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Abstract Introduction: Monoclonal antibodies (MoAbs) have shown activity in relapsed and refractory multiple myeloma (MM). Elotuzumab is an anti-SLAMF7 MoAb that synergizes with immunomodulatory agents (IMiDs) and is approved for treatment of relapsed and refractory MM. Anti-CD38 MoAbs (daratumumab, FDA approved and isatuximab, in clinical trials) have also entered the therapeutic MM landscape but little is known about how to best sequence MoAbs and the existence of cross resistance between different classes of MoAbs. We analyzed outcomes of patients who become refractory to elotuzumab with emphasis on the activity of anti-CD38 MoAbs in the post-elotuzumab setting. Methods: We identified patients from 14 academic institutions within the US who were refractory to elotuzumab administered alone or in combination with other agents. Patients were considered refractory to elotuzumab if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) within 60 days of last dose. Time zero (T0) was defined as point when myeloma became refractory to elotuzumab-containing regimen. Data were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. We analyzed demographics, characteristics of their myeloma and prior therapy including number and type of therapy prior to elotuzumab, duration of elotuzumab therapy, and outcome after becoming refractory to elotuzumab. We performed a multi-variable analysis of these factors to determine significant factors associated with survival post T0. We subsequently identified a subset of patients who received an anti-CD38 MoAb alone or in combination as next or subsequent line of therapy after T0 and report their outcomes. Results: Eighty-nine patients were evaluated. Eighty-six (96.6%) had progression on elotuzumab in combination with IMiD (N=82) or another agent (N=4). Median age at T0 was 65 years (range 28-90), 51% of patients were males, 65% were White, 54% had IgG subtype, 27% had ISS stage III at diagnosis, and 27% had high-risk cytogenetics. Patients received a median of 4 prior lines of treatment (range 1-11) prior to elotuzumab-containing regimen, including 66% who underwent autologous transplant. Sixty-one patients (69%) were refractory to at least one IMiD and one proteasome inhibitor (PI) at T0, classified as double-refractory. Twenty-one (23.6%) were quad-refractory, i.e. refractory to 2 IMiDs and 2 PIs. Twenty-eight patients (31.5%) were refractory to prior anti-CD38 MoAb. The median time from diagnosis to T0 was 59.5 months and duration of elotuzumab therapy was 3 months (range 0.4 - 59.5). Median OS from T0 for the entire cohort was 15.1 months (95% C.I. 9.3-20.9). In multivariate analysis, the only factors affecting OS after T0 were high-risk cytogenetics (HR 3.31, 95% C.I. 1.74-6.27, P<0.001) and refractoriness to prior anti-CD38 MoAb (HR 4.22, 95% C.I. 2.22-8.01, P<0.001). Interestingly, median OS for patients not refractory to anti-CD38 MoAb was 33.1 months vs. 4.5 months for anti-CD38 MoAb-refractory patients (Figure 1). After T0, 45 patients (50.6%) received an anti-CD38 MoAb in the next (N=28, 62.5%) or subsequent regimens (N=17, 37.8%). Median time between T0 and initiation of anti-CD38 MoAb was 1.2 months (0-15.0). Anti-CD38 MoAbs employed were: isatuximab in 4 (8.9%) and daratumumab in 41 patients (91.1%). In most cases, the anti-CD38 MoAb was administered in combination with IMiD (N=30, 66.6%) or bortezomib (N=7, 15.6%). The overall response rate (ORR) for anti-CD38 MoAb regimens was 35.6%; responses to specific combinations are outlined in the Table. Median PFS for elotuzumab-refractory patients receiving therapy with anti-CD38 MoAbs was 4.6 months (95% C.I. 1.6-7.6), while median OS was 15.3 months (95% C.I. 8.2-22.4) (Figure 2). Conclusion: Patient who become refractory to elotuzumab have guarded prognosis, particularly dismal among patients also refractory to anti-CD38 MoAb, defining a population with great need for novel therapies. Failure of elotuzumab-based therapy does not preclude disease control with anti-CD38 MoAb, particularly in combination. Disclosures Paul: Bristol Myer Squibb: Other: Stock and pension plan (past employee). Amarendra:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Caelum: Membership on an entity's Board of Directors or advisory committees; celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; BlueBirdBio: Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding. Vij:Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Sanofi: Honoraria; Janssen: Research Funding.

Abstract Introduction Development of anti-CD38 monoclonal antibody therapies (MoABs), including daratumumab and isatuximab, have drastically changed the therapeutic landscape for management of relapsed and/or refractory multiple myeloma (RRMM). However, there is a paucity of information regarding response to treatment after progression on CD38 MoABs. This collaborative research study (MAMMOTH: Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure) investigates the therapeutic choices and outcomes of subsequent treatments after refractoriness to MoABs. Methods Patients from 14 US academic institutions with diagnosis of MM and refractory to daratumumab or isatuximab, administered alone or in combination, were evaluated. Patients were considered refractory to a CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. Time of progression was defined as time zero (T0). Data was collected by electronic platform and submitted to peer-based quality check for completeness and internal consistency. Results Two hundred and seventy-five patients with MM refractory to CD38 MoAB were evaluated; 249 (90.5%) of those patients who received at least one subsequent line of therapy were included in this analysis. The median age at T0 was 65 years (range 27-90) and 54% were male. At the time of diagnosis, 28% had ISS stage III disease and 29% had high-risk cytogenetics. Patients were heavily pre-treated at T0 with a median of 5 lines of therapy (range 2-17); most (74%) underwent a prior autologous stem cell transplant. The majority of patients were refractory to other anti-myeloma therapies including lenalidomide (78%), pomalidomide (65%), bortezomib (69%) and carfilzomib (45%). In total, 97.1% of patients were exposed to at least one immunomodulatory agent (IMiD) and one proteasome inhibitor (PI), 79.3% were ≥ triple-refractory (refractory to 1 IMiD, 1 PI and 1 CD38 MoAB), while 25.3% were penta-refractory (refractory to 2 IMiDs, 2 PIs and 1 CD38 MoAB). Responses to the next subsequent line of therapy after progression with CD38 MoAB are shown (Table). The overall response rate (ORR; ≥PR) of first regimen post-T0 was 31% with a median progression free survival (PFS) of 3.4 mo and median overall survival (OS) of 9.3 mo. Carfilzomib-based therapy resulted in an ORR of 32% with median PFS 4.2 mo and overall OS of 10.9 mo. The addition of an IMiD to daratumumab yielded an ORR of 37% with median PFS 4.5 mo and OS 12.6 mo. The addition of a PI to daratumumab yielded no responses. Elotuzumab-based therapy had an ORR of 21% with median PFS 2.6 mo and OS 8.3 mo. By multivariate analysis, alkylator-based therapies were found to have the highest ORR (OR 3.1, 95% CI 1.8-5.7, p<0.001), however, resulted in median PFS of only 3 mo and OS of 7.7 mo. Multivariate analysis evaluating for PFS and adjusting for refractoriness to prior therapies found lower risk of progression with carfilzomib-based therapy (HR 0.60, 95% CI 0.42-0.85, p=0.004, Figure 1) and with the addition of an IMiD to daratumumab (HR 0.64, 95% CI 0.43-0.94, p=0.02). The benefit of IMiD + daratumumab was essentially restricted to patients previously refractory to CD38 MoAB as monotherapy. These patients demonstrated improved PFS with subsequent daratumumab-combination therapy at time of progression compared with patients refractory to CD38 MoAB combination therapy (log-rank p=0.02, Figure 2). No particular regimen was associated with improved OS compared with the rest. Conclusions After progression on CD38 MoAB, treatment with carfilzomib-based regimens and the addition of an IMiD to daratumumab-monotherapy resulted in a higher ORR and PFS compared with other regimens. Alkylating agents resulted in the highest ORR but relatively short PFS and OS. The use of elotuzumab and the addition of a PI to daratumumab monotherapy resulted in relatively low response rates. Overall, progression after CD38 MoAB therapy is associated with a poor prognosis and innovative therapeutic strategies are needed. Disclosures Malek: Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Neppalli:Celgene: Consultancy; Amgen: Consultancy. Liedtke:Amgen/Onyx: Consultancy, Honoraria, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Research Funding; BlueBirdBio: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Costa:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Honoraria. Kumar:Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Most studies on the management of RT were either small retrospective series or early phase non-randomized trials before the era of novel agents. The natural history, prognostication and optimal treatment of patients with RT remain undefined. Here we report the clinical characteristics and outcomes of a large series of RT from a single center. Methods: Biopsy-confirmed RT (limited to non-Hodgkin lymphoma) diagnosed from 4/1993 to 4/2018 were identified from the Mayo Clinic CLL database. Clinical characteristics, treatment information and follow-up data were abstracted by chart review. Overall survival (OS) was defined as time from RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analysis was done in SAS 9.4. Results: A total of 204 patients with CLL who developed RT were identified. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (73%) were male. The median time to transformation was 4.7 years (range 0-34.5). Prior to RT, 68 (33.3%) patients received no treatment for CLL, 109 (53.4%) received chemoimmunotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL. The median lines of CLL therapy prior to RT was 2 (range 0-13). The median age at RT diagnosis was 69 years (range 30-88). Pathology of RT was DLBCL and high grade B-cell lymphoma in 193 (94.6%) and 11 (5.4%) patients, respectively. The median LDH was 306 IU/L (range 99-9000). 62/125 (49.6%) patients had bulky disease (≥ 5 cm), and the median PET SUVmax was 13.9 (range 2.9-30.0). 45/131 (34.4%) patients had del(17p) or TP53 mutation, 12 (9.2%) had del(11q), 21 (16.0%) had trisomy 12, 27 (20.6%) had del(13q), and 25 (19.1%) had normal FISH. The CLL and RT were clonally related in 12/21 (57.1%) patients. For the transformed lymphoma, cell of origin by Han's algorithm was germinal center B cell-like (GCB) and non-GCB in 31/100 (31.0%) and 69/100 (69.0%) patients, respectively. EBV was positive in 14/52 (26.9%) patients. The median Ki-67 was 80% (range 10-100). Myc and Bcl-2 were positive by IHC in 31/43 (72.1%) and 83/103 (80.6%) patients, respectively; 27/56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18/68 (26.5%), 10/34 (29.4%), and 4/31 (12.9%) patients, respectively; 8/66 (12.1%) were double/triple-hit. The most common first-line treatment (Table 1 notes) of RT was R-CHOP-like regimen (n=114, 65.5%). Other treatments included R-EPOCH-like (n=6, 3.4%), high-intensity chemotherapy (n=15, 8.6%), novel agents (eg, ibrutinib, venetoclax, pembrolizumab; n=19, 10.9%), other chemotherapy (n=12, 6.9%), and palliative therapy (n=8, 4.6%). Response to first-line treatment was CR in 57 (38.0%), PR in 33 (22.0%), SD in 18 (12.0%), and PD in 42 (28.0%) patients. The median OS of the entire cohort after RT diagnosis was 12.0 months. The median OS for patients who received no prior CLL treatment, CIT only or at least one novel agent for CLL were 65.5, 7.3, and 12.0 months, respectively (P<0.0001; Figure 1). Of note, in patients who received CIT only for CLL, ~10% and 60% received high-intensity and R-CHOP/R-EPOCH-like chemotherapy, respectively, as first-line RT therapy. In contrast, in patients who had prior novel agents for CLL, 56% and 26% were treated with novel agents and R-CHOP/R-EPOCH-like chemotherapy, respectively, as first-line RT therapy. Patients with or without del(17p)/TP53 mutation had a median OS of 8.3 and 12.8 months, respectively (P=0.046). Patients who were treated with high intensity chemotherapy, R-CHOP/R-EPOCH-like regimens, novel agents, and other therapies for RT had a median OS of 35.1, 14.4, 10.9 and 6.1 months, respectively (P=0.02; Figure 2). OS comparisons by CLL/RT clonal relationship, double expressor or double/triple-hit status are shown in Table 1, with no significant differences noted. Conclusions: Over two thirds of RT were the non-GCB subtype, and about half were Myc/Bcl-2 double expressors. Patients who developed RT without prior CLL therapies had a significantly better OS. In contrast, patients who had received prior CLL therapies had poor outcomes. Myc/Bcl-2 double expressor and MYC/BCL2/BCL6 double/triple hit status had no impact on OS. Disclosures Kenderian: Humanigen: Research Funding; Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Parikh:Janssen: Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding.

