ALBERT

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. 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: Daratumumab (DARA) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with DARA in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. This is a single-arm, phase II study evaluating efficacy and safety of using DARA in patients with HR-MGUS and LR-SMM. Methods: Patients enrolled on this study met eligibility for either: 1) HR-MGUS defined as