ALBERT

Description: Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike 〉 2 gm/dL OR an involved to uninvolved FLC ratio 〉 20 OR bone marrow PC% 〉 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Description: Introduction: B-cell maturation antigen (BCMA) is primarily expressed by malignant and normal plasma cells, making it an attractive target for the treatment of multiple myeloma (MM). bb21217 is a BCMA-directed chimeric antigen receptor (CAR) T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (ide-cel, bb2121), but adds the PI3K inhibitor bb007 during manufacturing to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. We conducted correlative analyses to investigate the mechanistic hypothesis that CAR+ T cells with memory like phenotypes may persist and function longer, which may be one determinant of duration of response (DOR). Methods: An ongoing phase I clinical study (CRB-402; NCT03274219) is assessing safety and efficacy of bb21217 in relapsed/refractory MM patients. A total of 44 patients had PBMCs, collected from apheresis, and DP characterized by RNA sequencing (RNAseq) and mass Cytometry (CyTOF). The correlation of T cell phenotype with peak expansion, response and DOR per IMWG Uniform Response Criteria was explored. P-values were determined by Wilcoxon test, Spearman correlation, or Cox PH regression on DOR with categorical marker values (high/low). Results: In this patient population, substantial cross patient heterogeneity in T cell phenotypes was observed both in PBMCs and DP. Late differentiation/senescent markers in PBMCs were negatively correlated with clinical response. In particular, patients whose DP had higher expression of CD57 had lower peak expansion (p

Description: Introduction: 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). bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007 during ex vivo culture to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. To investigate whether DP properties correlate with clinical outcomes including duration of response (DOR), we conducted extensive molecular characterization of patient DPs. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in RRMM patients who received ≥3 prior regimens, including proteasome inhibitor and immunomodulatory agent, or are double-refractory to both classes. In the expansion cohort, patients additionally required prior exposure to an anti-CD38 antibody and were required to be refractory to last line. Planned enrollment is 74 patients, including 50 in the expansion cohort. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive a single infusion of bb21217 at 150, 300 or 450 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. We profiled DP and apheresis starting material (PBMC) by RNAseq and cyTOF and correlated expression of memory/senescence markers from apheresis to DP with clinical outcomes, including DOR. Results: Asof March 1, 2020, 46 patients (median age 62 [33-74]) received bb21217, 24 in escalation (12 at 150, 6 at 300 and 6 at 450) and 22 in expansion (8 at 300 and 14 at 450); median follow up for all patients is 8.5 (

Description: Background: Multiple myeloma (MM) is a clonal plasma cell neoplasm typically associated with chronic therapy and resultant potential toxicities, including clonal cytopenias, myelodysplastic syndrome (MDS), or therapy-related myeloid neoplasms (tMN). Early identification of myelodysplasia is important for patient management and outcome. Next generation sequencing (NGS) is playing an ever increasing role in this field. Materials and Methods: The retrospective study was approved by Moffitt institutional review board (IRB). We searched our in-house NGS database with ~6000 patients and clinical databases to identify the patients with MM and sustained cytopenia with accompanying NGS data. The NGS results were analyzed for associations