Treatment of Patients with T Cells Expressing a Fully-Human Anti-BCMA CAR with a Heavy-Chain Antigen-Recognition Domain Caused High Rates of Sustained Complete Responses and Relatively Mild Toxicity

Multiple myeloma (MM) is a malignancy of plasma cells that is nearly always incurable. T cells expressing chimeric antigen receptors (CAR) that target B-cell maturation antigen (BCMA) can recognize and eliminate MM. The murine or other non-human sequences in the single-chain variable fragments (scFv) of many anti-BCMA CARs can elicit recipient immune responses against CAR T cells. We constructed a CAR incorporating an anti-BCMA fully-human heavy-chain variable domain designated FHVH33. FHVH33 lacks the light chain, the artificial linker sequence, and the 2 linker-associated junctions of a scFv, so FHVH33 is smaller than a scFv and is likely to be less immunogenic. The FHVH33-containing CAR utilized in this clinical trial also incorporated a CD8a hinge and transmembrane domain, a 4-1BB domain, and a CD3z domain. The CAR was designated FHVH33-CD8BBZ and was encoded by a gamma-retroviral vector. T cells expressing FHVH33-CD8BBZ were designated FHVH33-T. The FHVH33-T production process was initiated with unsorted peripheral blood mononuclear cells and took 7 days. The treatment protocol was 300 mg/m 2 of cyclophosphamide and 30 mg/m 2 of fludarabine on days -5 to -3 followed by infusion of FHVH33-T on day 0. Twenty-five patients received FHVH33-T infusions. Median age of the treated patients was 62 (range 39-73). Patients received a median of 6 prior lines of therapy (range 3-10). Five dose levels were assessed (Table). Dose level 4, 6x10 6 CAR + T cells/kg was identified as the maximum feasible dose after considering efficacy and manufacturing factors. Twenty-three of 25 patients (92%) obtained objective responses (OR) of partial response (PR) or better. Seventeen patients (68%) attained a best response of stringent complete response (sCR) or very good partial response (VGPR). Thirteen patients have ongoing responses. To date, the median duration of response is 50 weeks for the highest two dose levels. At present, the overall median progression free survival (PFS) is 78 weeks; as responses are ongoing in 13 patients (52%), PFS will likely improve. Nine of 25 patients had extramedullary plasmacytomas at baseline; patients with extramedullary plasmacytomas at baseline were less likely to achieve sCR (P=0.011). All 25 treated patients were evaluable for toxicity. Eighteen patients had grade 1 or 2 cytokine-release syndrome (CRS), and 6 patients had grade 3 CRS. One patient had no CRS. No patients had grade 4 CRS. Five patients received tocilizumab and 4 patients received corticosteroids for CRS. Two of twenty-five patients had grade 3 neurological toxicity possibly attributable to FHVH33-T. No patient had grade 4 neurologic toxicity attributable to CAR T cells. One patient died of influenza pneumonia. We assessed blood CAR+ cells by quantitative PCR. The median peak blood CAR+ cell level was 126.5 cells/µl (range 3-1071 cells/µl), and the median time post-infusion of peak blood CAR + cell levels was 10.5 days (range 7-14). Peak CAR T-cell level was not associated with obtaining a sCR. In contrast, blood CAR+ T cell levels at both 1 and 2 months after infusion were statistically higher for patients obtaining sCR. For the 1-month time-point, blood CAR+ cell levels in cells/mL were 20 for sCR patients and 4 for not sCR patients (P=0.04). Pretreatment serum BCMA was not statistically different when patients obtaining or not obtaining sCR were compared (median serum BCMA in pg/mL: sCR patients 86,243; not sCR patients 261,675, P=0.20). We assessed cell-surface BCMA expression level on MM cells by antibody binding capacity (ABC) flow cytometry. Cell-surface BCMA expression level was not statistically different in sCR versus not sCR patients (median ABC in sites/cell: sCR patients 844; not sCR patients 535, P=0.29). Patients with MM expressing low levels of BCMA obtained durable responses of greater than 2 years duration, which suggests that FHVH33-T can recognize low levels of cell-surface BCMA. Eight patients had extramedullary plasmacytomas at relapse; 4 patients had plasmacytomas biopsied. Two of the biopsied plasmacytomas were BCMA+, and two were BCMA-negative by immunohistochemistry. FHVH33-CD8BBZ CAR T cells caused relatively mild toxicity and a high rate of sCRs in patients with relapsed MM including MM with low cell-surface BCMA expression. Figure 1 Figure 1. Disclosures Brudno: Kyverna Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lam: Kite, a Gilead Company: Patents & Royalties. Kochenderfer: Kite, a Gilead Company: Patents & Royalties: on anti-CD19 CARs, Research Funding; Bristol Myers Squibb: Research Funding.

