Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Introduction: There are limited data on treatment options for patients with multiple myeloma whose disease has progressed after chimeric antigen receptor T-cell (CAR-T) therapy. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The activity of Sel-dex was preserved regardless of specific prior therapies, as expected given its unique and novel mechanism of action. The efficacy of selinexor after CAR-T therapy remains unknown. Here, we report on observations of the efficacy of Sel-dex alone or administered as a triplet in combination with bortezomib or carfilzomib in patients with multiple myeloma whose disease has progressed after CAR-T therapy. Methods: We identified 7 patients across all selinexor myeloma trials who had received lymphodepleting conditioning (fludarabine/cyclophosphamide n=6; Cyclophosphamide n=1) followed by an effective dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. Four were female and 3 were male. Median age was 64 years (range: 35-70 years). One patient was treated in the STORM study, with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice-weekly), 1 patient was treated with selinexor (100 mg once-weekly) plus bortezomib (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly) and 5 patients were treated with selinexor (100 mg once-weekly) plus carfilzomib (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once-weekly or 20 mg twice-weekly). Response was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Results: Patients had a median of 10 prior therapeutic regimens (range:5-15), all had high-risk cytogenetics, and 6 of the 7 had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days). All patients responded to treatment, including 1 unconfirmed complete response (uCR), 2 very good partial responses (VGPR), 3 partial responses (PR), and 1 minimal response (MR). Responses were rapid and typically occurred within the first cycle of treatment (median 28 days; range 14-83 days). At the time of data cutoff, the median time on a selinexor-based regimen was 4.1 monthsange: 2.5-8.0 months); 2 patients' disease had progressed, 1 patient had withdrawn consent, and 4 patients were still responding on therapy. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia. Conclusions: These results suggest that Sel-dex alone or in combination with bortezomib or carfilzomib may offer therapeutic benefit for patients who have exhausted available treatment options, have rapidly progressing disease, and who have progressed after CAR-T therapy. Importantly patients are able to tolerate and remain on therapy with weekly Sel-dex in combination with bortezomib or carfilzomib, with time on therapy of >4 months and 4/7 patients remaining on therapy. Although based on a small sample size, the findings of this analysis are intriguing and warrant further investigation in a larger study. Disclosures Chari: Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Jagannath:Merck: Consultancy; Celgene: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Novartis: Consultancy. DeCastro:Karyopharm Therapeutics: Employment, Equity Ownership. Unger:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Jakubowiak:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Development and Evaluation of a Human Single Chain Variable Fragment (scFv) Derived Bcma Targeted CAR T Cell Vector Leads to a High Objective Response Rate in Patients with Advanced MM

Blood ◽

10.1182/blood.v130.suppl_1.742.742 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 742-742 ◽

Cited By ~ 1

Author(s):

Eric L Smith ◽

Sham Mailankody ◽

Arnab Ghosh ◽

Reed Masakayan ◽

Mette Staehr ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Equity Ownership

Abstract Patients with relapsed/refractory MM (RRMM) rarely obtain durable remissions with available therapies. Clinical use of BCMA targeted CAR T cell therapy was first reported in 12/2015 for RRMM, and based on small numbers, preliminary results appear promising. Given that host immune anti-murine CAR responses have limited the efficacy of repeat dosing (Turtle C. Sci Trans Med 2016), our goal was to develop a human BCMA targeted CAR T cell vector for clinical translation. We screened a human B cell derived scFv phage display library containing 6x1010 scFvs with BCMA expressing NIH 3T3 cells, and validated results on human MM cell lines. 57 unique and diverse BCMA specific scFvs were identified containing light and heavy chain CDR's each covering 6 subfamilies, with HCDR3 length ranges from 5-18 amino acids. 17 scFvs met stringent specificity criteria, and a diverse set was cloned into CAR vectors with either a CD28 or a 4-1BB co-stimulatory domain. Donor T cells transduced with BCMA targeted CAR vectors that conveyed particularly desirable properties over multiple in vitro assays, including: cytotoxicity on human MM cell lines at low E:T ratios (>90% lysis, 1:1, 16h), robust proliferation after repeat antigen stimulation (up to 700 fold, stimulation q3-4d for 14d), and active cytokine profiling, were selected for in vivo studies using a marrow predominant human MM cell line model in NSG mice. A single IV injection of CAR T cells, either early (4d) or late (21d) after MM engraftment was evaluated. In both cases survival was increased when treated with BCMA targeted CAR T cells vs CD19 targeted CAR T cells (median OS at 60d NR vs 35d p<0.05). Tumor and CAR T cells were imaged in vivo by taking advantage of luciferase constructs with different substrates. Results show rapid tumor clearance, peak (>10,000 fold) CAR T expansion at day 6, followed by contraction of CAR T cells after MM clearance, confirming the efficacy of the anti-BCMA scFv/4-1BB containing construct. Co-culture with primary cells from a range of normal tissues did not activate CAR T cells as noted by a lack of IFN release. Co-culture of 293 cells expressing this scFv with those expressing a library of other TNFRSF or Ig receptor members demonstrated specific binding to BCMA. GLP toxicity studies in mice showed no unexpected adverse events. We generated a retroviral construct for clinical use including a truncated epithelial growth factor receptor (EGFRt) elimination gene: EGFRt/hBCMA-41BBz. Clinical investigation of this construct is underway in a dose escalation, single institution trial. Enrollment is completed on 2/4 planned dose levels (DL). On DL1 pts received cyclophosphamide conditioning (3g/m2 x1) and 72x106 mean CAR+ T cells. On DL2 pts received lower dose cyclophosphamide/fludarabine (300/30 mg/m2 x3) and 137x106 mean CAR+ T cells. All pts screened for BCMA expression by IHC were eligible. High risk cytogenetics were present in 4/6 pts. Median prior lines of therapy was 7; all pts had IMiD, PI, high dose melphalan, and CD38 directed therapies. With a data cut off of 7/20/17, 6 pts are evaluable for safety. There were no DLT's. At DL1, grade 1 CRS, not requiring intervention, occurred in 1/3 pts. At DL2, grade 1/2 CRS occurred in 2/3 pts; both received IL6R directed Tocilizumab (Toci) with near immediate resolution. In these 2 pts time to onset of fever was a mean 2d, Tmax was 39.4-41.1 C, peak CRP was 25-27mg/dl, peak IL6 level pre and post Toci were 558-632 and 3375-9071 pg/ml, respectively. Additional serum cytokines increased >10 fold from baseline in both pts include: IFNg, GM CSF, Fractalkine, IL5, IL8, and IP10. Increases in ferritin were limited, and there were no cases of hypofibrinogenemia. There were no grade 3-5 CRS and no neurotoxicities or cerebral edema. No pts received steroids or Cetuximab. Median time to count recovery after neutropenia was 10d (range 6-15d). Objective responses by IMWG criteria after a single dose of CAR T cells were observed across both DLs. At DL1, of 3 pts, responses were 1 VGPR, 1 SD, and 1 pt treated with baseline Mspike 0.46, thus not evaluable by IMWG criteria, had >50% reduction in Mspike, and normalization of K/L ratio. At DL2, 2/2 pts had objective responses with 1 PR and 1 VGPR (baseline 95% marrow involvement); 1 pt is too early to evaluate. As we are employing a human CAR, the study was designed to allow for an optional second dose in pts that do not reach CR. We have treated 2 pts with a second dose, and longer follow up data is pending. Figure 1 Figure 1. Disclosures Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Almo: Cue Biopharma: Other: Founder, head of SABequity holder; Institute for Protein Innovation: Consultancy; AKIN GUMP STRAUSS HAUER & FELD LLP: Consultancy. Wang: Eureka Therapeutics Inc.: Employment, Equity Ownership. Xu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Park: Amgen: Consultancy. Curran: Juno Therapeutics: Research Funding; Novartis: Consultancy. Dogan: Celgene: Consultancy; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liu: Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME)

Blood ◽

10.1182/blood-2019-129562 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3184-3184 ◽

Cited By ~ 16

Author(s):

Caitlin L. Costello ◽

Tara K. Gregory ◽

Syed Abbas Ali ◽

Jesus G. Berdeja ◽

Krina K. Patel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Car T Cells ◽

Car T ◽

Equity Ownership

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study. A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be >=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials. Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM). Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.

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Immune Profiling of Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide and Low-Dose Dexamethasone in Combination with Daratumumab

Blood ◽

10.1182/blood-2018-99-111554 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2012-2012 ◽

Cited By ~ 2

Author(s):

William E. Pierceall ◽

Nizar Bahlis ◽

David S Siegel ◽

Gary J. Schiller ◽

Christy J. Samaras ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Ki 67 ◽

Equity Ownership

Abstract Background: Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a Phase II study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory multiple myeloma who have received a first or second line treatment of lenalidomide-based therapy. Immunomodulatory agents (IMiD® compounds) continue to be the backbone of multiple myeloma therapy especially when combined with monoclonal antibodies, more specifically pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity. We sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. IMiD agents are the backbone of combination regimens in the treatment of patients with newly diagnosed or relapsed and/or refractory multiple myeloma. The anti-myeloma properties of these agents derive from a dual mechanism of pro-apoptotic effects on tumor cells as well as enhanced immune stimulation. An understanding of how IMiD agents interact with new monoclonal antibodies to modify patient immune profiles offers key insights into the role of such in innate and adaptive immunity in determining patient outcomes. Methods and Results: Peripheral blood samples were collected at screening, Cycle1 Days 1, 8, and 15, and Cycle 2 Days 1 and 15 to monitor pharmacodynamic changes in populations of T cells, NK cells, monocytes and MDSCs by flow cytometry. From 112 patients enrolled in Arm B, 98 patients had baseline and post-treatment specimens available for these analyses. As expected, combination treatment with POM + LoDEX + DARA led to decreased peripheral counts of CD56+CD16+ NK cells as well as CD4+CD38+ and CD8+CD38+ T cell subpopulations. Decreased counts were also noted in CD3-CD19+ B cells. In contrast, total counts of CD14+ monocytes and CD3+CD4+ or CD3+CD8+ T cells were stably maintained and pronounced increases were observed in proliferating CD4+Ki-67+ and CD8+Ki-67+ T cells. Further, when examined as a percent of total counts, increases were observed in CD14+ monocytes, CD3+CD4+ and CD3+CD8+ T-cells, with decreases in CD3-CD19+ B-cells and CD3-CD56+CD16+ NK cells. Correlation of these pharmacodynamic changes with clinical outcomes will be presented. In addition, baseline immune profiling of specific cell population subsets and associations with best overall response and progression-free survival is currently being analyzed. Conclusions: The triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed multiple myeloma patients progressed and are or refractory to lenalidomide. Immune characterization here is consistent with a model for clinical activity in which the loss of CD56+CD16+ NK cells along with a concomitant immune suppression by loss of CD38+CD4+ and CD38+CD8+ T- cells is offset by an increase in proliferating cytotoxic CD4+Ki-67+ and CD8+Ki-67+ T-cell populations. Our results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment. Pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity; these data are consistent with a mechanism of action in which pomalidomide administration facilitates the ability to overcome immunosuppressive effects of Dara and LoDex. Potential associations of immune biomarkers with patient outcomes is ongoing and will be updated. Disclosures Pierceall: Celgene Corporation: Employment, Equity Ownership. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Takeda: Research Funding; Genentech: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Glenmark: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bluebird: Research Funding; Teva: Research Funding. Ganguly:Amgen: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy; Seattle Genetics: Speakers Bureau. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Srinivas:VAHCSNJ: Employment. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Serbina:Celgene: Employment. Zafar:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

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Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-127350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3873-3873

Author(s):

