-aGVHD grading system (p<0.0001), independent of these confounders. Also for NRM, the multivariate analysis confirmed the distinction as by the ML-aGVHD grading (p<0.0001). Finally, we compared the performance of the ML-aGVHD algorithm to the keystone consensus grading. Here 35.2% of patients were diagnosed with grade I aGVHD, 39.4% with grade II, 17.3 with grade III and 8.1% with grade IV aGVHD. In short, the ML-aGVHD grading system was successfully validated on an independent multi-national EBMT cohort. It integrated multi-organ aGVHD involvement different from conventional aGVHD grading by accounting for each affected organ. Our findings support the additional use of the ML-aGVHD grading system for the assessment of aGVHD severity in patients after HCT, in order to identify patients at risk for high NRM and reduced OS. Figure 1 Figure 1. Disclosures Turki: CSL Behring: Consultancy; Jazz Pharma: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau. Penack: Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Schoemans: Janssen: Membership on an entity's Board of Directors or advisory committees; CIBMTR: Consultancy, Other: travel grants; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: personal fees , Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants and personal fees; Gilead: Other: travel grants; BHS: Membership on an entity's Board of Directors or advisory committees, Other: travel grants and personal fees , Research Funding; Jazz Pharmaceuticals: Other: personal fees; Takeda: Other: personal fees. Socie: Alexion: Research Funding. Reinhardt: Abbvie: Consultancy; AstraZeneca: Consultancy; Vertex: Consultancy; Merck: Consultancy; Gilead: Research Funding; CDL Therapeutics: Current holder of individual stocks in a privately-held company. Blaise: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau; Immunicum: Other: Data safety monitoring board. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: MSD: Other: Travel Support; Jazz: Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Novartis: Consultancy, Other: Travel Support, Speakers Bureau. Basak: Saventic Health: Current holder of individual stocks in a privately-held company. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria.

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Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone for Treatment of Previously Untreated Light Chain Amyloidosis

Blood ◽

10.1182/blood-2020-138814 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 52-53

Author(s):

Eli Muchtar ◽

Morie A Gertz ◽

Betsy Laplant ◽

Francis K. Buadi ◽

Nelson Leung ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Advisory Board ◽

Organ Involvement ◽

Al Amyloidosis ◽

Advisory Committees ◽

Hematologic Response ◽

Phase 2 Trial

Background: Bortezomib, a proteasome inhibitor, has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and the combination of bortezomib, cyclophosphamide and dexamethasone is a commonly used regimen in AL. Ixazomib is the first oral proteasome inhibitor to be approved, and the combination of ixazomib with cyclophosphamide and dexamethasone is an all oral effective regimen for the treatment of multiple myeloma. This phase 2 trial was designed to evaluate the efficacy of this regimen in patients with AL, who have not received any therapy. Patients and methods: Newly diagnosed patients with biopsy proven AL amyloidosis, with organ involvement requiring therapy, were enrolled if they had measurable disease (Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum free light chain ratio) and adequate organ function. Patients with severe organ involvement were excluded (Alkaline phosphatase >750 U/L, creatinine clearance <30 mL/min or NT-ProBNP ≥ 7500 ng/dL). Treatment consisted of ixazomib 4 mg days 1, 8, 15; cyclophosphamide 500 mg PO weekly and dexamethasone 40 mg, weekly for twelve 28-day cycles, followed by ixazomib maintenance (days 1, 8, 15) at the last tolerated dose till progression. The primary objective was to determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated AL. A one-stage binomial design was utilized to test the null hypothesis that the hematologic response rate is at most 30% against the alternative hypothesis that it is at least 50%, with 85% power and 9% type I error. Results: Thirty-five patients were enrolled, median age was 67 (range 38-78) years; 69% were male. Organ involvement included cardiac in 23 (65.7%), renal in 19 (54.3%), and nervous system involvement in 5 (14.3%). At data cutoff 8 patients still remain on study with a median follow up of 4.4 months for those who are alive. Across the trial a median of 4 cycles (range 0-23) of treatment have been completed; the most common reason for going off study was institution of alternate therapy in 17 patients (63%). The overall hematologic response was 57% (20/35) and included amyloid CR in 5 (14%), VGPR in 9 (26%) and a PR in 6 (17%) patients. Confirmed organ responses have been observed in 5 patients so far, 2 each for cardiac and renal and 1 hepatic. The median PFS and OS have not been reached; 4 patients had hematological progression; 6 patients (17%) have died. Across 193 cycles of treatment administered, dose modification was required in 5, 3, and 10 patients, respectively, for ixazomib, cyclophosphamide and dexamethasone. A grade 3 or higher adverse event (AE), at least possibly attributed to the study drugs, was observed in 41% of patients. The figure shows the maximum grade of adverse events for individual patients seen in more than one patient across the study. Conclusions: The all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone is active in patients with previously untreated AL amyloidosis with hematologic responses observed in 57% of patients, including complete responses. Organ response has been observed but will likely need longer follow up for accurate assessment, given the delay in organ responses in this disease. Further evaluation of this combination is warranted. Disclosures Gertz: Alnylam: Consultancy; Ionis/Akcea: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy. Kapoor:Celgene: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dingli:Apellis: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Dispenzieri:Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Kumar:Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; MedImmune: Research Funding.

