Citations

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Introduction Minimal residual disease (MRD) status at day 100 following autologous stem-cell transplant (ASCT) in multiple myeloma (MM) patients is an important determinant of prognosis. Bone marrow (BM) based assays, i.e. next-generation flow cytometry (NGF) or next-generation sequencing (NGS) that are currently used in determining MRD are vulnerable to sampling biases due to patchy marrow involvement and extramedullary disease. BM examination alone may lead to false-negative results. MRD assessment through newer, more sensitive peripheral blood based methodologies such as mass spectrometry (MS) can potentially overcome the limitations associated with BM based assays. At our institution, traditional immunofixation electrophoresis (IFE) has been replaced by a MS method termed Mass-Fix which utilizes the unique light chain mass associated with each patient's monoclonal protein to monitor disease over time. In this study, we assessed the prognostic impact of serum Mass-Fix MRD status in MM patients who were MRD negative by NGF around day 100 post-ASCT. Methods Patients with MM who underwent ASCT between 01/01/2015 and 12/31/2018 at Mayo Clinic, Rochester were included in this study provided they had attained post ASCT day 100 complete response (CR) by IMWG 2016 criteria and MRD- state as assessed by BM based NGF, utilizing 2 eight-color tubes (total 10 colors), with a minimum sensitivity 10-5. Presence of non-secretory MM and unavailability of pre-ASCT serum samples or serum IFE results were important exclusion criteria. Peripheral blood samples drawn concurrently with the BM assessment were evaluated by Mass-Fix as described previously (Mills et al., Clin. Chem, 2016). The isotype and mass of the M-protein light chain (LC) obtained by Mass-Fix were compared to the pre-ASCT M-protein LC and/or IFE isotype. Patients with the following genetic alterations: deletion 17p, translocation (4;14), (14;16), t(14;20) and1q gain/amplification and were considered high risk. All time-to event analyses were performed on JMP 14.1.0 from the time of ASCT using the Kaplan-Meier method. Results Sixty-two patients with MM (57 newly diagnosed and 5 relapsed/refractory) who underwent ASCT and were MRD- by BM based NGF around day 100 (range: day 60-120) were included in the study. Median age at ASCT was 61 (range: 40-76) years and 61% were males. Thirty (48%) patients had IgG MM, 15 (25%) patients had IgA MM and 17 (27%) patients had light chain only disease. Forty-one (66%) patients received bortezomib, lenalidomide and dexamethasone (VRD) as induction regimen. Median time from diagnosis to ASCT was 6 months (IQ range: 4.7-7.2). Pre-ASCT fluorescence in- situ hybridization data were available on 47 (76%) patients; 23 (49%) were high risk. Of 62 patients, all of whom were day 100 MRD- by NGF, 36 (58%) patients had Mass-Fix identified MRD (MRD+). MRD positivity by Mass-Fix around day 100 was observed in 70% of patients with high risk MM versus 71% of patients with standard risk MM, p=0.9. The median follow-up was 18 months (95%CI: 14-21); 19 months (95%CI: 15-21) for patients who were MRD+ by Mass-Fix versus 17 months (95%CI: 12-21) for those who were MRD- by Mass-Fix at day ~100, p=0.5. Of 57 (92%) patients who received post ASCT maintenance therapy, 32 (89%) were MRD+ and 25 (96%) were MRD- by Mass-Fix, p=0.5. Eighty-seven percent of patients with IgG MM had MRD+ status by Mass-Fix at day~100. By contrast, only 33% and 30% of patients with IgA MM and light chain MM, respectively, had MRD+ status at day 100; p<0.0001. This suggests that IgG half-life which is longer than that of IgA or free light chains may affect the day 100 MRD status. At 18 months, 76% and 93% of patients, who were MRD+ and MRD- , respectively by Mass-Fix were alive and free from disease progression, p=0.03 (Table 1, Figure 1a). At 18 months after ASCT, none of the patients who were MRD- by Mass-Fix required salvage treatment following ASCT while 25% of patients who were MRD+ by Mass-Fix required next line of therapy due to disease progression, p=0.05 (Table 1, Figure1b). Conclusion Our data suggest that outcomes [progression free survival (PFS) and time-to-next therapy (TTNT)] of patients with MM who are in CR, and have achieved MRD- state by BM NGF post ASCT, can be adversely impacted if there is concurrent evidence of serum monoclonal protein by Mass-Fix, thereby demonstrating incremental prognostic value of this sensitive assay in clinical practice. Disclosures Murray: The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Dasari:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Gertz:Teva: Speakers Bureau; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Celgene: Consultancy; Research to Practice: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Ionis/Akcea: Consultancy; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials. Dingli:Karyopharm: Research Funding; Millenium: Consultancy; Rigel: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lacy:Celgene: Research Funding. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy.