Abstract Background: Sickle cell disorder (SCD) and transfusion dependent beta-thalassemia (TDT) are inherited disorders of β-globin genes leading to ineffective erythropoiesis, hemolysis and multi-organ damage. Though allogenic hematopoietic cell transplantation (allo-HCT) in the only potentially curative therapy, lack of full HLA-matched donor, increased risk of myeloablative conditioning (MAC) regimen related toxicity, poor prognosis in older age groups (>14 years), and a high risk of infections and graft versus host disease (GVHD) culminating into a high transplant related mortality (TRM) preclude HCT as a treatment option for many patients. Gene therapy has been proposed as a relatively new treatment option for these monogenic disorders. It involves transfection of harvested CD34+ hematopoietic stem cells (HSC) with viral vector to transfer a normal beta globin gene, which are then transplanted back to the autologous donor. However, the available data on gene therapy is extremely variable. The purpose of this review is to evaluate the risks and outcomes of SCD and TDT patients undergoing gene therapy. Methods: A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on with no restrictions of language or time period. A total of 4312 articles were identified and after duplicates removal, 3508 articles were screened for relevance. Clinical studies reporting the most recent follow up results about the efficacy and safety of gene therapy in patients with hemoglobinopathies were considered for inclusion. Their quality assessment was done using the Cochrane tool, and bias was evaluated regarding the study selection, performance, detection, attrition and the reporting of the clinical trials. RESULTS (table-1): Only 7 articles qualified for the strict selection criteria with an N of 47: six studies were phase I trials (Cavazzana, M. et al 2010, Boulad, F. et al 2013, Marktel, S. et al 2017, Kwiatkowski, J. et al 2017, Cavazzana, M. et al 2017, Kanter, J. et al 2017) and one was a phase III trial (Walters, M. et al 2017). Thirty five patients (74.4%) had TDT while 12 patients (25.5%) had SCD. All these patients did not have a suitable HLA-matched HCT donor. The length of follow up was heterogeneous owing to the step wise enrollment of participants and ranged from 2-36 months. Except for 4 cases, the age of included population was >13 years. Lentivirus BB305 encoding the HbAT87Q globin gene was used for gene delivery in 81% patients (n=38). The normal beta globin gene was transduced in remaining 9 TDT cases and it involved transduction using TNS 9.3.55 vector in two cases and with GLOBE lentivirus in 7 cases. MAC with busulfan was used in 81% cases (n=38), while treosulfan+thiotepa was used in 7 cases. The non-myeloablative (NMA) conditioning with busulfan was used in only 2 cases (both TDT). Bone marrow harvest was the source of HSCs in all SCD cases. Except for 3 SCD cases in HGB-204 trial and 3 TDT cases in HGB-207 which measured the potential improvement in outcome by an increase in DP-VCN, the range of drug vector copy number (DP-VCN) was 0.3-1.5 copies per diploid genome. The total hemoglobin (HB) level at last follow up was reported for 62% cases (n=29) and it was >8.8 g/dl in all cases. Twenty-one (60%) thalassemia cases were in a transfusion (Tx) free state at last follow up, including the 7 cases (20%) who developed a complete independence from transfusions. No such Tx-free state was noted in SCD cases although they developed a reduction in the Tx-requirement and 75% SCD cases (n=9) had a 30-100% reduction in the frequency of VOCs. All the cases were alive at their recent follow up with manageable toxicity form conditioning. Acceptable safety until the median follow-up from the 7 trials was established in all cases, with no reported development of post-treatment leukemia or new malignancy in these trials. DISCUSSION: In this largest series of gene therapy for the treatment of hemoglobinopathies (to our knowledge), we find it to be clinically effective in terms of reduction in transfusion needs; data to suggest an improved OS and disease free survival is promising, however long term data is awaited. Gene therapy appears to bypass the limitations faced by allo-HCT especially a high early TRM. Randomized trials reporting the efficacy and safety outcomes with longer follow ups are urgently required. Disclosures No relevant conflicts of interest to declare.

Abstract History of prior cancer is a widespread exclusion criterion in cancer trials. Up to 80% of NCI-sponsored and 80% of industry-sponsored lung cancer trials exclude patients with a prior cancer. We suspect this exclusion is commonly applied in other cancer trials, although no definitive data exist. Prior cancer is especially common among older patients and those with certain cancer types. Among patients >65 years, 15.1% overall have prior cancer. In Multiple Myeloma, the most common plasma cell disorder (PCD), prevalence of prior cancer is as high as 17.4%. Examining the prior cancer exclusion criterion is important because the number of US cancer survivors is large and rapidly growing. Arbitrarily excluding cancer survivors from trials is not evidence-based and exclusion presumably arises from assumptions that higher mortality of patients with prior cancer could hinder study conduct and bias trial outcomes. However, few data exist to support this assumption of higher mortality. In fact, we demonstrated that lung cancer patients