with myeloma and myelodysplasia. Results: Of the 196 identified patients identified (Table 1), there were 114 males (58%) and 82 females (42%) with a median age of 68 years. Eighty-four myeloma patients with cytopenia (43%) were found to have one or more somatic mutations and 112 patients (57%) showed no mutations. The most frequently mutated genes are as following: TP53 (12%), DNMT3A (8%), TET2 (6%), ASXL1 (5%), KRAS (5%), ETV6 (3%), RUNX1 (2%), CUX1 (2%), BCOR (2%), SF3B1 (2%), ZRSR2 (2%), EZH2 (2%), IDH2 (2%), SRSF2 (2%), and BRAF (1%). We divided the patients into four groups according their disease status at the time of NGS testing: 1) patients with myeloma but no myelodysplasia (MM_Only, 105 patients and 53.57%); 2) Patients with myelodysplasia but no overt residual myeloma (Myelodysplasia_Only, 14 patients, 7.14%); 3) Patients with both myeloma and myelodysplasia (MM+Myelodysplasia, 27 patients, 13.78%); 4) Patients with neither myeloma or myelodysplasia (Negative_for_Both, 50 patients, 25.51%). The "Myelodysplasia" in this study is defined as having either overt morphologic dysplasia (〉10% of the lineage cells), or equivocal dysplasia but having myeloid-related (non-myeloma) cytogenetic abnormalities. NGS results were not included in the classification to assess the added diagnostic value of NGS. The Mutational profiles of the four disease groups are displayed in Figure 1 and compared in Table 1 and 2. The MM+Myelodysplasia group showed highest percentage of mutations (88.89% of patients tested), followed by Myelodysplasia_Only group (57.14%) and MM_Only group (35.24%), with Negative_for_Both group showing the lowest mutation rate (30.00%). The average number of somatic mutations/case also followed the same order: 1.63, 1.00, 0.48, and 0.36, respectively. Of the 196 patients, 58 patients (29.59%) had no morphologic dysplasia or myeloid-related cytogenetic abnormalities but showed one or more somatic mutations by NGS. These patients harbored clonal cytopenia of uncertain significance (CCUS) clones and would have been missed without NGS testing. Of these 58 patients, retrospective review actually identified 7 patients with morphologic dysplasia and were reclassified as MDS. Further mutational analysis revealed the following interesting findings. ASXL1, DNMT3A, KRAS, and SF3B1 mutations showed highest frequencies in MM+Myelodysplaisa group when compared with other 3 groups (Table 2), indicating a close association with myelodysplasia development in patients with persistent myeloma. In contract, among the 4 groups, RUNX1 mutations were most common in Myelodysplasia_only patients, suggesting a potential alternative pathway for myelodysplasia development in patient with myeloma in remission. It is possible that presence of myeloma clones create different evolution pressure on neoplastic myeloid clones. TP53 mutations were present in MM_Only group, but were much more frequent in patients with MM+Myelodysplasia and Myelodysplasia_only groups. The presence of TP53 mutations might therefore suggest increased risk for myelodysplasia. Finally, TET2 were similar between these groups and therefore not of significant diagnostic value. Conclusion: NGS testing is valuable in identifying CCUS, MDS, or tMN in myeloma patients, especially in those with no morphologic or cytogenetic abnormalities. Statistically significant differences are seen in the mutational profiles of the four groups of patients, suggestive of different roles in myelodysplasia development. Further studies are necessary to better distinguish the origin of these mutations as being derived from the myeloma versus the myeloid components of the disease. Disclosures Hussaini: Stemline: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Boston Biomedical: Consultancy. Shain:Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution.