Michael J. Burke ◽

David S. Ziegler ◽

Francisco José Bautista Sirvent ◽

Andishe Attarbaschi ◽

Lia Gore ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Salvage options for children with relapsed ALL remain sub-optimal, particularly for T-cell ALL patients, and relapse remains the leading cause of death. Achieving complete remission (CR) after relapse is the first critical step to cure. Combining the proteasome inhibitor (PI) bortezomib with chemotherapy has previously shown promising results in achieving CR in pediatric phase 2 studies in ALL (Messinger 2012, Horton 2013, Bertaina 2017). In this ongoing dose-escalation phase 1 study, the second generation PI carfilzomib was combined with chemotherapy in children with relapsed ALL. Subjects received one 4-week cycle of induction chemotherapy with either UKALLR3 (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine) or VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) plus carfilzomib administered intravenously on days 1, 2, 8, 9, 15, and 16. The primary endpoint was dose limiting toxicities (DLTs) occurring during induction (grade 4 neutropenia or thrombocytopenia extending past day 45 or grade 4 non-hematological toxicity). Efficacy endpoints included CR (with or without hematological recovery) based on bone marrow (BM) and LP on day 29 of induction and consolidation. Subjects < 21 years of age and diagnosed with first early BM relapse (<36 months from diagnosis), multiply relapsed ALL, or primary induction failure were eligible; subjects with T-cell disease with any BM relapse were eligible. Subjects achieving ≥ stable disease could receive a cycle of modified BFM consolidation therapy (6-MP, cyclophosphamide, cytarabine, PEG-asparaginase, IT chemotherapy) plus carfilzomib at the same dose level and schedule given in induction therapy. Dose escalation was based on an evaluation of DLT's using a Bayesian logistic regression model. Ten subjects with B (n=9) or T- (n=1) cell ALL were treated with UKALLR3 at 2 carfilzomib dose levels (20 or 27 mg/m2, 5 subjects each). Among DLT-evaluable subjects, 3 DLTs (meningoencephalitis, hemolytic uremic syndrome and neutropenia) were observed, 2 at 27 and 1 at 20 mg/m2 dose levels with an MTD of 27 mg/m2. The UKALLR3 regimen was considered too toxic by the protocol steering committee and was replaced with VXLD in January 2016. The VXLD cohort started at 27 mg/m2 and is currently in the 56 mg/m2 dose level. Fifteen subjects (7 B-cell and 8 T-cell) were treated with VXLD at carfilzomib dose levels of 27 (n=3), 36 (n=7), 45 (n=4), and 56 (n=1) mg/m2. One DLT of posterior reversible encephalopathy syndrome (PRES) occurred in the 36 mg/m2 cohort, with no further DLTs identified after expansion to 7 subjects. Table 2 lists the patient characteristics of the 15 subjects in the VXLD cohort. Grade 3-4 hematological AEs were nearly universal for both UKALLR3 and VXLD. Non-hematological > Grade 3 AE's of note are listed in Table 1. PRES occurred in 2 subjects in the VXLD cohort (both with prior allogeneic SCT) and rapidly reversed in both cases. Re-challenge with carfilzomib in one case was tolerated without PRES recurrence. Serious AE's (SAE) were reported in 50% and 56% of subjects receiving carfilzomib in combination with UKALLR3 or VXLD, respectively, with the most common SAE's among all subjects being sepsis (16%), pancreatitis and PRES (8% each). In the UKALLR3 cohort, 60% of subjects (n=6) achieved a remission, however only 30% proceeded to consolidation. In the VXLD cohort, 53% of evaluable subjects (n=8) achieved remission and 13% were non-evaluable due to hypocellular BM at day 29 of induction. All responding subjects recovered hematological counts by day 42 without evidence of progression. Eight subjects (53%) proceeded to consolidation, including 2 subjects with non-evaluable BM results and 1 with 8% BM blasts after induction. All subjects entering consolidation were in remission on day 29 post-consolidation. The overall remission rate with VXLD-carfilzomib was 67% at the end of consolidation. Detailed response data are listed in Table 3. Carfilzomib in combination with VXLD chemotherapy was tolerable in a predominantly T-cell ALL population, very early or post stem cell transplant relapse. Efficacy is promising in this small cohort of patients with carfilzomib dose escalation continuing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau. Bautista Sirvent:EusaPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending symposia; Takeda: Other: Support for attending symposia; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: Support for attending symposia; Amgen, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Bellicum: 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. O'Brien:BMS: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; BTG: Research Funding. Obreja:Amgen, Inc.: Employment, Equity Ownership. Morris:Amgen, Inc.: Employment, Equity Ownership. Baruchel:Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bellicum: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: Kyprolis is a proteasomal inhibitor indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