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Lenalidomide As Maintenance Treatment for Patients with Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation: A Pharmacoeconomic Assessment in the Netherlands

Blood ◽

10.1182/blood-2018-99-112826 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3555-3555 ◽

Cited By ~ 4

Author(s):

Carin A. Uyl-de Groot ◽

Rachel Ramsden ◽

Janneke Boersma ◽

Sonja Zweegman ◽

Sujith Dhanasiri

Keyword(s):

Cost Effectiveness ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Maintenance Treatment ◽

Cost Effective ◽

Line Treatment ◽

Second Line ◽

Advisory Committees ◽

The Cost

Abstract Background: Standard of care for patients with newly diagnosed multiple myeloma (NDMM) who are ≤ 70 years of age and who are fit is induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). However, this approach is not curative, and residual disease leads to disease relapse. Sustaining response and postponing relapse following ASCT is an important clinical goal, as early progression is associated with an increased risk of death. Lenalidomide (LEN) maintenance therapy has emerged as an important standard of care post-ASCT. Several clinical studies have shown that patients who received LEN maintenance therapy after ASCT had significantly longer progression-free survival (PFS) and overall survival (OS) in comparison with those who did not receive maintenance therapy. Other studies have indicated that active LEN maintenance treatment does not impair quality of life (Tay J, et al. Blood. 2017;130:abstract 2150). A recent EU5 cost-impact analysis suggested that LEN maintenance is potentially cost saving on direct medical costs by 24% over a 5-year period (Jackson G, et al. Blood. 2017;130:abstract 3405). To date, no study has specifically assessed the cost-effectiveness of LEN as maintenance treatment. Aims: To assess the cost-effectiveness of LEN treatment versus no maintenance treatment in transplant-eligible NDMM patients from a Dutch healthcare service perspective. Methods: A partitioned survival model structure was selected to provide a good fit to the supporting efficacy and safety data. The model was structured around 3 primary health states relevant to an NDMM patient's treatment trajectory: pre-progression state (encompassing on- and off-treatment periods), post-progression state (encompassing periods just prior to second-line treatment, on second-line treatment, and post-second-line treatment), and death. Efficacy and safety data were taken from a pooled meta-analysis of the CALGB 100104, GIMEMA RV-MM-PI-209, and IFM 2005-02 studies. Parametric models were used to estimate long-term survival. Utility data were applied from a real-world setting captured in the Connect® MM Disease Registry, which was used to calculate the progression-free (LEN), progression-free (no treatment), progressive disease (treatment-free), and progressive disease (second-line treatment) utilities. A 21 out of 28-day cycles dosing regimen for LEN was applied as recommended in the Dutch HOVON clinical guidelines. Costs (2016) and subsequent therapy data were derived from published literature and sources appropriate for the Dutch market. All drug costs are presented at list price. Healthcare resource utilization was informed from a EU5 (France, Germany, Italy, Spain, and the UK) real-world study (Ashcroft J, et al. Int J Hematol Oncol. 2018;Epub ahead of print). The total costs, life years gained (LYG) and quality-adjusted life years (QALYs) were estimated over a lifetime horizon. Multiple scenario and sensitivity analyses were conducted to test the robustness of the model results to key assumptions and data inputs. Results: The cost-effectiveness model predicted a QALY gain of 2.26 and a LYG of 2.79 for LEN in the base case analysis (Table). First-line drug costs of LEN contributed to an increase of EUR 147,707 in total costs versus no maintenance treatment. However, this was partially offset by savings of EUR 77,462 in subsequent treatment costs. LEN was shown to represent a cost-effective use of resources when compared with the Dutch willingness-to-pay (WTP) threshold for NDMM of EUR 50,000/QALY. Scenario analyses showed LEN remained cost-effective in settings representative of Dutch clinical practice. For instance, use of only the Dutch recommended dose (10 mg with dose reductions if needed) of LEN for NDMM gave an incremental cost-effectiveness ratio (ICER) of EUR 30,709. Scenario ICERs evaluating the key assumptions, aligning the subsequent therapy data as per in-trial use (EUR 49,059) and up to 83.9% of patients receiving 28 out of 28-day dosing, also remained below the WTP threshold. Conclusions: Introducing LEN as a maintenance therapy post-ASCT delays progression, improves survival, and reduces subsequent treatment-line costs. The use of LEN post-ASCT is cost-effective in comparison with no maintenance therapy in the Netherlands. Disclosures Uyl-de Groot: Merck: Research Funding; Janssen- Cilag: Research Funding; Gilead: Research Funding; Genzyme: Research Funding; Celgene Corp.: Research Funding; Boehringer Ingelheim: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Roche: Research Funding; Sanofi: Research Funding. Ramsden:Celgene Corp.: Consultancy; BresMed: Employment. Boersma:Celgene BV: Employment, Equity Ownership. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dhanasiri:Celgene International: Employment, Equity Ownership.

