Abstract: Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1–196), the 3‐year progression‐free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3‐year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper‐CVAD or auto‐SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p  = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.

Abstract: Background: Waldenström Macroglobulinemia (WM) or Lymphoplasmacytic Lymphoma (LPL) is an indolent B-cell neoplasm accounting for only 1-2% of all hematological malignancies. More than 90% of patients with WM carry a point mutation L265P in the MYD88 gene which promotes tumor survival and is shown to be significant for diagnostic and risk stratification. Criteria for diagnosis requires presence of serum monoclonal IgM protein and 〉 10% bone marrow lymphocytes with plasmacytoid differentiation. We aimed to present the patients characteristics and survival outcomes of WM/LPL patients treated at our center, according to their MYD88 gene status. Methods: We reviewed medical records of all patients diagnosed with WM/LPL between May 2002 and May 2018 for whom MYD88 status was known. Baseline demographic characteristics, ECOG PS, pertinent laboratory values including IgM level at diagnosis, initial therapy, mutation status and cytogenetics was obtained. Kaplan-Meier survival estimation curves were used to illustrate the probability of survival over time stratified by MYD88 status and compared by the log rank test. Results: A total of 99 patients diagnosed with WM/LPL were included, 91 Caucasians (92%), 54 (55%) male, median age 67 years (range, 43-89) and with 63 (64%) patients having ECOG PS 0 or 1. IgM level at diagnosis was available for 88 patients, with a median of 2055 mg/dL (range, 10-11,700) and serum free light chain ratio was estimated at a median of 2.13 (range, 0.01- 37331). Other pertinent laboratory data were: median hemoglobin 11.4 g/dL (range, 6.2- 16.4), median serum viscosity 2.4 CP (range, 1.5- 6.7), median serum M protein 1.4 g/L (range, 0- 5.84), median 24 hour urine protein 11mg (range, 4- 1344) and median serum LDH 173 U/L (range, 71-476). The median international prognostic score (ISSWM) for our cohort was 3. A mutant MYD88 was positive in 85 (86%) patients, while 14 (14%) patients had wild- type MYD88. Complex karyotype was present in 24 (25%) patients. Rituximab monotherapy was the initial treatment in 48 (49%) patients. Twenty-two [22%] patients each received bortezomib-based and bendamustine-rituximab regimen as initial therapy and 7 (7%) patients received frontline rituximab- chemotherapy. Median follow-up of the cohort was 2.8 years (0.08-15.5). At last follow-up, 25 (25%) patients had died. Median OS from diagnosis for the entire cohort was 7.9 years (95% CI, 6.6 to N.R.). OS rate at 5 years was 0.73 (95% CI, 0.61 to 0.87). Patients with mutant MYD88 had significantly longer median OS as compared to those with wild-type MYD88 - 16.3 years (95% CI, 6.7 to N.R.) vs 6.6 years (95% CI, 1.9 to N.R.) [P=0.01] (Figure 1). Conclusion: Within the limitations of a retrospective study with a heterogeneously treated cohort, these data add to the body of literature supporting that outcomes of patients wild-type for MYD88 are worse than those with the L265P mutation when treated with rituximab alone, a proteasome inhibitor or conventional rituximab- chemotherapy. Also, despite an expansion on the therapeutic landscape, the treatment of choice in Waldenström Macroglobulinemia is still lead by rituximab monotherapy in newly diagnosed patients. Further studies should investigate the prognostic impact of MYD88 mutation in the context of BTK inhibitors. Disclosures Hill: Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria.