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Targeted MEK Inhibition in Patients with Previously Treated Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4775.4775 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4775-4775 ◽

Cited By ~ 4

Author(s):

Christoph Heuck ◽

Yogesh Jethava ◽

Rashid Z Khan ◽

Scott Miller ◽

Alan Mitchell ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Mapk Pathway ◽

Objective Response ◽

Genomic Profiling ◽

Employment Equity ◽

Advisory Committees ◽

Comprehensive Genomic Profiling ◽

Equity Ownership

Abstract Background: Diagnostic and therapeutic advances have significantly improved the outcomes for multiple myeloma (MM) patients. However, pts who are refractory to or relapse after therapy with immune modulatory drugs and proteasome inhibitors remain a therapeutic challenge. Comprehensive genomic profiling via clinical next generation sequencing (NGS)-based assays studies of MM cases have revealed multiple targetable mutations that were previously unexploited in MM. Methods: Between June 2013 and May 2014 we performed genomic profiling of 351 patients who had progressed after initial therapy to assist physicians in therapy planning. Comprehensive genomic profiling was performed using the FoundationOne¨ or FoundationOne Heme¨ assays. FoundationOne assays 374 cancer-related and 24 frequently rearranged genes via DNA-seq, and FoundationOneHeme assays 405 cancer-related and 31 frequently rearranged genes via DNA-seq as well as 265 frequently rearranged genes by RNA-seq. All samples were sequenced in a CLIA-certified CAP-accredited laboratory to an average depth >500x . Patients with activating alterations of KRAS, NRAS or BRAF were considered for therapy with the targeted agent trametinib (TMTB) as were patients who had a gene expression signature suggesting activation of the MAPK pathway. Retrospective review of this case series was approved by the UAMS institutional review board. Results: We identified 63 patients who underwent treatment with Trametinib. 60 were treated based on activating mutations of KRAS, NRAS or BRAF and 3 were treated based on a GEP signature. The median age was 65 and patients had a median of 5 lines of prior therapy (range 1-20). 38 of 63 patients had prior treatment with Total Therapy. 43 underwent salvage with chemotherapy prior to initiation of TMTB, 15 had salvage transplants, 33 patients were exposed to novel agents (Pomalidomide, Carfilzomib) and 33 had Metronomic therapy before TMTB. 25% of patients were ISS stage 3 and 37% had GEP70 defined high risk. 13 had PET defined extra medullary disease (EMD). 41 patients were administered TMTB monotherapy and 22 received TMTB treatment in combination with other agents. In general the treatment was well tolerated. 10 patients discontinued therapy because of toxicities, 29 discontinued because of disease progression or death. None of the deaths were attributed to TMTB, Best treatment responses were SD in 30, PR in 8, VGPR in 2 and CR in 3 of the 63 pts. For 25 patients with evaluable PET data, treatment resulted in complete resolution of FDG avid lesions in 9 patients and a better than 50% reduction in 15 (Figure 1). We will present updated data on clinical responses as well as toxicities. Conclusions: Treatment with targeted therapy guided by prospective comprehensive genomic profiling across all classes of genomic alterations in this heavily pretreated population of MM patients resulted in an unexpectedly high objective response rate. Observation of CR with TMTB monotherapy further supports continued investigation of this individualized approach to MM management. Disclosures Van Laar: Signal Genetics: Employment, Equity Ownership. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc: Employment. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Millenium: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

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Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3026.3026 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3026-3026 ◽

Cited By ~ 5

Author(s):

Jesús F. San-Miguel ◽

Vania T.M. Hungria ◽

Sung-Soo Yoon ◽

Meral Beksac ◽

Meletios A. Dimopoulos ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Final Analysis ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

Study Therapy

Abstract Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months]; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72]). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: 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; Celgene: 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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: 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.