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Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

Blood ◽

10.1182/blood-2019-130537 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3198-3198

Author(s):

Chutima Kunacheewa ◽

Lei Feng ◽

Elisabet E. Manasanch ◽

Qaiser Bashir ◽

Krina K. Patel ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Maintenance Therapy ◽

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Maintenance Treatment ◽

Single Center ◽

Advisory Committees ◽

Treatment Groups

INTRODUCTION Several phase 3 randomized studies have validated the use of novel 3-drug regimens with lenalidomide (LEN) and dexamethasone (Rd) in combination with carfilzomib (ASPIRE), elotuzumab (ELOQUENT-2), ixazomib (TOURMALINE-MM1), and daratumumab (POLLUX) in relapsed and/or refractory multiple myeloma (MM) with ≥ 1 line of prior therapy. However, these studies notably excluded patients (pts) who were LEN-refractory since the control arm in these studies received Rd. In practice though, many MM pts at first relapse for which these LEN-based triplets are often utilized are progressing on low-dose LEN maintenance therapy, and their outcomes have not been well characterized in the context of these pivotal trials that excluded such pts. In this single-center retrospective analysis, we report the outcomes of LEN-retreatment with a novel LEN-based triplet in pts progressing on LEN-based maintenance therapy, and compare to a smaller, similar cohort of pts treated with a pomalidomide (POM)-based regimen. METHODS MM pts progressing on LEN-based maintenance therapy between 1/1/2015 and 6/30/2018 at MD Anderson Cancer Center after autologous stem cell transplant (ASCT) who were then treated with a LEN-based triplet or POM-based therapy were eligible for this study. Post-maintenance LEN-based triplet regimens included Rd in combination with bortezomib (VRd), carfilzomib (KRd), elotuzumab (ERd), ixazomib (IRd), and daratumumab (DRd). Disease response and progression were assessed by International Myeloma Working Group response criteria. The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS), and cohorts were compared by log-rank test. Pts who had not progressed were censored at the time of last disease evaluation prior to any change in therapy or data cut-off of 6/23/2019. RESULTS A total of 88 pts with a median of 1 prior line of therapy were eligible for the study. Baseline characteristics and prior treatment history are summarized in the Table. 66 pts received a LEN-based triplet, and 22 pts received a POM-based regimen after disease progression on LEN-based maintenance. A similar proportion of pts had high-risk cytogenetics (del 17p, t(4;14), and/or t(14;16)) in the LEN-based (21%) and POM-based (18%) post-maintenance treatment groups. The most common LEN-based maintenance regimens included LEN monotherapy (66%), ixazomib and LEN (14%), and elotuzumab and LEN (10%). Median PFS after ASCT on LEN-based maintenance was 26.0 months, and similar between the LEN-based (25.7 months) and POM-based (29.1 months) post-maintenance treatment groups, suggesting enrichment of pts with early progression on LEN-based maintenance in this analysis. In pts retreated with LEN-based therapy, the median LEN dose increased from 10 mg during maintenance therapy to 25 mg in the post-maintenance regimen. The overall response rate (ORR, ≥ PR) to LEN-based retreatment was 56% (≥ VGPR 33%) and median duration of response (DOR) was 11.7 months (95% CI 9.23 - NA). In comparison, the ORR and DOR with POM-based treatment were 73% (≥ VGPR 41%) and 19 months (95% CI 7.88 - NA), respectively. At a median follow-up time of 20.5 months, median PFS and OS were 13.6 and 40 months, respectively, with