Abstract: Background: Lenalidomide (Len) and low-dose dexamethasone (dex) in combination with proteasome inhibitor (PI) or cytotoxic agent is an integral part of front-line therapy in multiple myeloma (MM). Use of Lenalidomide (Len) in MM had demonstrated an increased risk of venous thromboembolism (VTE) in initial studies which led to the incorporation of routine thromboprophylaxis with Len-based regimens. Existing estimate of VTE incidence from a prior analysis on Len-based regimens in newly diagnosed MM is 0.8 per 100 patient-cycles [Carrier et al. 2011]. However, there is a gap in literature on the incidence of VTE in patients receiving contemporary Len-based combination regimens along with adequate thromboprophylaxis. Hence, we conducted a systematic review and meta-analysis of clinical trials to assess the incidence of VTE with Len-based regimens in newly diagnosed MM patients. Method: We queried Ovid Medline, Ovid Embase and Cochrane Library databases to obtain relevant studies until March 2018. We included all phase I-III clinical trials testing a Len-based combination regimen for induction +/- consolidation therapy along with protocol-mandated thromboprophylaxis. VTE was defined as deep vein thrombosis or pulmonary embolism (CTCAE Grade 2 or above). Our primary outcome was pooled incidence of VTE events per patient-cycle, which was subsequently converted to VTE events per 100 patient-cycle for ease of comparison with existing literature in MM. We performed meta-analyses with random-effects model using a comprehensive meta-analysis software. Heterogeneity was calculated using I2 statistic and a value 〈 25% was considered negligible, up to 50% moderate, and ≥70% was considered substantial heterogeneity. The protocol for this systematic review is registered with PROSPERO [CRD42018102971] . Results: Initial search generated 1069 citations. After screening, 15 clinical trials with 3381 patients were included. Among 15 trials, 4 were phase I/II, 6 were phase II and 5 were phase III. All but one trial used low-dose dex. The pooled incidence of VTE events was 0.4 per 100 patient-cycles [95% CI. 0.3-0.5; I2: 70%]. Incidence rate of VTE in individual studies are summarized in Table I. The Forest Plot is shown in Figure I. Subsequently, we performed pre-specified subgroup analyses on trials with Len-dex, Len-dex + PI, Len-dex + doxorubicin and Len with Melphalan-Prednisone (MPR). The pooled incidence of VTE per 100-patient cycle with Len-dex was 0.3 [95% CI. 0.1-0.4; I2:92%], Len-dex with PI was 0.9 [95% CI. 0.3-1.6; I2: 69%] , Len-dex with doxorubicin was1.5 [95% CI. 0.7-2.2; I2: 0%] and MPR was 0.3 [95% CI. 0.2-0.4; I2: 0%] . Notably, the incidence of VTE was higher with Carfilzomib-Len-dex when compared to Bortezomib-Len-dex regimens. Two trials with Len-dex + Doxorubicin had a higher rate of VTE irrespective of the dex dose. The most common modes of thromboprophylaxis used were ASA (range, 70-325 mg) and low molecular weight heparin. Conclusion: Patients with newly diagnosed MM receiving contemporary Len-based regimens have a significant incidence of VTE despite adequate thromboprophylaxis. However, the incidence rate compares favorably with prior estimate. The rate of VTE was highest with the use of Len-dex + Doxorubicin triplet regimen. In the Len-dex+PI subgroup, the incidence of VTE was higher in trials using Carfilzomib-Len-dex compared to Bortezomib-Len-dex regimen. These findings can be clinically applied at an individual level to choose a Len-based combination regimen based on the risk of thrombosis. New prophylactic agents like direct oral anticoagulants should be tested to further decrease the rate of VTE with Len-based combination regimens. Disclosures Khorana: Janssen: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.