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Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy

Blood ◽

10.1182/blood.v130.suppl_1.740.740 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 740-740 ◽

Cited By ~ 4

Author(s):

Jesus G. Berdeja ◽

Yi Lin ◽

Noopur Raje ◽

Nikhil Munshi ◽

David Siegel ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Research Funding ◽

Employment Equity ◽

Car T Cells ◽

Car T ◽

Clinical Responses ◽

Equity Ownership ◽

Dose Levels

Abstract Introduction: Chimeric antigen receptor (CAR) T cell therapies have demonstrated robust and sustained clinical responses in several hematologic malignancies. Data suggest that achieving acceptable benefit:risk profiles depends on several factors, including the specificity of the antigen target and characteristics of the CAR itself, including on-target, off-tumor activity.To test the safety and efficacy of CAR T cells in relapsed and/or refractory multiple myeloma (RRMM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM cells. BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on malignant cells. Peripheral blood mononuclear cells are collected via leukapheresis and shipped to a central facility for transduction, expansion, and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 50, 150, 450, 800, and 1,200 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures were quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, evaluation of minimal residual disease (MRD), overall and progression-free survival, quantification of bb2121 in blood, and quantification of circulating soluble BCMA over time. Results: Asof May 4, 2017, 21 patients (median 58 [37 to 74] years old) with a median of 5 (1 to 16) years since MM diagnosis, had been infused with bb2121, and 18 patients were evaluable for initial (1-month) clinical response. Patients had a median of 7 prior lines of therapy (range 3 to 14), all with prior autologous stem cell transplant; 67% had high-risk cytogenetics. Fifteen of 21 (71%) had prior exposure to, and 6 of 21 (29%) were refractory to 5 prior therapies (Bort/Len/Car/Pom/Dara). Median follow-up after bb2121 infusion was 15.4 weeks (range 1.4 to 54.4 weeks). As of data cut-off, no DLTs and no treatment-emergent Grade 3 or higher neurotoxicities similar to those reported in other CAR T clinical studies had been observed. Cytokine release syndrome (CRS), primarily Grade 1 or 2, was reported in 15 of 21 (71%) patients: 2 patients had Grade 3 CRS that resolved in 24 hours and 4 patients received tocilizumab, 1 with steroids, to manage CRS. CRS was more common in the higher dose groups but did not appear related to tumor burden. One death on study, due to cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history, was observed while the patient was in sCR and was assessed as unrelated to bb2121. The overall response rate (ORR) was 89% and increased to 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. No patients treated with doses of 150 x 106 CAR+ T cells or higher had disease progression, with time since bb2121 between 8 and 54 weeks (Table 1). MRD negative results were obtained in all 4 patients evaluable for analysis. CAR+ T cell expansion has been demonstrated consistently and 3 of 5 patients evaluable for CAR+ cells at 6 months had detectable vector copies. A further 5 months of follow up on reported results and initial data from additional patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 50 x 106 CAR+ T cells, with manageable CRS and no DLTs to date. ORR was 100% at these dose levels with 8 ongoing clinical responses at 6 months and 1 patient demonstrating a sustained response beyond one year. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in RRMM. CT.gov study NCT02658929, sponsored by bluebird bio and Celgene Disclosures Berdeja: Teva: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding; Vivolux: Research Funding; Amgen: Research Funding; Constellation: Research Funding; Bluebird: Research Funding; Curis: Research Funding. Siegel: Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Jagannath: MMRF: Speakers Bureau; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau. Turka: bluebird bio: Employment, Equity Ownership. Lam: bluebird bio: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Morgan: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Quigley: bluebird bio: Employment, Equity Ownership, Patents & Royalties. Kochenderfer: Bluebird bio: Research Funding; N/A: Patents & Royalties: I have multiple patents in the CAR field.; Kite Pharma: Research Funding.

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Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies

Blood ◽

10.1182/blood-2018-99-113169 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1882-1882 ◽

Cited By ~ 1

Author(s):

Samuel A Danziger ◽

Mark McConnell ◽

Jake Gockley ◽

Mary Young ◽

Adam Rosenthal ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Expression Profiles ◽