with a prior cancer have similar or lower mortality risk, compared to those without prior cancer. In this abstract, we reviewed prior cancer related eligibility criteria in three of the most common PCD (Multiple Myeloma, Amyloidosis and Waldenström Macroglobulinemia) clinical trials sponsored or endorsed by 5 major Co-Operative groups in North America (Table 1). We use descriptive statistics (n, %) and Fisher's exact tests to describe characteristics of trials with and without exclusion criteria. Of 33 trials, 26 (79%) excluded patients with prior cancer as follows - active cancer (12%), within 2-3 years of PCD diagnosis (9%), or within 5 years of PCD diagnosis (55%). Many trials had exceptions to prior cancer exclusion. Specifically, 67% of trials allowed non-melanoma skin cancer, 58% allowed in-situ cervical cancer, 12% allowed early stage prostate cancer. Table 2 shows the association between clinical trial characteristics and prior cancer exclusion. There was no association between prior cancer exclusion and phase of study, transplant studies, or survival end point. Exclusion criteria varied across year of activation (p=0.01); for example, 75% of studies activated 1990-1999 excluded prior cancer, compared to 100% of studies activated after 2010. Type of PCD was marginally associated with exclusion criteria (p=0.08); 74% of Multiple Myeloma trials excluded patients with prior cancer compared to 100% of the Amyloidosis and Waldenström Macroglobulinemia trials. Conclusion: A substantial proportion of potential participants may be excluded from PCD clinical trials because of a history of prior cancer. This practice impacts accrual, generalizability, and fair access to cutting-edge treatments and the highest level of clinical care. As treatment outcomes for other cancers continue to improve, it is likely that the prevalence of multiple primary cancers will increase. This exclusion criterion is applied widely across studies, including more than two-thirds of those with non-survival endpoints. Our study is the first to examine the prevalence and potential impact of prior cancer exclusion in PCD clinical trials. Using population-based cancer registry data, we plan to undertake further research to understand the appropriateness and ramifications of this standard exclusion policy in PCD cancer trials. Disclosures Collins: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Celgene Corporation: Research Funding; Arog Pharmaceuticals: Research Funding. Devine:Kiadis Pharma: Consultancy. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Anderson:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have significantly improved survival in patients with multiple myeloma (MM). Refractoriness to PIs and IMiDs results in poor outcomes with a median survival of about 13 months.Daratumumab and isatuximab are CD38-targeting monoclonal antibodies (MoABs) with remarkable activity in relapsed and refractory MM. The outcome of MM patients in US clinical practice who becomes refractory to CD38 MoABs is unknown. The aim of this multicenter, retrospective study is to investigate the natural history of patients with MM who become refractory to CD38 MoABs (Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure: MAMMOTH study). Methods We identified patients from 14 academic institutions in the US with diagnosis of active MM and refractory to daratumumab or isatuximab, administered alone or in combination. Patients were considered refractory to CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. The time when patients met the above criteria of progression was defined as time zero (T0). Data including patient-disease characteristics and all therapies administered before and after T0 were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. For survival outcome analysis, patients were classified into three groups: "Penta-refractory" (refractory to 1 CD38 MoAB + 2 PIs + 2 IMiDs), "Triple-refractory and quad-refractory" (refractory to 1 CD38 MoAB + 1 PI + 1/2 IMiDs, or 1 CD38 MoAB + 1/2 PIs + 1 IMiD), and "Not triple-refractory" (refractory to 1 CD38 MoAB, and not both of a PI and an IMiD). Responses were evaluated using the IMWG criteria. Results Two hundred and seventy-five patients were included in this study; median age at T0 was 65 years (range 27-90). Fifty five percent of patients were males, 52% had IgG isotype, 29% had ISS stage III disease, and 29% had high-risk cytogenetics at diagnosis. Median interval from diagnosis of MM to T0 was 50.1 months (mo) (range 2.5-230.1). Patients received a median of 4 lines of treatment (1-16) prior to the CD38 MoAB-containing regimen; 72% underwent prior autologous transplant. Daratumumab-refractory patients formed a majority (256, 93.1%) of this cohort. Most of the patients were refractory to lenalidomide (77%), pomalidomide (65%), bortezomib (68%), and carfilzomib (47%). Seventy patients (25.5%) were "penta-refractory" and 148 (53.8%) were "triple-refractory and quad-refractory". Median follow-up from T0 for survivors was 10.6 mo (range 1.9-42.3 mo). The median overall survival (OS) from T0 for the entire cohort was 8.6 mo (95% C.I. 7.2-9.9); OS for the groups based on refractoriness to prior treatments are shown (Figure). Two hundred and forty-nine patients (90.5%) received at least one line of treatment after T0, (median 2, range 1-10). The response rates and depth of responses to each line of treatment post T0 are shown (Table). Among patients who received ≥ 1 