Abstract: INTRODUCTION: R-CHOP is effective for diffuse large B-cell Lymphoma (DLBCL), but many patients (Pts) relapse or have refractory disease, likely due to inherent biologic differences in DLBCL subtype. Activated B-Cell (ABC) subtype DLBCL signals through Nuclear Factor-κ-B (NF-κB) and is more likely to display treatment failure than DLBCL arising from the germinal center (GC). Proteasome inhibitors disrupt NF-κB signaling, but randomized trials have failed to demonstrate clinical benefit of adding bortezomib to R-CHOP for the treatment of non-GC DLBCL. Carfilzomib (Car) displays superior clinical activity relative to bortezomib in plasma cell neoplasms and, while occasionally associated with cardiac events, does not have dose-limiting neuropathy. To explore the safety and efficacy of Car in upfront treatment of DLBCL, we initiated a phase I/II clinical trial of Car + R-CHOP and report the phase I results. METHODS: 24 adult (age ≥ 18) Pts with untreated de novo or transformed DLBCL, adequate organ function and performance status were enrolled. During 3 x 3 dose escalation, Car was given at 20 mg/m2 on days 1 and 2, with R-CHOP on day 2 for 6 cycles (n = 6). Due to grade 4 thrombocytopenia, the protocol was amended to administer Car at a dose (in mg/m2) of 20 on days 1 and 2 of cycle 1 with rituximab (R) on day 2 and CHOP on day 3, followed by a Car dose of 20 (n=3), 27 (n=3), 36 (n=3), 45 (n=3) and 54 (n = 6) on days 1 and 2 of cycles 2-6. All Pts received pegfilgrastim the day after CHOP and zoster prophylaxis with acyclovir x 6 months post treatment. Echocardiograms were obtained at baseline and at conclusion of therapy to assess the cardiac safety of combining Car with anthracycline. Interim response assessments with CT +/- PET were performed after cycle 3 and end-of-treatment response assessments were uniformly captured with PET. RESULTS: The median age was 57 (range 24-77) years old. 63% of patients were female. Stage at diagnosis was I-II (58%) or III-IV (32%). The majority of Pts had ECOG performance status of 0-1 (88%). B symptoms were present in 21% of Pts and 54% had an increased LDH at diagnosis. 29% had 〉 1 extranodal site. IPI score was 0-1 (50%), 2 (21%) or 3-4 (39%). For this phase I dose escalation study, eligible Pts included primary mediastinal lymphoma (n = 1) and DLBCL of GC (n = 9), non-GC (n = 13) and unknown (n = 1) Hans algorithm subtypes. Hematologic adverse events (AEs) included 60 grade 1/2, 27 grade 3 and 16 grade 4 AEs. Grade 3/4 hematologic toxicities included neutropenia (n=14), thrombocytopenia (n = 6) anemia (n = 6), with only 4 cases of grade 3 febrile neutropenia. Grade 3/4 non-hematologic AEs were generally consistent with known R-CHOP toxicity were notable for: hypertension (n = 2), decreased ejection fraction (n =2), GI hemorrhage (n = 2) dizziness, headache, and syncope (n = 1 each), thromboembolic event (n=1), hyperglycemia (n=2), increased ALT (n=1) and nausea/vomiting (n=2). Compared to age-matched controls, end-of-treatment echocardiograms of CarR-CHOP treated Pts showed no statistically significant additional effect on ejection fraction (EF) [94.8% vs. 90.0% of pre-treatment value, respectively (P = 0.19)] after 6 cycles of treatment and there was no association of change in EF with Car dose (P = 0.61). There were no dose limiting toxicities. As of June 2018, median follow-up among s urviving Pts was 16 months. There were 3 deaths during the study period, 2 from lymphoma and 1 from lung cancer. The overall response rate was 92% [75% complete remission (CR), 17% partial remission]. 18-month Kaplan Meier estimates of PFS and overall survival were 77% and 88%, respectively (Figure). There was no significant difference in CR rates or PFS for patients with GC vs. non-GC subtype (P = 0.65 and 0.61, respectively). CONCLUSION: CarR-CHOP is safe at a recommended phase II dose of 20 mg/m2 on day 1 & 2 for cycle 1 followed by 56 mg/m2 for cycles 2-6, without significant excess cardiac effects. Within the limitations of a prospective phase I clinical trial with potential patient selection bias, preliminary efficacy data suggest a high complete metabolic response rate and equivalent outcomes for patients with GC and non-GC subtype. Phase II accrual is ongoing for non-GC DLBCL only and additional correlative studies of the molecular subtype of DLBCL will be incorporated into future analysis. Disclosures Hill: Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tomlinson:Foundation Medicine: Consultancy. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction Post-transplant lymphoproliferative disorders (PTLD) are mostly Epstein-Barr virus (EBV) positive lymphoid proliferations resulting from immunosuppression following allogeneic stem cell or solid organ transplantation (SOT). Despite this strong association, there is a lack of data evaluating the risk of PTLD in SOT patients (pts) with (w/) EBV viremia. The significance of EBV detection remains unclear and can lead to unwarranted preemptive treatments in SOT pts. The aim of this study is to assess the association between peripheral blood EBV viral load and risk of PTLD post SOT. Methods We identified 6468 adult and pediatric pts from the Cleveland Clinic SOT database who underwent SOT from 2002-2016. We included pts who had ≥1 EBV viral load test by PCR, and excluded pts w/ first EBV test at or after PTLD diagnosis. EBV viral load was quantified by polymerase chain reaction (PCR) of whole blood samples and expressed as log copies/mL. Lower detection limits varied from 2.00 to 2.70 log copies/mL. EBV monitoring post SOT was done at the physician's discretion. Potential risk factors for PTLD were assessed using Fine and Gray competing risk regression. Stepwise analysis was used to identify multivariable risk factors. Landmark analyses at 2 and 6 months post SOT (LM-2 and LM-6) were performed based on pts' peak pre-landmark EBV levels. Pts were excluded if they died, lost follow-up (f/u) or developed PTLD prior to the landmark. Two multivariable models were assessed at each landmark using EBV level cutoffs of 3.00 and 4.00 log. Results Of 6324 pts w/ available f/u data, 3348 (52%) had ≥1 quantitative EBV PCR test and were included in this analysis w/ a total of 91,067 tests performed. Median age at SOT was 54 years (range 0.3-79) and 63% were male. The most common SOT was kidney (38%) followed by lung (37%), liver (18%), heart (7%), pancreas (6%) and intestine (2%), w/ 7% receiving 〉 1 organ type (Table 1). Of 3348 pts included, 1503 (45%) developed EBV viremia and 68 (2%) developed PTLD; 45/1503 (3.0%) and 23/1845 (1.2%) of pts w/ and without (w/o) EBV viremia, respectively. EBV was detected in 44% of pts w/o PTLD and 66% of pts w/ PTLD. Median age at PTLD diagnosis was 58 years (range 1-75), with a median time from SOT to PTLD of 33 months (range 2-146). PTLD morphology was DLBCL (n=39), polymorphic (n=9) Burkitt (n=5), other (n=10) and unknown (n=5). EBV-encoded RNA (EBER) testing in tumor was positive in 47%, negative in 44% and unknown in 9% of cases. In pts w/ and w/o PTLD, tacrolimus was the most common immunosuppressant used at 1 month (99% and 89%), 1 year (94% and 88%) and 2 years (81% and 74%) post SOT, respectively. First EBV was checked at a median of 54 days (range 0-5090) in pts w/o PTLD and 28 days (range 0-4308) in pts w/ PTLD. The median number of EBV tests/pt before PTLD or last f/u was 4 (range 1-214) in pts w/o PTLD and 6 (range 1-123) in pts w/ PTLD. Peak EBV levels ≥3.00 and ≥4.00 log were detected in 36% and 13% of pts w/o PTLD, and 60% and 40% of pts w/ PTLD, respectively. Median f/u in both cohorts for pts who were alive was 6.1 years. In multivariable analysis (MVA) for non-EBV risk factors for PTLD, liver (HR 2.19, 95% CI 1.31 - 3.66, p=.003) and intestine SOT (HR 4.62, 95% CI 1.84 - 11.6, p=.001) were the only factors associated w/ higher PTLD risk; age, years since SOT, gender, race, other types of SOT and 〉 1 SOT were not significant. 1685 pts were eligible for LM-2 (43 w/ PTLD) and 2093 for LM-6 (36 w/ PTLD). In univariable analysis at LM-2 and LM-6, peak EBV levels ≥4.00 log (LM-2: HR 2.72, p=.016; LM-6: HR 7.08, p 〈 .001) and ≥5.00 log (LM-2: HR 8.64, p=.006; LM-6: HR 7.06, p=.002) were associated w/ increased risk for PTLD (Table 2 and Figure). Additionally, at LM-6, peak EBV level ≥3 was predictive for PTLD development (HR 2.18, p=.018). MVA at LM-2 was significant using cutoff ≥4 log (HR 2.90, p=.011), and at LM-6 using ≥3 (HR 2.21, p=.02) and ≥4 log (HR 6.91, p 〈 .001). The cumulative incidence rate (CIR) for PTLD was 2.4% at 6 months and 4.9% at 1 and 2 years post SOT in pts w/ EBV ≥4 log by LM-2. By LM-6, EBV value of ≥4 log resulted in a CIR of 3.7% and 5.7% at 1 and 2 years, respectively. Conclusion In this large cohort of SOT pts, 〈 50% had EBV viremia post SOT with only 3% of pts with EBV viremia developing PTLD. EBV viral load of ≥4 log copies/mL at 2 and 6 months was associated with increased risk of PTLD. EBV monitoring post-transplant may benefit a subset of pts, and prospective studies are warranted to evaluate if preemptive treatment can reduce PTLD risk in high-risk pts. Figure. Figure. Disclosures Hill: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: Daratumumab (DARA) is an anti-CD38 human monoclonal antibody FDA-approved for the treatment of multiple myeloma (MM) and has demonstrated efficacy in AL