Cell Types ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction The multiple myeloma (MM) tumor microenvironment (TME) strongly influences patient outcomes as evidenced by the success of immunomodulatory therapies. To develop precision immunotherapeutic approaches, it is essential to identify and enumerate TME cell types and understand their dynamics. Methods We estimated the population of immune and other non-tumor cell types during the course of MM treatment at a single institution using gene expression of paired CD138-selected bone marrow aspirates and whole bone marrow (WBM) core biopsies from 867 samples of 436 newly diagnosed MM patients collected at 5 time points: pre-treatment (N=354), post-induction (N=245), post-transplant (N=83), post-consolidation (N=51), and post-maintenance (N=134). Expression profiles from the aspirates were used to infer the transcriptome contribution of immune and stromal cells in the WBM array data. Unsupervised clustering of these non-tumor gene expression profiles across all time points was performed using the R package ConsensusClusterPlus with Bayesian Information Criterion (BIC) to select the number of clusters. Individual cell types in these TMEs were estimated using the DCQ algorithm and a gene expression signature matrix based on the published LM22 leukocyte matrix (Newman et al., 2015) augmented with 5 bone marrow- and myeloma-specific cell types. Results Our deconvolution approach accurately estimated percent tumor cells in the paired samples compared to estimates from microscopy and flow cytometry (PCC = 0.63, RMSE = 9.99%). TME clusters built on gene expression data from all 867 samples resulted in 5 unsupervised clusters covering 91% of samples. While the fraction of patients in each cluster changed during treatment, no new TME clusters emerged as treatment progressed. These clusters were associated with progression free survival (PFS) (p-Val = 0.020) and overall survival (OS) (p-Val = 0.067) when measured in pre-transplant samples. The most striking outcomes were represented by Cluster 5 (N = 106) characterized by a low innate to adaptive cell ratio and shortened patient survival (Figure 1, 2). This cluster had worse outcomes than others (estimated mean PFS = 58 months compared to 71+ months for other clusters, p-Val = 0.002; estimate mean OS = 105 months compared with 113+ months for other clusters, p-Val = 0.040). Compared to other immune clusters, the adaptive-skewed TME of Cluster 5 is characterized by low granulocyte populations and high antigen-presenting, CD8 T, and B cell populations. As might be expected, this cluster was also significantly enriched for ISS3 and GEP70 high risk patients, as well as Del1p, Del1q, t12;14, and t14:16. Importantly, this TME persisted even when the induction therapy significantly reduced the tumor load (Table 1). At post-induction, outcomes for the 69 / 245 patients in Cluster 5 remain significantly worse (estimate mean PFS = 56 months compared to 71+ months for other clusters, p-Val = 0.004; estimate mean OS = 100 months compared to 121+ months for other clusters, p-Val = 0.002). The analysis of on-treatment samples showed that the number of patients in Cluster 5 decreases from 30% before treatment to 12% after transplant, and of the 63 patients for whom we have both pre-treatment and post-transplant samples, 18/20 of the Cluster 5 patients moved into other immune clusters; 13 into Cluster 4. The non-5 clusters (with better PFS and OS overall) had higher amounts of granulocytes and lower amounts of CD8 T cells. Some clusters (1 and 4) had increased natural killer (NK) cells and decreased dendritic cells, while other clusters (2 and 3) had increased adipocytes and increases in M2 macrophages (Cluster 2) or NK cells (Cluster 3). Taken together, the gain of granulocytes and adipocytes was associated with improved outcome, while increases in the adaptive immune compartment was associated with poorer outcome. Conclusions We identified distinct clusters of patient TMEs from bulk transcriptome profiles by computationally estimating the CD138- fraction of TMEs. Our findings identified differential immune and stromal compositions in patient clusters with opposing clinical outcomes and tracked membership in those clusters during treatment. Adding this layer of TME to the analysis of myeloma patient baseline and on-treatment samples enables us to formulate biological hypotheses and may eventually guide therapeutic interventions to improve outcomes for patients. Disclosures Danziger: Celgene Corporation: Employment, Equity Ownership. McConnell:Celgene Corporation: Employment. Gockley:Celgene Corporation: Employment. Young:Celgene Corporation: Employment, Equity Ownership. Schmitz:Celgene Corporation: Employment, Equity Ownership. Reiss:Celgene Corporation: Employment, Equity Ownership. Davies:MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; Abbvie: Consultancy; ASH: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Copeland:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Barlogie:Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; Multiple Myeloma Research Foundation: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Millenium: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Trotter:Celgene Research SL (Spain), part of Celgene Corporation: Employment, Equity Ownership. Hershberg:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Dervan:Celgene Corporation: Employment, Equity Ownership. Ratushny:Celgene Corporation: Employment, Equity Ownership. Morgan:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding.

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Initial Results from a Phase 1 Clinical Study of bb21217, a Next-Generation Anti Bcma CAR T Therapy

Blood ◽

10.1182/blood-2018-99-116953 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 488-488 ◽

Cited By ~ 41

Author(s):

Nina Shah ◽

Melissa Alsina ◽

David S Siegel ◽

Sundar Jagannath ◽

Deepu Madduri ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Equity Ownership

Abstract Introduction: Immunomodulatory chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy bb2121 (Friedman 2018, Hum Gene Ther 29:585). It uses the same scFv, 4-1BB costimulatory motif and CD3-zeta T cell activation domain as bb2121 with the addition of phosphoinositide 3 kinase inhibitor bb007 during ex vivo culture to enrich the drug product for T cells displaying a memory-like phenotype. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human clinical study of bb21217 in patients with RRMM designed to assess the safety, pharmacokinetics, efficacy and duration of effect of bb21217. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in approximately 50 patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ cells in blood. Results: Asof June 15, 2018, 8 patients (median age 64 [min;max 54 to 70]) have received bb21217. All patients to date received a dose of 150 x 106 CAR+ T cells. Four had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 9 (min;max 4 to 17) prior lines of therapy and 7/8 had prior autologous stem cell transplant; 50% had high-risk cytogenetics. Four of 8 (50%) had previously received Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 16 weeks (2 to 27 weeks) and 7 patients were evaluable for initial (1-month) clinical response. As of data cut-off, 5 of 8 patients developed cytokine release syndrome (CRS; 1 Grade 1, 3 Grade 2, 1 Grade 3) and responded to supportive care or tocilizumab. This included 1 patient with high tumor burden who experienced DLTs consisting of grade 3 CRS and grade 4 encephalopathy with signs of posterior reversible encephalopathy syndrome on MRI. This patient received tocilizumab, corticosteroids and cyclophosphamide, improved neurologically and achieved a sCR. Following this event, the dose escalation cohort was divided into two groups based on tumor burden and dosing continued at 150x106 CAR+ T cells. No deaths occurred. With 1 to 6 months since treatment, 6 of 7 patients had demonstrated clinical response per IMWG criteria: currently 1 sCR, 3 VGPR, 2 PR. MRD negative results at 10-5 nucleated cells were obtained by next-generation sequencing in 3 of 3 evaluable responders. Robust CAR+ T cell expansion during the first 30 days was observed in 7 of 7 evaluable patients. Two of 2 patients evaluable at 6 months had detectable CAR vector copies. Conclusions: Early efficacy results with bb21217 CAR T therapy in RRMM at a dose of 150 x 106 CAR+ T cells are encouraging, with 6 of 7 patients demonstrating clinical responses. The adverse events observed to date are consistent with known toxicities of CAR T therapies. CAR+ T cells were measurable at 6 months post treatment in both evaluable patients. Enrollment in the study is ongoing; longer follow-up and data in more patients will establish whether treatment with bb21217 results in sustained CAR+ T cell persistence and responses. Disclosures Shah: Kite: Consultancy; Indapta Therapeutics: Consultancy; University of California San Francisco: Employment; Nekktar: Consultancy; Teneobio: Consultancy; Sanofi: Consultancy; Janssen: Research Funding; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy; Bluebird: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Consultancy; Takeda: Consultancy; Sutro Biopharma: Research Funding; Nkarta: Consultancy. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medicom: Speakers Bureau. Kaufman:Karyopharm: Other: data monitoring committee; BMS: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Turka:bluebird bio, Inc: Employment, Equity Ownership. Lam:bluebird bio, Inc: Employment, Equity Ownership. Massaro:bluebird bio, Inc: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: multiple; Mersana: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; SITC: Membership on an entity's Board of Directors or advisory committees; Arcus Biosicences: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio, Inc: Employment, Equity Ownership. Berdeja:Glenmark: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Raje:AstraZeneca: Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Amgen Inc.: Consultancy; Research to Practice: Honoraria; Medscape: Honoraria.

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