ALBERT

Description: Introduction The oral BTK inhibitor ibrutinib was recently approved for frontline CLL therapy based on RESONATE-2, which included only patients (pts) age ≥65 (Burger et al., 2016). In the absence of comparative data, FCR remains a standard initial therapy for younger CLL pts, particularly in light of recent data suggesting that mutated IGHV predicts long disease free survival after FCR (Thompson et al., 2016, Fischer et al., 2016). However, pts with higher risk CLL such as del(17p) and unmutated IGHVhave less durable responses. Moreover, only about 20% of CLL pts will achieve complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) with frontline FCR (Boettcher et al., 2012). Given the favorable toxicity profile and substantial efficacy of ibrutinib across CLL risk types, we developed an investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548). Methods The primary objective is to determine the rate of CR with BM MRD-neg in younger CLL pts treated upfront with iFCR. Secondary endpoints include response rate, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is started 7 days prior to FCR, which is given at standard doses together with ibrutinib for up to 6 cycles. Responders continue on ibrutinib maintenance until progression or unacceptable toxicity. Growth factor support and antimicrobial prophylaxis are mandatory. Eligibility criteria include: age ≤ 65, requiring initial treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. CTCAE v4 and IW-CLL criteria are used to evaluate toxicity and efficacy, with response evaluations after 3 cycles, 2 mos. after final FCR (primary endpoint evaluation), and q6 mos. thereafter. MRD is assessed by 4-color flow cytometry (10-4sensitivity). Results As of August 1, 2016, the study reached full accrual at 35 pts. The median age at enrollment was 55 yrs (range 38-65). 9/33 tested (27%) had del(11q) and 4/33 tested (12%) had del(17p). Unmutated IGHV was present in 20/31 tested (65%), ZAP-70 was positive in 21/32 tested (66%), TP53 mutation was present in 2/31 tested (6%), and NOTCH1 mutation was present in 2/21 tested (10%). We initially enrolled 10 pts in a safety lead-in cohort and did not see any unexpected toxicities. In the entire cohort of 35 pts, hematologic toxicity included grade (gr) 4 neutropenia in 1 pt (3%), as well as gr 3 neutropenia (15%), thrombocytopenia (18%), and anemia (6%). All grade non-hematologic toxicities occurring in 〉15% of pts included nausea (68%), bruising (35%), fatigue (29%), and rash (21%) (all gr 1/2) and diarrhea (21%) (all gr 1). The only bleeding events were gr 1 epistaxis in 2 pts. SAEs included gr 4 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumonia, and gr 3 appendicitis in 1 pt each. 9% of pts experienced ≥gr 3 infection. A median of 6 cycles of FCR were given (range 3-6). One pt had ibrutinib dose reduction (pt with febrile neutropenia), and 18% of pts had at least 1 dose reduction of chemotherapy. Twenty-eight pts have undergone primary endpoint re-staging after completing the iFCR combination and 26 pts have been tested for BM MRD. In these 26 pts, the rate of CR with BM MRD-neg is 39% (10/26). In the 28 pts with re-staging, the ORR is 100%, including 39% (11/28) with CR or CRi. 17/28 (61%) pts had a PR, and all 17 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. BM was MRD-neg in 23/26 tested (89%), including 13/17 (76%) of pts in PR. With a median follow-up of 12.1 months (range 0.1-21.1), all pts are alive, and 33 of the 35 pts remain on treatment. One pt who completed 6 cycles of iFCR and achieved CR with BM MRD-neg declined ibrutinib maintenance and remains in MRD-neg CR at 10 months off therapy, and one pt with del(17p) achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant. Conclusions iFCR induces deep responses in previously untreated young CLL pts, with 39% of evaluable pts achieving CR with BM-MRD-neg and 89% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities were observed, possibly due to mandatory use of growth factor support and antimicrobial prophylaxis. 76% of PR pts have achieved BM MRD-neg, and all of these pts have small residual lymph nodes. Pts continue on ibrutinib maintenance and will be monitored for conversion to CR with BM MRD-neg. over time. Disclosures Davids: Genentech: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Abramson:Gilead: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Consultancy. Fisher:Pharmacyclics: Consultancy. Brown:Acetylon, Gilead: Research Funding; Celgene, Roche/Genentech, Gilead, Infinity, Janssen, Pharmacyclics, ProNai, Sun BioPharma: Consultancy.