Extramedullary Plasmacytomas of the Oral Cavity: A Case Report and Review of the Literature

Introduction: Multiple myeloma is a hematologic malignancy characterized by the proliferation of plasma cells and typically presents with lesions in bone, known as plasmacytomas. Through hematogenous spread, extramedullary plasmacytomas can develop in soft tissue in any location of the body. This case report describes a patient with multiple myeloma who presented with an extramedullary plasmacytoma on his maxillary gingiva and provides an updated review on the classification and characterization of extramedullary plasmacytomas of the oral cavity. Case description: A 53-year-old male with a known diagnosis of multiple myeloma was referred to our clinic for evaluation of a gingival nodule, which was tender to palpation and had been present for a month. Clinical examination revealed a 1.5 cm violaceous, red nodule of the maxillary buccal attached gingiva, which did not blanch on palpation. He had a similar 1 cm, smooth, red nodule of his cutaneous skin on his left arm. Radiographic examination with within normal limits without evidence of dental or bony pathology. An incisional biopsy revealed the diagnosis of plasmacytoma, indicating relapse and progression of the patient’s multiple myeloma.Practical implications: Multiple myeloma can present in the oral cavity either as intra-bony plasmacytomas, paraskeletal plasmacytomas, or extramedullary plasmacytomas in the soft tissue. Extramedullary disease representative of hematogenous spread is concerning for high-risk disease with a poor risk prognosis.

Multiple Upper Aerodigestive Tract Masses Presenting With Stridor—A Rare Case of Aggressive Multifocal Extramedullary Plasmacytoma

Extramedullary plasmacytomas represent a rare group of B-cell malignancies that arise outside the bone marrow and their disease process is still poorly understood. Here, we will describe a case of a 76-year-old patient who presented with a large chest wall and subglottic mass causing airway compromise and stridor. Biopsies showed atypical plasma cells with prominent nucleoli which were in keeping with an extramedullary plasmacytoma. Disease progressed despite surgical debulking, targeted radiotherapy, and multiple chemotherapy regimens. Although response to treatment is classically good, patients occasionally present with aggressive disease.

Multiple Myeloma in a Young Female Presenting with Neurological Symptoms

Background. Multiple myeloma is overall the 14th most common malignancy but is rarely seen in those younger than 35 years. Those in the younger age group have been shown to have a more aggressive course but reportedly have had similar responses to treatment compared to older cohorts. Extramedullary plasmacytomas are discrete soft tissue masses of neoplastic monoclonal plasma cells that often occur in patients with multiple myeloma. Case. This case entails a young female with new diagnosis of multiple myeloma and multiple extramedullary plasmacytomas presenting with neurological symptoms. She was treated with CyBorD regimen but was refractory and progressed. Treatment was changed to DCEP regimen, and daratumumab was added for primary refractory myeloma. The patient improved rapidly. Conclusion. This is a unique case of multiple myeloma in a young female that had failed first-line treatment but responded to targeted therapy of daratumumab. It highlights that multiple myeloma may present atypically in young patients. More research is needed on appropriate initial diagnosis and treatment of patients in this age group.

Minimal Residual Disease Assessment Using Euroflow-NGF in Patients with Multiple Myeloma Treated with a Combination of Carfilzomib, Lenalidomide, and Dexamethasone (KRD)

Background: Owing to the development of novel agents, the rate of complete response (CR) in multiple myeloma (MM) has increased. Additionally, the development of methods for measuring minimal residual disease (MRD) (e.g., multiparameter flow cytometry [MFC] and next-generation sequencing) has enabled us to stratify CR patients according to MRD levels. In this study, we hypothesized that deep response predicts better prognosis in MM. To investigate this hypothesis, we assessed the response of patients treated with carfilzomib + lenalidomide + dexamethasone (KRD) using MFC and compared survival outcomes between different groups defined by the MRD status. Methods: The response of patients with relapsed/refractory MM treated with KRD at four different centers between September 2016 and October 2018 was prospectively investigated using the EuroFlow next-generation flow (EuroFlow-NGF) method. In this method, ammonium chloride-based bulk lysis was used, followed by surface staining with antibodies against CD138-BV421, CD27-BV510, CD38 multiepitope (ME)-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, and CD81-APC C750 in tube 1 and surface/intracellular staining with antibodies against CD138-BV421, CD27-BV510, CD38 ME-FITC, CD56-PE, CD45-PerCP Cy5.5, CD19-PECy7, CD117-APC, CD81-APC C750, cytoplasmic (cy) Igκ-APC, and cyIgλ-APC C750 after permeabilization in tube 2. MRD levels were assessed using bone marrow (BM) cells after several KRD cycles, with the lower limit of detection set at 1 × 10−5. Presence of high-risk cytogenetics [del 17p, t(4;14) and/or t(14;16)] in BM cells was analyzed through FISH. Results: A total of 21 patients (12 males, 9 females) were treated with KRD and assessed for MRD levels. The median age of these patients was 66 years at KRD initiation (range 30-83 years), and 11 patients had ISS 1, 6 had ISS 2, and 4 had ISS 3. Four patients displayed high-risk chromosomal abnormalities, including del 17p (n = 3) and t(14;16) (n = 1). The median number of prior treatments was 3 (range 1-6); these included bortezomib (n=12), lenalidomide (n=19), and autologous stem-cell transplantation (n=12). The median number of KRD cycles was 4 (range 1-22). The proportion of patients achieving ≥CR and overall response (≥ partial response [PR]) was significantly higher after KRD treatment than the proportion that had been achieved by previous therapies (71% vs. 9.5%, p < 0.001; 100% vs. 71%, p = 0.008, respectively). Pre-KRD responses included 2 stringent CR (sCR), 7 very good PR (VGPR), 6 PR, 3 stable disease, and 3 progressive disease. Post-KRD responses included 13 sCR, 2 CR, 3 VGPR, and 3 PR. A total of 95% (20/21) of patients achieved sCR, and 5% (1/21) VGPR as best response. After KRD, response was upgraded in 19 (90%) patients and maintained in two PR (10%) patients. During and after KRD treatment, MRD negativity was achieved in 12 of 16 (75%) and in 15 of 21 (71%) patients, respectively. The median number of therapy lines after KRD was 1 (range 0-5). All 4 high-risk cytogenetic cases achieved MRD negativity. Among MRD-positive cases, both 2-year progression-free survival (PFS) and 2-year overall survival (OS) from KRD initiation were 100%. Among MRD-negative cases, 2-year PFS and OS from KRD initiation were 92% and 100%, respectively. The median follow-up was 1.8 years (range 0.5-2.5 years). One MRD-negative case showed extramedullary relapse 1.4 years after the last KRD cycle. This patient did not have high-risk cytogenetics and achieved "flow MRD negativity" after two KRD cycles, and the treatment was stopped after 7 KRD cycles due to peripheral neuropathy. Paiva et. al. also reported that only 6 of 225 (3%) MRD-negative patients relapsed. Strikingly, all 6 relapsing cases in the report had extramedullary plasmacytomas at diagnosis; all relapsed with extramedullary plasmacytomas and only 2 developed concomitant serological relapse (ASH 2017, abstract #905). Conclusions: KRD induced deep responses in relapsed/refractory MM patients who eventually displayed excellent PFS. All patients with high-risk cytogenetics achieved EuroFlow-NGF negativity. Post-remission imaging studies such as MRI/PET-CT may be necessary for patients who presented with extramedullary plasmacytomas even when they achieved flow MRD negativity. Figure Disclosures Yoroidaka: Ono Pharmaceutical: Honoraria. Takamatsu:Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Becton, Dickinson and Company: Honoraria; Abbvie: Consultancy; Daiichi-Sankyo Company: Honoraria. Yamashita:Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Daiichi-Sankyo Company: Honoraria; TEIJIN PHARMA LIMITED: Honoraria. Murata:Celgene: Honoraria; Ono pharmaceutical: Honoraria. Yoshihara:Kyowa Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Eisai Co., Ltd.: Honoraria. Yoshihara:Chugai Pharmaceutical Co.,Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Kyowa Kirin: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria. Nakao:Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical Co.,Ltd: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Celgene: Honoraria; Alaxion Pharmaceuticals: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Kyowa Kirin: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Ono Pharmaceutical: Honoraria; Daiichi-Sankyo Company, Limited: Honoraria; SynBio Pharmaceuticals: Consultancy. Matsue:Takeda Pharmaceutical Company Limited: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria.