Summary Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first-in-human study of umbilical cord blood-derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto-HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB-NK cells on day −5 and auto-HCT on day 0. Twelve patients were enrolled, 3 on each of four CB-NK cell dose levels: 5×106, 1×107, 5×107 and 1×108 CB-NK cells/kg. Ten patients had either high-risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft-versus-host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back-up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including 8 with near complete response or better. With a median follow-up of 21 months, 4 patients have progressed or relapsed, 2 of whom have died. CB-NK cells were detected in vivo in 6 patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy.

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple MyelomaTable of Contents KarMMa-3 Study Countries and Sites. Methods Study Design and Patients Long-term Follow-up Endpoints and Assessments Statistical Analyses Results Patients and Treatment Odds Ratio for Overall Response Rate Cellular Kinetics-Pharmacokinetics BCMA Expression KarMMa-3 Study Countries and Sites.

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PURPOSE Idecabtagene vicleucel (ide-cel) is an autologous B-cell maturation antigen–directed chimeric antigen receptor T-cell therapy approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase II pivotal KarMMa trial, which demonstrated best overall and ≥ complete response rates of 73% and 33%, respectively. We report clinical outcomes with standard-of-care (SOC) ide-cel under the commercial Food and Drug Administration label. METHODS Data were retrospectively collected from patients with RRMM who underwent leukapheresis as of February 28, 2022, at 11 US institutions with intent to receive SOC ide-cel. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines and managed according to each institution's policies. Responses were graded on the basis of the International Myeloma Working Group response criteria. RESULTS One hundred fifty-nine of 196 leukapheresed patients received ide-cel by data cutoff. One hundred twenty (75%) infused patients would have been ineligible for participation in the KarMMa clinical trial because of comorbidities at the time of leukapheresis. Any grade and grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 82/3% and 18/6%, respectively. Best overall and ≥ complete response rates were 84% and 42%, respectively. At a median follow-up of 6.1 months from chimeric antigen receptor T infusion, the median progression-free survival was 8.5 months (95% CI, 6.5 to not reached) and the median overall survival was 12.5 months (95% CI, 11.3 to not reached). Patients with previous exposure to B-cell maturation antigen–targeted therapy, high-risk cytogenetics, Eastern Cooperative Oncology Group performance status ≥ 2 at lymphodepletion, and younger age had inferior progression-free survival on multivariable analysis. CONCLUSION The safety and efficacy of ide-cel in patients with RRMM in the SOC setting were comparable with those in the phase II pivotal KarMMa trial despite most patients (75%) not meeting trial eligibility criteria.

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell therapeutic targeting BCMA, which is highly expressed on MM cells. It is designed to increase efficacy while minimizing toxicity through reduced immunogenicity, lack of tonic signaling, a safety switch, and a product comprised predominantly of early memory T cells that are effectively all CAR-positive. Rather than using a traditional antibody-based binder, P-BCMA-101 utilizes an anti-BCMA Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic. P-BCMA-101 is produced using the piggyBac™ (PB) DNA Modification System instead of a viral vector, and requires only plasmid DNA and mRNA. This eliminates the need for virus, is less costly, and produces a purified population of CAR+ cells with a preponderance of the favorable stem cell memory T phenotype (TSCM). The higher cargo capacity permits the incorporation of other genes, a safety switch that allows for rapid depletion of product in vivo if indicated by adverse events, and a selection gene that allows for enrichment of CAR+ cells. These features are predicted to result in a greater therapeutic index. Efficacy of P-BCMA-101 in NSG mice bearing aggressive human MM.1S and p53 -/- MM.1S MM was reported (Hermanson, AACR 2016). Whereas control animals died early, tumor burden was reduced to the limit of detection after P-BCMA-101 treatment, and recurrences were spontaneously re-controlled without re-administration of product. A Phase 1, 3+3 dose escalation trial is being conducted in patients with r/r MM (≥ 3 prior lines, including a proteasome inhibitor and an IMiD, or double refractory) to assess the safety and efficacy of P-BCMA-101 (NCT03288493). No pre-specified level of BCMA expression was required. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. As of 31Jul18, 12 patients have been treated with 48, 50, 55, 118, 122, 124, 143, 155, 164, 238, 324 and 430 x 106 P-BCMA-101 CAR-T cells in 3 weight-based cohorts. Patients were heavily pre-treated (3-9 prior therapies), 100% had failed IMiDs, proteasome inhibitors and daratumumab, and 64% had high-risk cytogenetics. Nine patients have yet reached their first 2-week response assessment. All patients have shown some improvement in myeloma assessments on study, yet only 1 patient (8%) has developed any cytokine release syndrome (CRS) (limited Grade 2). Of 3 patients in the first cohort 1 attained a PR and 1 with non-secretory disease near CR of her plasmacytomas on PET/CT. Of the subsequent 6 patients, 3 patients have thus far reached a PR, 1 a VGPR, and 1 a sCR. Thus of the yet evaluable patients treated above Cohort 1, the overall response rate (ORR) is 83% (5/6), in spite of only one experiencing CRS. This CRS was scored as Grade 2, based on short-lived fever and hypotension managed with IV fluids and antibiotics, with minimal CRS marker elevations. Likewise, CRS markers were minimally elevated in other patients. The maximal IL-6 level in any patient was 86 pg/mL, which is orders of magnitude lower than levels generally reported in patients experiencing meaningful CRS after treatment with CAR-T products. No patients required treatment with tocilizumab or safety switch activation. There have been no patient deaths, and no neurotoxicity, DLTs or unexpected/off-target toxicities related to treatment. Generally, infusions were well-tolerated, with cytopenias, including transfusion requiring cytopenias and febrile neutropenia, being the most common Grade 3+ adverse events. Consistent with the hypothesis of the early memory phenotype conveying durability, circulating P-BCMA-101 cells were detected in the blood by flow and PCR, peaking at 2-3 weeks, and remaining detectable at the last timepoint tested in all patients (3 patients thus far assessed at 3 months). In conclusion, current clinical trial data in patients with r/r MM support preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, comparing favorably with other anti-BCMA CAR-T products at similar doses, with notably less CRS and no neurotoxicity, consistent with the hypothesis of an improved therapeutic index. Funding by Poseida Therapeutics and CIRM. Disclosures Gregory: Poseida Therapeutics, Inc.: Research Funding. Cohen:Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Poseida Therapeutics, Inc.: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Research Funding. Costello:Celgene: Consultancy; Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy. Ali:Celgene Inc: Research Funding; Aduro Biotech: Consultancy, Research Funding; Amgen Inc: Consultancy; Juno: Consultancy; Takeda Oncology: Consultancy; Poseida Therapeutics: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Glenmark: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Teva: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Resler:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Millenium Pharmaceuticals: Consultancy, Research Funding; Poseida: Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Janssen Pharmaceuticals: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.