Description: Background.This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods.Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results.In total, 53 of the planned 62 patients have been enrolled in this study from February 2017 to May 2019. The median age of the patients enrolled was 61 years (range, 41 to 84) with 22 male (41.5%). The analysis was conducted on patients who have completed at least 1 cycle of therapy (n=45). The median follow-up for the trial is 14.4 months (range: 2- 27.6). Interphase fluorescence in situ hybridization (iFISH) was successful in 37 patients (82.2%). High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 20 patients (54%). The median number of cycles completed was 14 cycles (range: 1-24). According to the study's inclusion criteria, baseline markers showed that 15, 14, and 13 patients had 3, 4, and 5 high-risk features, respectively. Moreover, 24 patients (53.3%) met the criteria of high-risk SMM, according to the Mayo 2018 model. The most common grade 3 adverse events were hypertension (6.3%), hypophosphatemia (4.2%), and rash (4.2%). Grade 4 thrombocytopenia and neutropenia were each reported in 4.4% of patients, and hyperglycemia was reported in 2.2%. Stem cells were collected in all eligible patients by the end of the induction phase. As of the abstract date, the overall response rate (partial response or better) in participants who completed at least 1 cycle of treatment was 91.1% (41/45), with 14 Complete Responses (CR, 31.1%), 9 very good partial responses (VGPR, 20%), 18 partial responses (40%), and 4 minimal Responses (MR, 10%). ORR in patients who completed the induction phase (≥9 cycles) was 97% (n= 32/33), with 14(42.4%) and 9 (27.2%) having CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. Six patients have completed the treatment protocol and are currently on follow-up. As of July 2019, none of the patients have progressed to overt MM. MRD testing by next-generation sequencing is ongoing for patients who achieved CR or VGPR and will be presented at the meeting. Conclusion.The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma with 91% ORR and 54.7% CR and VGPR to date. The high response rate, convenient schedule and manageable toxicity build on prior studies which have shown efficacy of lenalidomide and dexamethasone in high risk smoldering myeloma. Longer follow-up for disease outcome is ongoing. Disclosures Bustoros, MD: Takeda: Honoraria. Nadeem:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy. Prescott:Janssen: Equity Ownership. Munshi:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Anderson:OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Ixazomib, Lenalidomide and Dexamethasone is an investigational combination in high-risk smoldering multiple myeloma and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the use under investigation.

Description: Background Studies from the chemoimmunotherapy (CIT) era and more recently with venetoclax have demonstrated the correlation between minimal residual disease (MRD) response measured by at least four-color flow cytometry (FC), and progression free (PFS) and overall survival (OS) in CLL. Despite high overall (ORR) and complete (CR) response rates observed with fludarabine-based combination CIT, the ability to achieve sustained undetectable MRD (uMRD) remission is lacking for the majority of patients treated with these regimens. We have previously reported on the promising combination of ibrutinib plus FCR (iFCR), which demonstrated a 98.8% ORR, 32.9% CR/CRi with bone marrow (BM) uMRD at EOT, and 77.7% BM-uMRD by flow at EOT (83.5% at best response) [Davids et al, Lancet Haematology, 2019]. Adaptive's next generation sequencing (NGS)-MRD assay targets immunoglobulin receptor sequencing with up to 10E-6 sensitivity for detection of B-cell malignancies. Here we present expanded MRD analysis by standard flow cytometry and the first results assessed using NGS-MRD, focusing on mid-FCR (C3) and 2 month post-FCR (EOT) timepoints. Methods iFCR is a multicenter single-arm phase 2 trial at seven sites in the USA. 85 patients aged 65 years or younger with previously untreated CLL were enrolled and treated with iFCR as previously published [Davids, Lancet Haematology, 2019]. Per protocol analyses of MRD in both peripheral blood (PB) and BM by standard four-color FC were performed at local laboratories at C3. Both PB and BM samples were submitted to Adaptive for NGS-MRD evaluation at EOT. Forty-eight patients had paired BM and PB samples with 16 additional PB only samples. NGS-MRD status was evaluated at 10E-5 and 10E-6 levels, and defined as positive if ≥ 1 rearrangement was detected per 100,000 or per million cells, respectively. An indeterminate finding was reported if insufficient cells were assayed, as NGS-MRD testing is limited by the number of cells evaluated, which can often be lower than needed for 10E-6 sensitivity, particularly in PB. Results At the C3 restage, the BM-uMRD rate by flow was 47%, with 100% concordance to flow PB-uMRD status in all patients with BM-uMRD. However, 33% (12/36 evaluable) with detectable cells in marrow had PB-uMRD, demonstrating