LEN-based retreatment versus 21.4 months (P 0.7) and not reached (P 0.6) with POM-based therapy. There was no significant difference in PFS or OS between LEN-based triplet regimens (VRd, KRd, ERd, IRd, and DRd). In the LEN-based retreatment group, high-risk cytogenetics did not significantly impact PFS (10.1 vs. 13.6 months, P 0.9), although OS was worse (22.5 vs. 42.8 months, P 0.003). However, pts who progressed on LEN-based maintenance ≥3 years after ASCT had a significantly better median PFS with LEN-based retreatment compared to pts who progressed <3 years after ASCT (median not reached vs. 9.9 months, P 0.001, Figure). CONCLUSION In pts progressing on LEN-based maintenance therapy, retreatment with a LEN-based novel triplet to maximize LEN dose intensity and synergy with other novel agents can lead to deep and durable responses in select pts, particularly in those with a more indolent disease course and longer (≥3 years) PFS after ASCT. However, ORR and PFS may favor switching to a POM-based regimen over LEN-based retreatment in this patient population, and warrants further investigation in studies evaluating optimal sequencing strategies in relapsed and/or refractory MM. Disclosures Manasanch: Sanofi: Research Funding; Quest Diagnostics: Research Funding; Merck: Research Funding; Skyline Diagnostics: Research Funding; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Iyer:Novartis: Research Funding; Genentech/Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; Seattle Genetics, Inc.: Research Funding; Incyte: Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. Lee:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy.

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A Phase II Study of Lenalidomide, Ixazomib, Dexamethasone, and Daratumumab in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (AFT-41)

Blood ◽

10.1182/blood-2021-146274 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4776-4776

Author(s):

Elizabeth K. O'Donnell ◽

Vera Jean Suman ◽

Susan M. Geyer ◽

Omar Nadeem ◽

Shira Dinner ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Maintenance Therapy ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Maintenance Treatment ◽

Newly Diagnosed ◽

Advisory Committees ◽

Unacceptable Toxicity

Abstract Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab. Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation. The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities. 1Kapoor et al. Blood (2019) 134 (Supplement_1): 864. Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures O'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

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Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

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A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽

10.1182/blood-2021-148139 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2455-2455

Author(s):

Carlos Bachier ◽

Henning Schade ◽

Behyar Zoghi ◽

Aravind Ramakrishnan ◽

Nirav N. Shah

Keyword(s):

Stem Cell ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Residual Disease ◽

Refractory Disease ◽

Advisory Committees ◽

Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽

10.1182/blood-2019-128467 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4451-4451

Author(s):

Sarah A. Holstein ◽

Sarah Cooley ◽

Parameswaran Hari ◽

Sundar Jagannath ◽

Catherine R Balint ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Nk Cell ◽

Single Infusion ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

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Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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