amyloidosis. Infusion-related reactions (IRRs) occur in over 50% of patients treated with DARA, most commonly with the first infusion despite premedication with corticosteroids, antipyretics, antihistamines, and post-infusion corticosteroids. If DARA is tolerated without IRRs, the infusion rate can be escalated in standardized increments to a final infusion rate administered over 90 minutes in patients with MM (Barr et al. Leukemia 2018). Rapid infusions of DARA decrease length of infusion visits, potentially improving patient satisfaction and optimizing healthcare resources. Recent studies showed that DARA is safe and highly effective in treating AL amyloidosis (Khouri et al, Br J Haematol 2018), but no information is available regarding the safety of administering rapid infusions of DARA in patients with AL amyloidosis. We hypothesized that patients with AL amyloidosis, especially those with cardiac involvement, may not tolerate a rapid administration of fluids. Thus, a DARA rapid infusion protocol for patients with AL amyloidosis was implemented at our institution in April 2018. We report findings from the protocol implementation. Methods: A retrospective observational study was conducted to review adult patients with AL amyloidosis who received rapid infusions of DARA from April 2018 to October 2018. Data collected included relevant past medical history, vitals, premedications, infusion rates, and management of IRRs. Patients were eligible for rapid DARA after tolerating two prior doses of DARA at standard infusion rates. Rapid DARA was infused at 200 mL/hr for 30 minutes, then increased to 450 mL/hr for 60 minutes. Protocol premedications included acetaminophen, diphenhydramine, famotidine, and dexamethasone. No post-infusion corticosteroids were required. The first two standard and first four rapid DARA infusions were evaluated for each patient. Results: 27 patients with AL amyloidosis were included in the study with 162 doses of rapid DARA evaluated. Baseline characteristics included age (median 72 years old), gender (55.6% male), diastolic heart failure (59.3%), combined systolic and diastolic heart failures (11.1%), chronic obstructive pulmonary disease (7.4%), asthma (7.4%), and chronic kidney disease (25.9%). 62.9% of patients had cardiac AL involvement and 51.9% had renal AL involvement. 11/27 (40.7%) patients had IRRs to the first infusion of DARA (cycle 1, day 1) requiring hypersensitivity medications. All 27 patients progressed to rapid rate DARA after both initial and subsequent rates were tolerated. 22/27 (81.5%) patients initiated the first rapid DARA with the protocol premedications. Premedication usage decreased by the fourth rapid DARA dose with only 23.1% patients receiving diphenhydramine, 57.7% receiving famotidine, and 38.5% receiving dexamethasone (Figure 1). No patients received post-infusion corticosteroids. There were no clinically significant IRRs with the DARA rapid infusion protocol across all patients, regardless of organ involvement. There were 10 cases of CTCAE grade 2-3 hypertension that did not require intervention. No hypersensitivity medications were required for any rapid DARA doses. 11/11 (100%) patients who experienced IRRs requiring hypersensitivity medications during their first or second standard DARA infusions tolerated rapid DARA administration without recurrence of IRRs. Conclusions: Rapid administration of DARA is safe and well-tolerated in patients with AL amyloidosis, regardless of organ involvement. Patients who experienced an IRR with the initial DARA dose were able to safely transition to the rapid infusion protocol without recurrence of IRRs. Furthermore, decreased premedication usage after tolerance of rapid DARA infusion did not increase IRRs, suggesting premedications can be discontinued to mitigate associated toxicities. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Valent:Celgene corporation: Speakers Bureau; Amgen corporation: Speakers Bureau; Takeda pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Daratumumab for the treatment of AL amyloidosis