enhanced sensitivity of BM-MRD testing as shown in Table 1. At EOT, BM-uMRD rates rose to 78%, compared with 86% in PB, including 14/24 patients converted from BM-pos/PB-pos to BM-neg/PB-neg and 7/12 BM-pos/PB-neg to BM-neg/PB-neg. In NGS-MRD analysis from 48 patients with evaluable BM and PB samples at EOT, a larger number of patients were MRD positive in BM (n=21; 43.8%) vs. PB (n=13; 27.1%) (McNemar test: p=0.04). Figure 1 illustrates the improving detection of residual disease in both BM and PB with increasing sensitivity, with greater detection in BM; 54% positive at 10E-6 sensitivity in this cohort, compared with 36% in PB. Evaluation for true negative samples at 10E-6 sensitivity was limited by samples with inadequate cells for evaluation (indeterminate), hence definite uMRD was seen in only 23% BM and 9% PB. Fifty-two patients with PB-uMRD by FC at EOT had associated PB NGS-MRD results: 10 PB-uMRD by FC were positive at 10E-5 with 8 additional positive at 10E-6 (35% greater than FC). Similar results were observed in BM: of forty-four patients with BM-uMRD by FC at EOT, 13 were positive at 10E-5 with 9 additional positive at 10E-6 by NGS-MRD (50% greater than FC), summarized in Table 2. When this higher sensitivity BM-uMRD data is used to define overall clinical response at EOT, the CR/CRi with BM-uMRD rate at 10E-5 is 32.6% (14/43), and at 10E-6 is 16.2% (6/37), compared to 43.8% (21/48) using four-color FC. The rate of BM-uMRD would be 60.5% (26/43) at 10E-5 sensitivity and 29.7% (11/37) at 10E-6, with NGS-MRD. Discussion This first report of NGS-MRD testing after iFCR demonstrates that 50% of patients with BM-uMRD by flow cytometry have detectable CLL cells at the level of detection of ≥ 1 per million cells. While iFCR has improved upon historical uMRD results by four-color flow cytometry, these findings suggest that CLL cells are still frequently present. Longer follow-up will be required to correlate these minimal levels of residual disease with PFS in this setting. Future studies should incorporate NGS-MRD assessment with larger volume cell sampling to ensure adequate sensitivity and evaluate venetoclax-based regimens. Disclosures Brander: Novartis: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Research to Practice: Honoraria. Brown:Novartis: Consultancy; Sunesis: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; AbbVie: Consultancy; Morphosys: Other: Data safety monitoring board; Pharmacyclics: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria.

Description: PURPOSE: This study aimed to determine activity and safety of the CXCR4 inhibitor plerixafor in combination with bortezomib and dexamethasone in patients with relapsed or refractory Multiple Myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Sanofi Corporation) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. PATIENTS AND METHODS: Theprimary endpoint of the phase I study was the maximum tolerated dose (MTD) and for the phase II study, the safety and response rate of the combination. Eligibility criteria included patients with relapsed or relapsed/refractory MM with 1-5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib). The phase I included 8 cohorts with different doses and two treatment schedules. In cohorts 1-5, patients received plerixafor at the recommended dose sq on days 1-6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. In cohort 5b-6, plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD established in phase I of trial, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. RESULTS: A total of 58 patients were enrolled on this study from June 2009 to March 2015, with 25 on the phase I and 33 on the phase II study. In the phase I study, the median age was 60 years (range, 43-85), the median number of prior therapies was 2 (range, 1-4), with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 4 (1-12). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). Therefore, 3 additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR), 1 partial remission (PR) and 2 (9%) MR, and 15 (65%) having stable disease with only 3 (13%) progressive disease (PD). In the phase II study, the median age was 63 (46-83). The median number of prior therapies was 2 (1-5), with 22 (66%) who have received prior bortezomib. The median number of cycles on therapy is 5 (1-24). The response rate included 5 VGPR (16%), 11 PR (35%) with an overall response rate of 51% and another 11 (35%) stable disease. Grade 3/4 toxicities included thrombocytopenia (68%), lymphopenia (6%), hypophosphatemia (2%), anemia (4%), infections (4%), hyponatremia (2%), hypercalcemia (2%) and neurological toxicity (2%). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are strongly encouraging with 51% ORR in this relapsed and refractory population. This study was supported by R01CA133799-01, and by Sanofi and Takeda Corporations. Disclosures Off Label Use: Plerixafor in myeloma. Azab:Verastem: Research Funding; Selexys: Research Funding; Karyopharm: Research Funding; Cell Works: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner . Schlossman:Millennium: Consultancy. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees.

Description: Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

Description: Introduction: Patients (pts) with newly diagnosed multiple myeloma (MM) are commonly treated with the standard of care combination of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex), also known as RVD. A recent randomized phase 3 study found that the addition of Bz to Len and Dex significantly increased median overall and progression free survival as well as response rate (Durie et al. Lancet 2017). Mild to moderate peripheral neuropathy (PN) is commonly reported with Bz use, although lower rates of PN have been reported with subcutaneous (SC) administration of single agent Bz compared with IV Bz (Moreau et al. Lancet Oncol 2011). Here we present preliminary results of a multi-center, open-label, single arm phase II trial of Len, SC Bz, and Dex in pts with newly diagnosed MM. Maintenance was risk-stratified, with high risk patients (defined as those with high risk cytogenetics (del17p, t(4:14), t(14;16)) or ISS stage II or III) receiving Bz in addition to Len. Primary endpoints included 1) overall response rate (ORR) after 4 induction cycles, 2) best response to induction therapy, and 3) rate and severity of PN during induction therapy. Methods: Patients enrolled in this study were newly diagnosed with active MM as defined by the revised IMWG criteria (Rajkumar et al. Lancet Oncol 2014). Protocol specified induction treatment consisted of 21-day cycles with Len 25 mg on days 1-14, SQ Bz 1.3 mg/m2 days 1, 4, 8, and 11, and Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Stem cell mobilization followed induction cycle 4 and patients subsequently proceeded to either high dose melphalan and autologous stem cell transplant (ASCT) or 4 additional cycles of induction therapy based on patient preference with provider input. Following ASCT or completion of the 8th induction cycle pts proceeded to risk-stratified maintenance therapy. Maintenance consisted of 28-day cycles of therapy with Len on days 1-21 for all patients, while those pts defined as high-risk also received SC bortezomib Bz on days 1 and 15. Patients remained on maintenance therapy until progression, unacceptable toxicity, or withdrawal from protocol-directed treatment. Response was based on the IMWG uniform criteria (Rajkumar et al. Lancet Oncol 2011) and toxicities were graded based on the NCI-CTCAE V4. Correlative samples of blood and bone marrow for genomics and proteomics were collected from baseline and then throughout the study, and are currently being analyzed. Results: Forty-five pts were enrolled across 8 US sites between December 2015 and June 2017. Median age at enrollment was 61 years (range: 43 to 79) and 60% of the patients were male, 40% female. FISH cytogenetics found del 17p in 8% of pts tested, t(14;16) in 9%, and t(4;14) in 14%. At baseline, 60% of pts were ISS II/III. High risk pts comprised 62% of the study population overall. 80% of pts (36/45) collected stem cells and 31% of pts (14/45) continued to ASCT. The median number of CD34+ stem cells collected was 9.67 x 10^6. The median number of induction cycles completed was 8 (1 to 8 cycles) and 43 of 45 pts were evaluable for the primary endpoint of response after 4 induction cycles, with preliminary results indicating an ORR of 91% (39/43). Three pts did not reach the end of cycle 4 and 1 patient had stable disease. ORR at any point up to the beginning of maintenance was 98% (42/43). Any grade PN was reported by 80% of patients, including 38% with grade 1 and 36% with grade 2 PN. There were two cases of Grade 3 PN and one case of Grade 4 PN. Among the three patients with Grade ≥ 3 PN, symptoms improved to Grade ≤ 2 with dose reduction, modification of treatment schedule, or discontinuation of Bz. Importantly, given the higher than expected rate of all and high-grade PN, hydration with IV normal saline 500-1000 ccs prior to Bz administration as part of supportive care in selected patients was instituted and a comprehensive evaluation of the impact of this intervention on PN is in process. Conclusions: The combination of RVD with SC Bz is a highly effective treatment regimen for patients with newly diagnosed MM, including high risk pts. However, rates of all- and high-grade PN were greater than expected despite the use of SC Bz. Prompt dose reduction and/or change in schedule of Bz administration to weekly administration is recommended, with careful attention to supportive care in order to further improve tolerability. Disclosures Rosenblatt: Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Farber:Charles M. Farber, MD, PhD, LLC-Medical legal consulting: Consultancy; Gilead: Honoraria; Genentech: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; ummit Medical Group-MD Anderson Cancer Center: Employment; BeiGene: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Speakers Bureau; Acerta: Research Funding. Ghobrial:Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: BACKGROUND: Patients (pts) with relapsed hematologic malignancies (HM) after alloHCT are a unique population, given the potential to harness a dormant graft-vs.-tumor effect therapeutically. We previously reported that CTLA-4 blockade with ipilimumab was feasible and active in this population (Davids et al., N Eng J Med, 2016). In retrospective studies, anti-PD1 antibodies were active in pts with relapsed lymphoid malignancies after alloHCT, though with substantial toxcity due to GVHD (Herbaux et al. and Haverkos et al., Blood, 2017). Here, we report on the first prospective clinical trial of PD1 blockade in pts with relapsed HM after alloHCT. METHODS: The primary objectives in this ph I/Ib, multicenter, investigator-initiated, CTEP-sponsored study (CTEP 9204) were to determine MTD and evaluate safety of nivolumab (nivo). Secondary objectives were to assess efficacy and immunologic correlates. Pts with any HM with relapse or persistent disease after alloHCT were eligible. Nivo was initially given to a 1 mg/kg cohort, with planned escalation to a 3 mg/kg cohort or de-escalation to a 0.5 mg/kg cohort depending on toxicities. Nivo was dosed q2 wks until progression or unacceptable toxicity, and disease-specific response evaluations were q4 cycles. RESULTS: A total of 28 pts with relapsed HM after alloHCT were treated. Median age was 57 (range 27-76), and pts had the following HM: AML (n=11), MDS (n=7), Hodgkin lymphoma (HL, n=5), non-Hodgkin lymphoma (NHL, n=3), MPD and CLL (n=1 each). Median number of prior therapies was 2 (range 1-9), and 18/28 (64%) had progressed after at least 1 prior therapy for relapse post alloHCT. The median time from alloHCT to study enrollment was 21 mo. (range 5.7-174 mo.). Six pts were treated initially with nivo 1 mg/kg. Two immune-related adverse events (irAEs) resulted in DLTs, including one pt with sepsis and fatal ARDS, and one pt with new anti-phospholipid antibodies and a fatal thrombotic cerebral vascular accident. Other irAEs included gr3 pneumonitis and transaminitis (n=1 each). One pt had cGVHD (NIH mild). Response was observed in 3/6 pts, including 1 CR (PMBCL) and 2 PR (HL and CMML). Due to the toxicities at 1 mg/kg, a cohort of 8 pts was then treated with nivo 0.5 mg/kg, which was generally well-tolerated, with no DLTs. A phase Ib expansion cohort then accrued 14 more pts at 0.5 mg/kg. Accrual was terminated after 14 pts were treated due to meeting the protocol-defined stopping rule of ≥4 DLTs in the first 15 pts in this cohort. These DLTs included 2 cases of grade III acute GVHD (liver and gut) as well as gr3 elevated bilirubin (n=1) and gr3 transaminitis (n=1) which did not recover to ≤gr1 within 4 wks. The 2 pts with liver dysfunction without histological evidence of GVHD eventually improved, but both pts with GVHD died due to complications from GVHD. Other toxicities included gr4 lipase elevation, gr3 rash, gr3 transaminitis, gr3 orthostatic hypotension, and gr2 seizure in a pt with a known seizure disorder (n=1 each). In the 22 pts treated at nivo 0.5 mg/kg, 10 pts (45%) had new onset or worsening of GVHD, including 1 with aGVHD only, 7 with cGVHD only (3 of whom had baseline cGVHD), and 2 with both acute and cGVHD. Shorter time from alloHCT was significantly associated with higher risk of developing GVHD (p=0.019). The overall response rate in the 19 evaluable pts treated at nivo 0.5 mg/kg was 16%, including 1 pt with HL with CR and 1 pt each with HL and AML achieving PR. Nine pts had stable disease for at least 1 response evaluation, and 7 pts had progressive disease as best response. Studywide, the overall response rate was 24% (6/25), the median number of cycles received was 3 (range 1-25), and 12/28 (43%) had at least 1 dose delay due to toxicity. With a median follow-up of 3.9 mo. (range 1.4-20.9 mo.), the 6 mo. PFS and OS were 39% and 61%, respectively. CONCLUSIONS: In this first prospective clinical trial of an anti-PD1 antibody for relapsed HM post-alloHCT, severe GVHD and irAEs occurred, even at the lower dose of nivo 0.5 mg/kg, leading to early closure due to toxicity. Modest anti-tumor activity was observed mainly in lymphoid malignancies known already to be responsive to anti-PD1 therapy, which may justify further exploration of anti-PD1 therapy in those populations in trials with strategies to mitigate toxicity; however, given the more favorable safety and efficacy profile of anti-CTLA-4 therapy in other HM, our future studies focus on combining ipilimumab with novel partners to improve outcomes. Disclosures Davids: Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; BMS: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Costello:Celgene: Consultancy; Takeda: Consultancy; Poseida Therapeutics, Inc.: Research Funding. Herrera:Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Takeda Pharmaceuticals: Consultancy. Nikiforow:Kite Pharma: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Wu:Neon Therapeutics: Equity Ownership. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Purpose: This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). The overarching objective of this trial is to determine progression free survival to symptomatic myeloma (MM). Furthermore, the study examined the activity and safety of the combination therapy in patients with high-risk SMM. Patients & Methods: Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. An initial cohort of patients were randomized to a low dose dexamethasone treatment arm (Arm B) based on the following stratification factors: age 〉65 years and high-risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation, and +1q amplification. For cycles 3-8, patients on both treatment arms were administered elotuzumab infusions on days 1, 8, and 15. Patients on treatment Arm A received dexamethasone (40mg) on days 1, 8 and 15. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients on both treatment arms were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28 day cycle. After 11 patients were enrolled on each arm, arm B closed due to similar activity and toxicity to the high-dose dexamethasone arm based on published data demonstrating that high-dose dexamethasone, given once a week, does not have a detrimental effect on the immune system in patients with smoldering myeloma. Results: In total, 39 patients were enrolled on this study from January 2015 to date, with the participation of eight sites. The median age of patients enrolled was 62 years (range 26 to 75) with 15 males (38%) and 24 females (62%). The median number of cycles completed is 6 (range 1 to 19). Therapy related grade 3 toxicities included hypophosphatemia (23%), neutropenia (8%), infection (8%), anemia (3%), pulmonary embolism (3%), rash (3%), and diarrhea (3%). No related grade 4 or 5 toxicities have occurred thus far. Stem cell collection was successful in all patients collected to date. Unrelated toxicities include one instance of grade 4 prolonged QTc Interval. Of the 34 evaluable patients enrolled to both arms of the study, the clinical benefit rate is 97%. The overall response rate is 71%, including 9 very good partial responses (26%) and 15 partial responses (44%). The VGPR cases are currently under evaluation of possible complete responses due to the potential interference of elotuzumab with immunoelectrophoresis. Thus far, no patients have progressed to active multiple myeloma during, or after, protocol therapy. Conclusion:The combination of elotuzumab, lenalidomide, and dexamethasone is very well tolerated among patients with high-risk SMM. The high response rates among this patient population, who would otherwise remain untreated, is a promising starting point for the paradigm shift towards early therapeutic intervention in patients with high-risk SMM. Disclosures Ghobrial: Amgen: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Rosenblatt:Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding. Usmani:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Array: Research Funding; Novartis: Speakers Bureau; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Description: Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.