Description: Introduction: While minimal residual disease (MRD) negativity is not yet an established regulatory surrogate for a clinical endpoint in multiple myeloma (MM), it does have value as a prognostic biomarker and in assessing disease status. Previously we reported results from a phase 1b trial that described the safety and efficacy of the triplet regimen carfilzomib (given weekly), lenalidomide, and dexamethasone (KRd) in patients with relapsed and/or refractory MM (RRMM) or newly diagnosed MM (NDMM) (Biran et al, Am J Hematol 2019;94:794-802; Alsina et al, Clin Lymphoma Myeloma Leuk 2019;19:Suppl E52). Here, we evaluate MRD status by flow cytometry after treatment with weekly KRd in this trial. Methods: A total of 56 patients with RRMM and 51 with NDMM were enrolled and treated with weekly KRd. Treatment was given in 28-day cycles. Carfilzomib was given on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, and 15 (also day 22 for cycle 1-8). In the NDMM cohort, patients were enrolled regardless of transplant eligibility, and treatment interruption for mobilization and collection with or without autologous stem cell transplant was allowed after cycle 4. Per the protocol, aspirate was collected for flow cytometry evaluation at two separate endpoints: at cycle 8 day 1 (C8D1); and at the time when laboratory data supported a response of complete response (CR) or better (on the basis of negative immunofixation on serum and urine). Sample quality was assessed by several measures (including the presence of mast cells, erythroid precursors, and immature B cells), and viability was determined using a flow assay. Adequate samples were tested for MRD using 8-color flow cytometry in two tubes, with a sensitivity of 10-5. MRD was reported as positive when a minimum of 2 x 106 CD138+ cells per tube were evaluated, and ≥ 20 abnormal events detected. Results: Overall, 58 of 79 (73.4%) study-specified samples were obtained and evaluated by flow cytometry. Of the NDMM patients, 15 had bone marrow aspirate evaluable for MRD at C8D1 (in total 22 patients were treated to C8D1), and 12 had bone marrow aspirate evaluable for MRD at the time of CR (14 patients achieved CR). At C8D1, 53% (8/15) of NDMM patients with flow data achieved MRD negativity, and at time of CR, 83% (10/12) of NDMM patients were MRD negative (the remaining patients with flow data were determined to be MRD positive). Among the 12 NDMM patients evaluated for MRD at time of CR, 17% had high-risk cytogenetics, 58% had standard-risk cytogenetics, and 25% had unknown cytogenetic risk status. Of the RRMM patients, 26 had bone marrow aspirate evaluable for MRD at C8D1 (30 patients were treated to C8D1), and five had bone marrow aspirate evaluable for MRD at the time of suspected CR or better (in total 13 patients achieved CR). Of RRMM patients with available flow data at time of CR, 40% (2/5) achieved MRD negativity, and of those with flow data at C8D1, 50% (13/26) achieved MRD negativity. Of all patient samples evaluated for MRD, 67% of NDMM and 48% of RRMM samples were MRD negative. The results reported here are directionally comparable to the rates of MRD-negative CRs observed in previous studies of twice-weekly KRd in NDMM (Jasielec J et al, Blood 2014;124:2127; Kazandjian D et al, JAMA Oncol 2018;4:1781-1783; Zimmerman T et al, Blood 2016;128:675). Our findings are limited by incomplete acquisition of samples to support a full MRD analysis per protocol (approximately 73% of the intended time point samples were acquired). Additionally, we reported MRD status without censoring for missing MRD data, as would be required to analyze MRD for a randomized controlled trial to eliminate acquisition bias. A robust comparison of MRD-negative CR rates between regimens would require an RCT with full MRD sampling, and sensitivity analyses that treat missing MRD data as MRD-positive (Chari A et al, Blood 2017;130:974-981; Voorhees PM et al, Blood 2020). Conclusions: We have previously shown that once-weekly KRd is active and has acceptable toxicity in both the RRMM and NDMM settings. We found that among MRD-evaluable patients who had a CR or better, MRD negativity rates were impressive in both the NDMM setting (83%) and in the RRMM setting (40%), suggesting that the weekly KRd regimen can induce MRD-negative CRs in both settings. Disclosures Landgren: Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Other; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Seattle Genetics: Research Funding. Alsina:Janssen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau. Biran:Janssen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; KAryopharma: Research Funding; Sanofi: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: reimbursement of travel and accomodation, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: reimbursement of travel and accommodation, Research Funding, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Janssen: Speakers Bureau; BMS: Speakers Bureau. Fang:Amgen: Current Employment, Current equity holder in publicly-traded company. Arnold:Amgen: Current Employment, Current equity holder in publicly-traded company. Kimball:Amgen: Current Employment, Current equity holder in publicly-traded company; WindMIL Therapeutics: Current equity holder in private company. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. OffLabel Disclosure: Carfilzomib is a proteasome inhibitor that can be used for the treatment of relapses/refractory multiple myeloma