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background: In the SCHOLAR-1 study, the largest published retrospective analysis of outcomes in patients with refractory large B-cell lymphoma (LBCL), the objective response rate (ORR) was 26% and complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump et al. Blood. 2017). These results served as a benchmark for assessing novel therapies. ZUMA-1 (NCT02348216) is the pivotal, multicenter, single-arm Phase 1/2 study evaluating axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T cell therapy, in patients with refractory LBCL that supported the approval of axi-cel in the United States and Europe. At a median follow-up of 27.1 months, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for potential imbalances in refractory status between the 2 studies. Methods: Patients in both studies had refractory LBCL defined as stable disease of ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant (SCT). To address potential imbalances between studies in refractory status which could affect response and survival outcomes, standardized analyses were performed which equally weighted the proportions of patients by refractory categorization (primary refractory, refractory to ≥ second-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity. Results: Axi-cel was administered to 101 patients in the pivotal Phase 2 portion of ZUMA-1. In the SCHOLAR-1 analysis, 508 patients were evaluable for response and 497 were evaluable for survival. The median follow-up in ZUMA-1 was 2.3 years, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6 to 14.8 years across different cohorts. In general, ZUMA-1 patients were more heavily pretreated with more patients receiving ≥ 3 lines of therapy as compared with SCHOLAR-1 (69% vs 23%). ZUMA-1 also had more patients who were refractory to second- or later-line therapy compared with SCHOLAR-1 (76% vs 62%). Fewer patients in ZUMA-1, however, were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and a similar proportion of patients between studies relapsed within 1 year of SCT (21% vs 18%). After standardization, the ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The odds ratios for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 2-year survival rate after standardization was 50% (95% CI, 40% - 59%) in ZUMA-1 and 12% (95% CI, 9% - 15%) in SCHOLAR-1, which translated to a 73% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.27; P < .0001). Conclusions: This standardized analysis of the ZUMA-1 and SCHOLAR-1 studies indicates that treatment with axi-cel in this selected population results in 11.5-fold higher odds of CR and a 73% reduction in the risk of death compared with standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support the previous literature indicating that axi-cel is a highly effective treatment option for patients with refractory LBCL. Disclosures Neelapu: Pfizer: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Allogene: Consultancy; Acerta: Research Funding; Cell Medica: Consultancy; Celgene: Consultancy, Research Funding; Karus: Research Funding; Novartis: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Bartlett:Genentech, Inc.: Research Funding; Gilead: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Miklos:Celgene-Juno: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Miltenyi: Consultancy, Research Funding; AlloGene: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Jacobson:Pfizer: Research Funding; Celgene: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Bayer: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Siddiqi:BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Crump:Kite/Gilead: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Servier: Consultancy. Kuruvilla:Seattle Genetics: Honoraria; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Janssen: Research Funding; Roche: Research Funding. Van Den Neste:Gilead: Other: travel support. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Navale:Kite, A Gilead Company: Employment, Equity Ownership; Gilead: Equity Ownership; Allogene: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Amgen: Equity Ownership; Organesis: Equity Ownership; Jounce: Equity Ownership; Editas: Equity Ownership; Intellia: Equity Ownership. DePuy:Kite, A Gilead Company: Consultancy, Other: travel support. Kim:Kite, A Gilead Company: Employment.