subsequent treatment, the median PFS and OS from T0 were 3.4 (95% C.I. 2.8-4.0) mo and 9.3 (95% C.I. 8.1-10.6) mo, respectively; the median OS for the 26 patients who received no further treatment was only 1.3 (95% C.I. 0.6-1.9) mo. By multivariate analysis, penta-refractoriness (HR 2.4, p <0.001), high-risk cytogenetics (HR 1.5, p=0.01), elevated LDH (HR 2, p<0.001) and creatinine > 2 (HR 2.4, p=0.01) at the onset of CD38-based therapy predicted inferior OS. Conclusions Patients with MM who become refractory to CD38 MoAB are increasingly less responsive to subsequent therapies. While survival is particularly dismal for penta-refractory patients, the outcomes are poor even for patients who are not refractory to other mainstream MM agents. The MAMMOTH study defines a MM population in urgent need for new therapies, and provides benchmark OS, PFS and response data for subsequent investigational therapies in this setting. Disclosures Malek: Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Neppalli:Amgen: Consultancy; Celgene: Consultancy. Liedtke:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Vij:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:Karyopharm: Research Funding; Sanofi: Honoraria; Janssen: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Abstract Introduction: Given the established role of PD-1 in mediating immune suppression in chronic lymphocytic leukemia (CLL), we tested and reported the efficacy of PD-1 blocking antibody pembrolizumab in relapsed and transformed CLL patients. A selective response of pembrolizumab (~40%) in patients with RT, particularly after prior ibrutinib, was observed (Ding, Blood, 129:3419). Correlative analysis showed PD-1 expression in tumor B-cells of patients with RT and aggressive CLL after progression on ibrutinib. PD-1, an inhibitory receptor expressed on CLL T-cells, inhibits the immune synapse and cytotoxic T cell functions via the interactions with its ligands. However, the expression pattern and role of PD-1 in tumor B-cells is not well defined. In this study we investigated the functional implication of the PD-1 signaling axis in B-cell pathobiology in CLL and RT patients. Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). For in vitro study, we checked PD-1 expression in 11 lymphoma cell lines and 1 CLL cell line by both flow cytometry and Western blot (WB) analysis. Effect of PD-1 knockdown using CRISPR/Cas9 system (Addgene) and over-expression of PD-1 using pLEX-lentiviral (Thermoscientific) or pRetro-retroviral (Clonetech) system were evaluated on pro-survival and apoptotic signaling pathways by Western blot analysis. Gene expression signatures in CLL and RT patients were also evaluated by Illumina-based RNA sequencing using FFPE-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL). Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN. (mean ± SEM in RT vs. CLL, 30.6 ± 4.7 vs. 11.5 ± 2.8, p < 0.001). PD-1 expression was highest in patients with RT where the immediate prior CLL therapy was ibrutinib (Figure 1A). Among all cell lines tested for PD-1 expression, the expression of PD-1 by WB and flow was highest in Mino (mantle cell lymphoma line), followed by moderate expression in Jvm2 (B-PLL line) and Mec1 (CLL line), and very low-level expression in both Jeko-1 (B-NHL line) and lymphoma line 'Karpas299'. CRISPR/Cas9 mediated depletion of PD-1 in Mino cells inhibited constitutively active Akt, p70S6K and mTOR pathway, accompanied by significant downregulation of the anti-apoptotic proteins, Bcl-2, Mcl-1 and XIAP, but P-ERK1/2 was not affected. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in Jeko-1 and doxycycline regulated inducible retroviral (pRetro-PD-1) mediated overexpression of PD-1 in Karpas299 activated Akt, mTOR and p70S6K pathway. Overexpression of PD-1 in Jeko-1 significantly increased Bcl-2 and Mcl-1 and in Karpas299 increased Bcl-2, Mcl-1 and XIAP expression (Figure 1B). A parallel genetic analysis using RNA sequencing was performed on 5 nodal tissues involved by either RT or progressive CLL after these patients developed clinical progression after prior ibrutinib therapy. In all 5 patients, overexpression of PD-1 was associated with increased expression of Bcl-2 and mTOR regardless of the genetic mutations detected (including TP53, ATM, BTK, NOTCH1, XPO1, SF3B1, TET2 etc). However, in 2 patients who received prior chemoimmunotherapy, similar overexpression of gene signature was not observed by RNA sequencing analysis, alternative pathways including Met or NFkB overexpression was detected. Given these clinical and laboratory findings, we have treated 2 RT patients with a combination of BTK and Bcl-2 inhibitors (ibrutinib and venetoclax, respectively) whose CLL transformed after prior ibrutinib. Significant reduction of tumor burden was observed in both cases with one complete response and one mixed response. Conclusion: An increased expression of PD-1, Akt/mTOR and Bcl-2 gene signature was first observed in RT patients after prior ibrutinib therapy. PD-1 overexpression in the tumor B-cells of RT and progressive CLL patients likely regulate AKT/mtOR to upregulate Bcl-2. Targeting both BTK and Bcl-2 pathways in addition to PD-1 blockade appear to be a promising strategy to treat these aggressive diseases. Disclosures Parikh: Gilead: Honoraria; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding. Ansell:Takeda: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Ding:Merck: Research Funding.

Abstract Background: Each additional line of therapy is associated with lower rates of deeper responses, shorter durations of treatment-free intervals, and increased rates of toxicities/comorbidities in patients with multiple myeloma (MM; Yong K, et al. Br J Haematol 2016. 175[2]:252-264), all of which are factors that contribute to treatment discontinuation. In order to characterize the newly diagnosed MM (NDMM) patient population in the United States not treated with a stem-cell transplant based on the number of subsequent lines of therapy (LOT) received, we examined baseline patient characteristics and pre-existing comorbidities, frontline treatment patterns, and attrition rates for these patients according to whether subsequent LOT was received or not received. Methods: NDMM patients were identified from 3 US patient-level data sources: the Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked database (from January 2007 through December 2014), the OPTUM™ Commercial Claims database (from January 2000 through March 2017), and the OPTUM™ Electronic Medical Records (EMR) database (from January 2007 through March 2016). Patients included in the assessment had 1) an index diagnosis of MM on or after 1 January 2007, 2) known gender, 3) medical prescription coverage in place at diagnosis, 4) a 1-year look-back period prior to the index diagnosis, 5) no prior malignancies in the 1-year period prior to index diagnosis, and 6) received ≥1 LOT. The analysis was limited to patients who did not receive stem cell transplantation at any time during their follow-up. Descriptive and logistic regression analyses were conducted to characterize and compare patients who received or did not receive a subsequent LOT. Results: The analysis included a total of 7,724 patients (1 LOT only: n = 3,906; 2+ LOT: n = 3,818). A summary of baseline patient characteristics and pre-existing comorbidities by LOT is summarized in Table 1. Patients who received a subsequent LOT vs those that did not were significantly younger (median age 72.0 vs 74.0 years; P <0.0001) and had significantly lower mean Charleston Comorbidity Index (CCI) score due to lower occurrence of renal, cardiac, and hepatic comorbidities (Table 1). Older age at diagnosis and presence of renal, congestive heart failure (CHF), hepatic, and pulmonary comorbidities were associated with higher attrition. The regimens used in frontline treatment included bortezomib/dexamethasone (26%), lenalidomide/dexamethasone (21%), bortezomib/lenalidomide/dexamethasone (11%), a bortezomib/alkylator ± steroid combination (6%), bortezomib monotherapy (10%), lenalidomide monotherapy (6%), thalidomide monotherapy (4%), and other (17%). The proportions of patients progressing to each subsequent line of therapy are shown in Table 2. In total, 49% of patients went on to receive a second line of therapy, and 55% of patients receiving a second line of therapy went on to receive a third line of therapy. The incidence of patients not receiving subsequent lines of therapy due to death or being lost to follow up by LOT is summarized in Table 2. Conclusions: A majority of non-transplant patients with NDMM in the study did not progress to subsequent lines of therapy, with attrition as high as 50% per line of therapy and only <8% of patients reaching LOT 5. This high level of attrition is associated with older age and poor comorbidity status of non-transplant patients with NDMM. Therefore, utilizing the most optimal regimens upfront (rather than reserving them for later lines) is warranted. Disclosures Fonseca: Mayo Clinic: Employment; Amgen: Consultancy. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Mehra:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment. Ukropec:Janssen Scientific Affairs, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Potluri:SmartAnalyst Inc.: Employment.

Abstract Introduction: C. difficile infection (CDI) is a common nosocomial infection. Immune suppression is thought to be a major risk factor for CDI. Hematopoietic stem cell transplant (HSCT) recipients represent a major subgroup of immunologically vulnerable patients. It is unclear if these patients have novel risk factors for CDI development. We, therefore, performed a systematic review and meta-analysis to evaluate the predictors of CDI in HSCT recipients. Methods: A systematic search of Medline, Embase, and Web of Science was performed from January 2000 up to June 2018. All studies that assessed risk factors associated with CDI development in HSCT recipients were eligible for inclusion. Data on clinical characteristics and risk factors associated with CDI development were collected. Study quality was assessed using the Newcastle-Ottawa scale. Meta-analyses were performed using random effects models and pooled odds ratios with 95% confidence interval (CI) for risk factors reported in ≥ 2 studies were calculated. Results: Overall, 17 studies, including 6328 HSCT patients were included. Of those 874 patients developed CDI. The rate of CDI development in these patients was 13.81% with a follow up ranging from 1- 36 months. A total of 34 different risk factors were studied, of which 20 were identified in ≥ 2 studies. Our analysis showed that cephalosporin use (Odds ratio [OR] 2.21, 95% confidence interval [CI] 1.26-3.87), cord blood transplant (OR 1.36, 95% CI 1.01-1.83), graft versus host disease (GVHD) (OR 1.63, 95% CI 1.07-2.48) & prior hospitalization within 90 days of HSCT (OR 1.85, 95% CI 1.21-2.83) were associated with statistically significant increased risk of CDI in HSCT patients (Figure 1). On the other hand, many characteristics of HSCT patients including age, diabetes, lung disease, fluoroquinolones, proton pump inhibitors, rituximab, mucositis, myeloablative therapy, melphalan use before BMT, total body irradiation, growth factor use during admission, neutropenia, autologous vs allogenic transplant and use of matched related donor were not associated with increased risk of CDI. Conclusion: HSCT recipients are at an increased risk of CDI compared to general population. In addition to the common risk factors like cephalosporin use and prior hospitalization, these patients have novel characteristics including presence of GVHD and cord blood transplant that puts them at a higher risk of CDI. HSCT patients with these risk factors may warrant a closer surveillance for early detection and treatment of CDI. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.

Abstract Background Predictors of outcomes after reduced intensity conditioning (RIC) stem cell transplantation (SCT) in chronic lymphocytic leukemia (CLL) are not well established. The Dana Farber (DF) investigators (Brown et al, leukemia 2013) developed a prognostic scoring model for overall survival (OS) and disease free survival (DFS) that assigned one point to each of comorbidity index, absolute lymphocyte count, LDH and disease status. The goals of the present study were to 1) validate the DF model 2) identify additional predictors of outcomes after SCT. Methods This study is a retrospective review of the Mayo Clinic CLL database and was approved by the Institutional Review Board. All CLL patients that underwent RIC-SCT were included. The prognostic significance of prognostic factors at time of RIC-SCT were analyzed, including the DF model. Survival was estimated and compared using the Kaplan Meier and Log Rank tests. Results From 2006 to 2012, 50 patients with CLL underwent RIC-SCT at the Mayo Clinic. Of these, 33 were male (66%) and the median age was 56 (29-69) years. The median time from diagnosis to RIC-SCT was 4.7 years (0.6-22.9). Indications for RIC-SCT were 17p deletion in 24 (48%) patients and purine nucleoside analogue (PNA) refractory disease in 26 (52%) patients. Transplant related mortality was 6% and non-relapse mortality at 5 years was 14%. Acute graft versus host disease (GVHD) developed in 30 (60%) patients and chronic (c) GVHD was noted in 32 patients (64%). The 5-year relapse rate was 38%. The DF prognostic score stratified three categories for OS (score of 0, 1-2, ≥ 3), but was not associated with DFS in this cohort. We next evaluated the impact of other patient, disease, and transplant characteristics on clinical outcome. Development of cGVHD post-transplant was the dominant predictor of both DFS (HR 0.26, 95% CI=0.10-0.69, P=0.006) and OS (HR 0.04, 95% CI=0.01-0.19, P<0.0001, figure 1). The presence of 17p deletion at time of RIC-SCT was associated with shorter DFS (HR 3.99, 95% CI=1.43-11.18, P=0.008), but did not impact OS. Developing cGVH but not DF score remained an independent predictor of OS on a multi-variate analysis including both factors. Given these findings, we evaluated what pre-treatment patient, disease, and transplant characteristics predicted for subsequent development of cGVHD. Patients with higher scores on DF prognostic model were less likely to develop cGVHD (score 0=66%, 1-2=76%, ≥3=31%; P=0.01). Three CLL characteristics (complete or partial remission at time of RIC-SCT, absence of 17p deletion, and absence of ZAP70 overexpression) were predictors for development of cGVHD while alemtuzumab exposure ≤3 months prior to RIC-SCT decreased likelihood of cGVHD. On multivariate modeling using these four predictors, only ZAP70 overexpression was an independent negative predictor of developing cGVHD (Table 1). Rates of cGVHD post RIC-SCT in ZAP 70 positive and ZAP70 negative patients were 50% and 92%, respectively (p=0.03). Conclusion This study found that while the DF prognostic score is an effective way to predict outcome prior to RIC-SCT, development of cGVHD post-transplant is ultimately the most significant predictor for both OS and DFS after transplant in patients with CLL. Pretransplant characteristics that predict subsequent cGVHD include DF prognostic score and ZAP70 status. This is the first report to identify biologic characteristics of CLL B-cells associated with development of cGVHD post-transplant. Disclosures: No relevant conflicts of interest to declare.