Abstract: Background: Prevention and management of venous thromboembolic events [VTE] is an important component of supportive care in newly diagnosed multiple myeloma [MM] , especially in the era of immunomodulatory drugs [IMiDs]. Recently, two validated risk assessment models [RAMs] , SAVED and IMPEDE-VTE, were developed to identify patients at high risk of VTE. However, these models have following limitations: (1) Patients were not uniformly treated in the era of contemporary MM therapy (2) Disease-specific variables were not available in the databases from which these scores were derived. Our primary aim was to develop a simple predictive model for VTE in MM using patient-specific, disease-specific, and treatment-specific variables. Our secondary aim was to assess the impact of VTE on overall survival [OS]. Methods: All consecutive patients with newly diagnosed MM treated at Cleveland Clinic from 1/1/2008 to 12/31/2018 were included in our analysis. The primary objective was to identify baseline variables associated with VTE within 12 months of treatment initiation. Candidate variables included those in IMWG, SAVED, and IMPEDE-VTE models as well as additional risk-factors from literature review in MM and cancer-associated VTE. Stepwise selection with variable entry criterion of p & lt;0.20 and a variable retention criterion of p & lt;0.05 was used to identify significant factors on multivariable analysis [MVA]. RAM was developed by subtracting 1 from the hazard ratio of a potential variable, rounding to the nearest 0.5, and multiplying by 2 to obtain a whole number. The impact of VTE on OS was assessed with landmark analysis. Results: A total of 934 patients with newly diagnosed MM and available data on VTE occurrence were considered for inclusion. We excluded patients with VTE within 6 months before starting therapy [n=5] and patients on therapeutic anticoagulation or receiving & gt;1 prophylactic regimen [n=146], resulting in a total of 783 patients for model development. The most common induction regimen was bortezomib [V] -lenalidomide [R]-dexamethasone [VRD; 41%] , followed by VD [22%], RD [20%] , V-cyclophosphamide-dexamethasone [VCD; 11%], and others [7%] . Median age at treatment initiation was 63 years [range, 22-91], 55% were males, and 20% were Blacks. ISS stage III disease was present in 32%, high-risk FISH in 23%, abnormal metaphase cytogenetics in 18%, and serum creatinine & gt;2 mg/dl in 19% of patients. Notably, 76% had received a dexamethasone dose of 120-160 mg/cycle, with only 5.9% started on a higher dose [ & gt;160 mg/cycle]. The most common thromboprophylaxis agent was aspirin [60%] , followed by low molecular weight heparin [LMWH; 3.8%]; 37% of patients received no thromboprophylaxis. Erythropoietin and intravenous immunoglobulin were used in 2.9% and 1.2% of patients respectively. Median time to VTE from treatment initiation was 3.2 months. Cumulative incidence of VTE at 6 and 12 months was 8.2% [95% CI, 6.6-10.1] and 11.5% [95% CI, 9.5-13.6] respectively. Factors significantly associated with development of VTE on MVA were combined to develop the PRISM score [Table 1]: Prior VTE history [HR 5 .06; 8 points], Black Race [HR 1.71; 1 point] , IMiD use [HR 2.17; 2 points], Surgery within 3 months [HR 3.44; 5 points] , and abnormal Metaphase cytogenetics [HR 2.10; 2 points]. The theoretical score range is 0-18, with a HR of 1.28 per 1-point increase in score [c-statistic 0.62] . Internal bootstrap validation including 1,000 samples showed a c-statistic of 0.62 [IQR, 0.60-0.64]. Using three risk groups by recursive partitioning analysis, 17.8%, 74%, and 8.1% belonged to low [0] , intermediate [1-6], and high-risk [ & gt;6] groups respectively. The 12-month cumulative incidence of VTE in the 3 respective groups were 2.7%, 10.8%, and 36.5% [Figure 1] . Occurrence of VTE in the first 12 months was not associated with worse OS on landmark analysis at 3, 6, 9, and 12 months. Conclusion: We have developed and internally validated a RAM for VTE in MM in the context of contemporary MM therapy including disease-specific variables. Studies of external validation and comparison with existing RAMs are warranted. The PRISM Score could be used to identify high-risk patients for thromboprophylaxis. Figure Disclosures Valent: Amgen Inc.: Other: Teaching, Speakers Bureau; Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau. Khouri:Sanofi Genzyme: Other: Advisory Board. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Khorana:Pharmacyclics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Leap: Research Funding; Bayer: Honoraria; Janssen: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); BMS: Honoraria, Research Funding.