Background: A variety of risk factors have been described in multiple myeloma and current risk assessment incorporates ISS stage with specific FISH results and serum LDH (R-ISS). However, this model does not include all the current abnormalities described as prognostic for survival in multiple myeloma. Importantly, the impact of many of these high-risk abnormalities are not uniform. We examined if we can better integrate FISH results into a risk assessment tool to better predict the outcomes of newly diagnosed MM. Patients and methods: We studied a cohort of 1316 patients with FISH done within 6 months of diagnosis of MM, in whom results for commonly observed abnormalities were available. We specifically examined the individual impact of common translocations involving chromosome 14, MYC rearrangements, chromosome 1q gain (single or multiple duplication) and del13q/monosomy 13. A risk assessment system was developed, weighting each abnormality according to their Risk Ratio and integrating ISS stage and serum LDH into the final model construction. Overall survival was calculated from diagnosis, with those alive at last follow up being censored. Results: We first examined the impact of each of the above FISH abnormalities: 1) high risk translocations [t(4;14), t(14;16), or t(14,20)], 2) trisomies, 3) t(11;14), 4) MYCrearrangements, 5) del13q/monosomy 13, and 6) 1q gain . Each of the abnormalities, except for t(11;14), was prognostic for survival (Table 1 with the risk ratios). For 1q gain, the median OS was NR, 105 mos and 79 mos respectively for no abnormality, duplication of 1 copy and duplication of multiple copies, (p<0.001). On multivariate analysis, t(11;14) and trisomies were no longer prognostic for overall survival (Table 1). The cumulative impact of abnormalities demonstrated worsening survival in the presence of increasing numbers of abnormalities (Figure 1). Including ISS stage 3 and LDH > ULN as additional variables for prognostication indicated both were individually prognostic for OS. In a multivariate analysis, including these two and FISH abnormalities, 1q gain and LDH were not independently prognostic. The final model consisted of HR translocations, MYCrearrangements, del17p/monosomy 17, del13q/monosomy 13, and ISS stage 3. Each of these variables was weighted using their risk ratio and a composite score was developed using 998 patients for whom all variables were available (range: 0-7.9; median 1.8). Three patient groups were characterized: group 1 (0; 32%), group 2 (1-4; 58%) and group 3 (>4; 10%) with a median OS of 53 mos, 106 mos, and NR, respectively, p <0.001 (Figure 2). Conclusion: Using the most relevant FISH and laboratory factors, in a large cohort of patients, we refined the current system to develop a risk stratification system that predicts survival in patients with newly diagnosed MM treated with contemporary treatment regimens. This needs validation in future studies. Disclosures Kumar: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Gertz:International Waldenstrom Foundation: Research Funding; Annexon: Consultancy; Medscape: Consultancy, Speakers Bureau; Amyloidosis Foundation: Research Funding; Abbvie: Other: personal fees for Data Safety Monitoring board; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Consultancy. Dispenzieri:Akcea: Consultancy; Janssen: Consultancy; Intellia: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Cellectar: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

Background CD38 is highly expressed on MM cells, hence anti-CD38 agents are of interest as a therapeutic approach in MM. The anti-CD38 monoclonal antibody, dara, as mono- or combination therapy, has substantially improved efficacy outcomes in RRMM, including in heavily pretreated pts. However, many pts relapse and new therapeutic approaches are needed, particularly for pts R/R to dara. TAK-169 is a dimeric fusion protein of an anti-CD38 antibody single chain variable fragment fused to a modified Shiga-like toxin-A subunit. Its unique mechanism of action involves specific binding to CD38+ cells, forced internalization into the target cells, retrograde transport to the cytosol, and irreversible, enzymatic inactivation of target cell ribosomes to cause apoptosis. TAK-169 showed potent, rapid in vitro activity on CD38-expressing cell lines and in vivo efficacy in MM mouse xenograft tumor models with a wide CD38 expression range when administered intravenously (IV) once weekly (QW) or once every 2 weeks (Q2W). Activity was also shown in ex vivo assays from 6 pt bone marrow aspirate (BMA) samples, including from a dara-resistant pt (EC50 5 nM). TAK-169 retained in vitro activity in the presence of dara with modest shifts in EC50 noted at higher dara concentrations. In contrast to dara, TAK-169 has direct tumor cell kill activity that is independent of a pt's immune function status and may therefore be effective in a dara-resistant setting. Accordingly, this phase 1 study will assess safety, tolerability, preliminary efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-169 in RRMM. Methods This first-in-human, multicenter, open-label study (NCT04017130; Figure) comprises dose escalation (Part 1) and expansion (Part 2). Eligible pts must be aged ≥18 years with a confirmed diagnosis of MM. Pts enrolled in Part 1 should not be candidates for available therapies known to confer clinical benefit in RRMM. In part 2, pts enrolled should have received ≥3 prior lines of therapy, or ≥2 if one included a PI and IMiD combined. Prior anti-CD38 therapy (including dara) is permitted, except in the Part 2 anti-CD38 therapy-naive expansion cohort. In Part 1, the primary objective is to assess safety/tolerability of TAK-169 in pts with RRMM, and determine maximum tolerated dose/recommended Phase 2 dose (MTD/RP2D). Secondary objectives include efficacy, PK, PD and immunogenicity of TAK-169. Approximately 60 pts are planned to be enrolled to receive IV TAK-169 QW on Days 1/8/15/22 in 28-day cycles. Dosing will start at 50 μg/kg, with subsequent dose levels of 100, 200, 335, 500, 665 μg/kg. A 2nd Q2W dose escalation cohort may be initiated, starting at the QW MTD. The Bayesian Logistic Regression Model with overdose control will be used for dose escalation cohort 2 and for all subsequent dose escalation cohorts, and other non-DLT-safety, clinical, PK, and PD data will be considered. In Part 2, the primary objective is preliminary evaluation of TAK-169 clinical activity in RRMM. Secondary objectives include further evaluating safety, efficacy, PK, PD, and immunogenicity of TAK-169. Part 2 will enroll approximately 54 pts into dara RR (QW and Q2W dosing) and anti-CD38 therapy-naïve (QW dosing) cohorts. TAK-169 will be administered at the MTD/RP2D (QW and Q2W) determined in Part 1. Response will be monitored longitudinally using orthogonal approaches. M-protein levels in serum and urine will be measured each cycle to determine objective responses by International Myeloma Working Group (IMWG) criteria. Minimal residual disease status in pts suspected to be at complete response will be assessed. Circulating free DNA (cfDNA) will be collected from longitudinal plasma samples for disease monitoring. Baseline cytogenetic data will be collected, and TAK-169 efficacy will be assessed in pts with high-risk cytogenetics. Serial blood samples will be used to characterize PK and PD of TAK-169 after IV administration, and to assess the presence of antidrug antibodies. BMA samples collected at screening will be used to evaluate baseline expression of candidate biomarkers. Toxicity will be evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Efficacy analyses will use descriptive statistics with a 95% confidence interval and the Kaplan-Meier method. PK parameters and immunogenicity status will be summarized using descriptive statistics. Recruitment is ongoing. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy. Landgren:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ailawadhi:Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Willert:Molecular Templates: Employment. Waltzman:Molecular Templates, Inc.: Employment, Equity Ownership. Lin:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Zhang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lublinsky:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Manoharan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leichter:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ottinger:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Newcomb:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Vorog:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. OffLabel Disclosure: TAK-169 is a dimeric fusion protein of an anti-CD38 antibody single chain variable fragment fused to a modified Shiga-like toxin-A subunit

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: Two-year follow-up from ZUMA-1 trial for axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor T-cell (CART) in aggressive non-Hodgkin lymphoma (NHL) demonstrated that patients (pts) achieving complete remission (CR) as their best response have the longest progression free survival (PFS), while PFS remained poor for others. Majority of the best response are achieved by month 3 post-infusion. Moreover, a subset of pts who do not achieve CR by month 1 may still achieve CR while others will progress within months. Having a clinically available test to predict for durable response can assist clinicians in selecting pts who can be observed for continued response vs. those who may need intervention earlier. Peak CAR-T expansion has been correlated with best clinical response to axi-cel. However there is no clinically available test to quantify CART cells post treatment. Given the prolonged lymphotoxic effect of the lymphodepletion (LD) chemotherapy administered before CART infusion, we hypothesize that the peak expansion of absolute lymphocyte count (ALC, ALCpeak) after infusion likely corresponds to CART expansion. We examined for correlation between ALCpeak and clinical response at month 3 post-infusion for pts who received axi-cel. Methods: Data was collected from pts who received axi-cel between June 2016 and March 2019 at Mayo Clinic Rochester (NCT02348216, NCT03153462, and standard of care). All infused pts were included in the intention to treat analysis for response and event-free survival (EFS). Lugano 2014 criteria were used for clinical response. EFS was defined as the date of infusion until progression or death due to any cause and evaluated using Kaplan Meier curves with log-rank test. Comparison between subgroups was investigated using Fisher's exact test and Wilcoxon test for categorical and continuous variables, respectively. Statistical analysis performed using JMP Pro 14.1. Results: Of the thirty-six NHL pts treated with axi-cel, the median age was 56 yrs (range 26-65); 78% (28) were male; 44% (16) had DLBCL; the median number of prior therapies was 3 (2-6), 47% (17) had stem cell transplant. Nineteen (53%) pts received bridging therapy after leukapheresis. All pts received fludarabine and cyclophosphamide for LD chemotherapy and achieved ALC nadir by the day of CART infusion (median 0.03 x 10^9/L, range 0.01-0.11). As CART expansion were found to peak within the first two weeks in ZUMA-1 trial, we examined ALC trend over 15 days post infusion and found that ALCpeak generally happened within the same timeframe (median ALCpeak day: 9, range 6-15). At 3 months post infusion, 33.3% (12/36) of pts achieved CR, 8.3% (3/36) pts were in partial remission (PR). No correlation was found between CR response and clinical characteristics: age >60 years, stage III/IV, B symptoms, elevated LDH, IPI score 3-4, number of previous treatments, use of bridging therapy, peak CRP and ferritin. However, the ALCpeak was significantly different between CR and non-CR pts (median, range: 1.09, 0.35-2.55; 0.67, 0.15-1.03; p=0.04). Using receiver operator curve (ROC)-derived area under the curve (AUC) estimates, ALCpeak 1.08 x 10^9/L was identified as the best threshold to discriminate patients at different likelihood to achieve CR at month 3. Pts achieving ALCpeak ≥ 1.08 showed a strong increased likelihood of achieving CR at month 3 (OR 2.8; 95% CI, 1.12-6.99; P=0.02). There was no statistical difference between the ALCpeak high and low groups in terms of use of bridging therapy, occurrence of any grade or higher grade cytokine release syndrome or neurotoxicity, or the use of tocilizumab or steroid. Interestingly, for pts who had changes in clinical response from month 1 to month 3, all 3 pts who converted to CR by month 3 had ALCpeak≥1.08, while the 13 of the 15 pts who had progressed by month 3 had ALCpeak<1.08. In addition, EFS was significantly different between pts who had ALCpeak above and below 1.08 (6 months EFS rate 75% vs. 25%, respectively, Figure 1). Conclusions: We found that the ALC expansion occurred in the first 15 days post axi-cel infusion, consistent with the known time frame for CART expansion. Higher ALCpeak level in this timeframe correlated with higher likelihood of achieving CR, and is associated with conversion to CR. This study is limited by the small sample size and limited follow-up, but the results are promising for further prospective investigation in a larger cohort of patients. Disclosures Paludo: Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding; Celgene: Research Funding. Ansell:Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Bennani:Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Karyopharm: Research Funding; Rigel: Consultancy. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

INTRODUCTION: Primary plasma cell leukemia (pPCL) is the most aggressive form of multiple myeloma (MM). Recently, pPCL has been defined by as few as >5% circulating plasma cells (cPCs) detected morphologically on a peripheral blood smear. However, this technique may not be sufficiently sensitive and is dependent on inter-observer bias to properly identify and quantify cPCs. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs. However, an optimal quantitative cutoff for cPCs by MFC to define the presence of pPCL has not been established to date. Thus, this is the first study to date that determines an optimal cutoff of cPCs/ microliter that could identity patients with pPCL at diagnosis. METHODS: We retrospectively evaluated all newly diagnosed MM patients seen at the Mayo Clinic, Rochester from January 2007 to December 2017 who had their peripheral blood samples evaluated morphologically by peripheral blood smear and immunophenotypically by MFC prior to beginning therapy. Patients with a peripheral blood smear detecting >5% cPCs were classified as having pPCL. Six-color MFC was performed on peripheral blood mononuclear cells by isolated by Ficoll gradient, and stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda immunoglobulin light chains. The data was collected using Becton Dickinson FacsCanto II instruments collecting 150,000 events and analyzed using the BDFacs DIVA Software. The gating strategy employed first used the expression of CD38, CD138, and cytoplasmic immunoglobulin light chains to identify all plasma cells in the specimen. The cPCs were then discriminated from polyclonal/normal plasma cells based on differential CD19 and CD45 expression. The cPCs detected were reported as the number of clonal events/150,000 collected total events and converted to the absolute number of cPCs/microliter using their absolute lymphocyte count and monocyte count determined at the time of the blood draw for cPC MFC assessment. A receiver operator curve (ROC) was performed to determine the absolute cPCs/microliter by MFC that best identified those patients with >5% cPC on their peripheral blood smear. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. RESULTS: A total of 591 patients were included in this analysis of which 59% were male and the median age was 66 years (range: 27 - 95) with 22% being 75 years of age or older. From this cohort, 133 (24%) patients had high risk FISH cytogenetics, 172 (30%) were classified as ISS 3 at diagnosis, 83 (15%) had an elevated LDH level and 61 (17%) had a plasma cell labeling index (PCLI) of 2% or greater. There were 65 (11%) patients with any amount of cPCs detectable by peripheral blood smear of which only 22 (4% of the total population) met criteria for pPCL with >5% cPCs. With MFC, 403 (68%) patients had detectable cPCs. The median number of cPCs per microliter was 0.81 (0 - 10,455) with 273 (46%) having >1 cPC/microliter. A ROC analysis determined that the presence of >50 cPCs/microliter by MFC was the optimal cutoff to identify patients with >5% cPCs by blood smear with approximately a specificity of 94% and a sensitivity of 86%. The presence of >50 cPCs/microliter by MFC was associated with higher presence of high risk FISH cytogenetics, ISS 3 classification, elevated LDH and PCLI > 2%. The median time to next treatment (TTNT) for patients with and without >5% cPCs by peripheral blood smear was 18 months vs. 30 months (P < 0.001). The median TTNT for patients with and without >50 cPCs/microliter by MFC was 19 months vs. 30 months (P < 0.01). The median overall survival (OS) for patients with and without >5% cPCs by peripheral blood smear was 25 months vs. 71 months (P < 0.001; Fig 1A). The median OS for patients with and without >50 cPCs/microliter by MFC was 38 months vs. 71 months (P < 0.01; Fig 1B). CONCLUSION: This is the largest study that attempts to identify an optimal cutoff of cPCs/microliter by MFC for diagnosing pPCL patients. The presence of >50 cPCs/microliter is an optimal cutoff by MFC that best predicts for the presence of >5% cPCs by peripheral blood smear. However, there remains discordance in the OS outcomes between the two cutoffs by different methodologies for pPCL. This could signify the presence of biological processes associated with the presence of >5% cPCs when detected by peripheral blood smear that are not captured by MFC. Disclosures Dispenzieri: Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lacy:Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Celgene: Honoraria. Leung:Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Russell:Imanis: Equity Ownership. Gertz:DAVA oncology: Speakers Bureau; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.