Abstract: INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

Abstract: Background: Plasmablastic lymphoma (PBL) is a rare subtype of Non-Hodgkin Lymphoma with a well-known association with HIV infection. The outcomes of PBL patients are typically described with high relapse rates and poor prognosis. (Loghavi S, J Hematol Oncol. 2015; Morscio J, Am J of Pathol. 2014; Castillo JJ, Clin Lymphoma Myeloma Leuk. 2011; Castillo JJ, Am J Hematol. 2008) There has been a paucity of data suggesting that limited stage disease (Ann Arbor stage I-II) may have a more favorable prognosis. However, due to the rarity of this disease there have been no large-scale reviews to confirm this. Thus, many patients with limited stage disease are subject to the aggressive therapy recommendations based on the poor outcomes of PBL patients as a whole. (Loghavi S, J Hematol Oncol. 2015; NCCN Guidelines, version 2.2020; Al-Malki MM, BBMT. 2014) We attempted to determine the treatment patterns and outcomes of patients with limited stage PBL. Methods: We conducted a multi-center (13 US academic centers) retrospective study of patients with limited stage (Ann Arbor stage I-II) Plasmablastic lymphoma. Determination of limited stage and diagnosis of PBL was determined by the investigators at each individual center. Patients diagnosed between 1/1/1990 and 6/1/2018 were included. Baseline demographic, clinical, laboratory, pathology, and outcomes data were extracted by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: Baseline characteristics are included in table 1. A total of 80 patients were identified with limited stage disease. With a median follow up of 34 months the 3-yr Progression free survival (PFS) and overall survival (OS) was 71.9% and 78.7% respectively (Figure 1A and 1B). Patients that received frontline chemotherapy with (n=29) and without RT (n=36) had a 3-yr PFS and OS of 84.6% and 96.2% as compared to 64.5% and 70.8%, respectively (Figure 2A and 2B; Figure 3A and 3B). The Hazard ratio (HR) for PFS and OS for chemo (reference) vs chemo-RT was 0.47 (95% CI 0.18-1.3; P=0.131) and 0.18 (95% CI 0.04-0.84; p=0.029) respectively. The HR for PFS and OS for CHOP (n=14, reference) vs EPOCH (n=33) based regimens was 0.37 (95% CI 0.11-1.2; p=0.106) and 0.36 (95% CI 0.079-1.6; p=0.182) respectively. Patients with stage I/IE disease (n=56) had a 3-yr PFS and OS of 73.1% and 81.2% respectively. Patients with stage II/IIE disease (n=24) had a 3-yr PFS and OS of 69.3% and 73.4% respectively. Patients that received aggressive treatment (n=17) with Hyper-CVAD based regimens and/or Auto-SCT as consolidation had a 3-yr PFS and OS of 63.6% and 72.7% respectively. Patients with concomitant HIV (n=16) had a 3-yr PFS and OS of 80.8% and 77.4% respectively. Seven patients received RT alone and 6 patients had surgical resection alone as frontline therapy; 1 patient received no therapy; 1 patient received HAART therapy only and remains in CR without any other treatment for PBL 29 months after diagnosis. There were 8 deaths (10%) related to PBL, 3 deaths (4%) related to treatment of PBL (2 during frontline chemo and 1 upon relapse with salvage chemo), and 9 deaths (11%) related to other causes. The 3-yr lymphoma free survival (LFS) of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (without including treatment related mortality (TRM) as an event) was 89.1%, 85.2%, and 100% respectively. The 3-yr LFS survival of the entire cohort, pts receiving chemo alone, and pts receiving chemo-RT (including TRM as an event) was 85.1%, 80.0%, and 96.2% respectively. Discussion: Here we report the largest review to our knowledge of limited stage PBL. Outcomes appear to be excellent with 3-yr PFS and OS of 71.9% and 78.7% respectively and a 3-yr LFS of 89.1% (85.1% when attributing TRM as an event). There was no obvious benefit to receiving aggressive therapy with H-CVAD based regimens and/or Auto-SCT. Although this is a small, uncontrolled sample size the HR for OS was improved in patients receiving frontline chemo-RT vs chemo alone 0.18 (95% CI 0.04-0.84; p=0.029). However, this did not take into account TRM with or progression while receiving frontline chemotherapy. Patients who were HIV+ had similar PFS and OS outcomes compared to the entire cohort. This retrospective study clearly demonstrates the favorable outcomes in this patient population, especially in those able to receive definitive therapy for their disease. Disclosures Hess: ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS, AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Patel:Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Nektar: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Chavez:Bayer: Consultancy; AbbVie: Consultancy; BeiGene: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; AstraZeneca: Speakers Bureau; Celgene: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Verastem: Consultancy; Pfizer: Consultancy. Hill:Beigene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Maddocks:Pharmacyclics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Kahl:AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; OncLive: Honoraria. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Janssen Scientific: Consultancy, Other; Seattle Genetics: Consultancy, Other; Stanford University: Patents & Royalties; NCI: Research Funding. Portell:Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Takeda: Research Funding; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau. Castillo:TG Therapeutics: Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding.