ALBERT

Description: BACKGROUND: Peripheral blood progenitor cell (PBPC) mobilization strategies vary considerably. Optimization of this critical aspect of autologous hematopoietic stem cell transplantation (ASCT) requires efficient use of resources including apheresis kits, machine run time, nursing and cell processing time and consumables. Equally important is the patient experience, which is strongly influenced by collection days and caregiver time that reduces their economic productivity and raises their expenses. We developed a mobilization algorithm designed to collect the target number of cells on day 1 of collection. The algorithm utilizes pre-emptive day 4 plerixafor to maximize collection day peripheral blood (PB) CD34+ cell numbers. METHOD: We analyzed data on all patients with multiple myeloma undergoing PBPC mobilization between March 2014 and July 2016. All patients were mobilized with the intent of collecting sufficient numbers of progenitor cells to permit two ASCT procedures. Patients received filgrastim 10 mcg/kg daily x 4 days. Patients in whom the PB white blood cell (WBC) count was 〈 50K/uL on day 4 received an extra dose of filgrastim that evening and plerixafor at 0.24 mg/Kg (Figure 1) or a fixed dose of 12mg (Figure 2) if the PBCD34 was 〈 50/uL. A fixed dose was administered if a patient could be paired with another patient simultaneously undergoing PBPC mobilization. The number of days of apheresis, run time, collection efficiency (CE2) and other relevant variables were analyzed and compared between the standard and fixed dose cohorts. We defined successful mobilization as ≥ 8 million CD34+ cells/Kg (based on our institutional ideal dose of 4 million CD34+ cells/Kg for a single ASCT), optimal mobilization as ≥ 6 million CD34+ cells/Kg (based on the International Myeloma Working Group (IMWG) recommended minimum dose of 3 million CD34+ cells/Kg for an ASCT), suboptimal mobilization as ≥ 2 million but 〈 6 Million CD34+ cells/Kg, and mobilization failure as 〈 2 million CD34+ cells/Kg. RESULTS: We identified 105 patients with MM. Median age was 61 years (range, 25 - 76) and 57% were female. Disease status at mobilization included: 7 CR, 14 stringent CR, 5 unconfirmed CR, 52 very good PR (VGPR), and 27 PR. The median day 4 PBCD34+ cell number was 19.9/uL (range, 0.8 - 118.7/uL), and median day 5 PBCD34+ count was 107.8/uL (range, 15.6 - 307.8/uL). Ninety percent of patients required plerixafor of which 16% (n = 17) received the 12 mg fixed dose. The median increase in day 4 to day 5 PBCD34+ cell count for patients receiving plerixafor was 6.6 fold (range, 1.5 - 56.4 fold). In patients not receiving plerixafor, the median increase was 1.8 fold (range, 1.5 - 2.6 fold). The median collection yield was 10.95 million CD34+ cells/Kg (range, 2.9 - 22.5 million CD34+ cells/Kg) no significant difference between patients who received standard dose or fixed dose plerixafor. By the criteria outlined above 96.2% of patients had an optimal mobilization i.e. ≥ 6 million CD34+ cells/Kg sufficient for 2 ASCT procedures with 94.2% achieving this with only 1 day of collection. Per our institutional criteria, 71.4% achieved a successful collection (〉 8 million CD34+ cells/Kg) in 1 day. There was no significant difference in days of collection among patients receiving 4 or less cycles of lenalidomide versus those receiving more than 4 cycles (p value = 0.104). The median duration of collection was 399 minutes (range, 180 - 495 minutes) with a median collection efficiency (CE2) of 42.3%. The mean number of days of collection was 1.23 days (range, 1 - 2 days). The median transplanted CD34+ cell dose was 5.48 million CD34+ cells/Kg. All patients had hematopoietic recovery with median neutrophil and platelet engraftment of 11 days and 18 days, respectively. CONCLUSION: The pre-emptive use of plerixafor on day 4 is effective and results in a high percentage of optimal day 1 collections. The cost of a more liberal plerixafor algorithm is offset by the savings incurred from reduced collection day numbers with the majority of patients requiring only 1 day of collection. Cost savings include limiting days away from work and family for the patient and caregiver and decreasing expenses for travel and overnight stays. Reducing collection day numbers also reduces the impact on quality of life for patients, caregivers and family members. Collectively, these data demonstrate utility of the pre-emptive day 4 plerixafor-based mobilization algorithm described here. Disclosures Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Jacobs:Magellan Health: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau. Bhutani:Onyx, an Amgen subsidiary: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Oncology: Research Funding, Speakers Bureau; Prothena: Research Funding. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Description: JNJ-4528 is a chimeric antigen receptor T cell (CAR-T) therapy containing two B-cell maturation antigen (BCMA)-targeting single-domain antibodies designed to confer avidity. We present translational data from the phase 1b cohort of an ongoing phase 1b/2 study conducted in the US to explore the safety and efficacy of JNJ-4528 in patients with R/R MM (NCT03548207). Apheresis samples were collected from 25 patients, and T cells were selected and transduced with a lentivirus encoding the BCMA CAR construct. Immune cell composition of both the apheresis samples and transduced cells following expansion ("drug product" [DP]) was evaluated by multiparametric flow cytometry. The median proportion of CAR+ T cells in the DP was 16% (range 6-28%) of total cells, with a median proportion of 12% (range 4-22%) CD4+ CAR+ and 7% (range 3-20%) CD8+ CAR+ T cells. The CD4:CD8 ratio of CAR+ T cells in the DP was variable between patients, with a median of 1.5 (range 0.62-4.40). Significant variability between patients was observed in the composition of the DP regarding T cell subsets (i.e., naïve, Tscm, Tcm, Tem, Teff, Temra) although this profile was comparable in the CAR- and CAR+ T cell subpopulations within each patient. Patients were administered a single infusion of the JNJ-4528 DP at a target dose of 0.75x106 CAR+ T cells/kg (target range 0.5-1.0x106). Of the 21 patients with a postbaseline disease evaluation, the overall response rate was 91% at a median follow-up of 3 months (range 1-10). Among the 15 patients with post-infusion day 28 evaluable bone marrow (BM) samples by next generation flow cytometry and/or next generation sequencing, 10 were minimal residual disease negative at the 10-5 level of sensitivity, 2 at 10-4 level of sensitivity, and 3 had unidentified clones. All patients expressed BCMA in BM tumor cells at baseline, as assessed by flow cytometry, although levels varied among patients. Clinical responses appear independent of BM BCMA expression. Following infusion, CAR+ T cells expanded reaching a peak between 20-87% of the total T cells in blood between days 10-14 post-infusion. The CD4:CD8 ratio and the proportion of T cell memory subsets in the final DP did not correlate with peak CAR+ T cell expansion. Peak CAR+ T cell expansion did not correlate with response. Ten patients had a follow-up of enumeration of CAR+ T cells in blood of at least 8 weeks. In 5 patients, CAR+ T cells decreased to below the limit of quantification (BLOQ) of the flow cytometry assay (5 cells/µl) within 8 weeks (range 2-7) post-infusion. Although preliminary, no difference was observed in the response rate between these patients compared with patients with measurable CAR+ T cells after 8 weeks. A similar trend was observed when expansion and persistence were assessed by measuring transgene levels. While both CD4+ and CD8+ CAR+ T cells expanded in vivo, the CD4:CD8 CAR+ ratio decreased at peak expansion compared with the final DP (from a median of 1.35 to 0.35), indicating a preferential expansion of CD8+ CAR+ T cells in blood. At peak expansion, CD8+ CAR+ T cells showed predominantly a central memory (Tcm) phenotype (CCR7+ CD45RO+; median of 90% [range 29.3-98.5%]). In contrast, CD4+ CAR+ T cells were enriched in effector memory (Tem) cells (CCR7- CD45RO+; median of 87% [range 69.5-98.1%]) at peak expansion. A similar trend in the CD4:CD8 ratio, as well as the T cell memory subset composition, was observed in BM of all 11 patients with evaluable samples at day 28. CD8+ CAR- T cells showed an approximate 50:50 ratio of stem memory (Tscm):Tcm subsets while CD4+ CAR- T cells showed an approximate 50:50 ratio of Tcm:Tem subsets, indicating a differential T cell maturation course for CD4+ and CD8+ CAR+ and CAR- T cells. Expansion of CAR+ T cells correlated with increases in serum cytokines levels (i.e., IL-6, IFNγ, IL-10) which peaked around day 10, coinciding with maximal expansion of CAR+ T cells. Generally, increases in some proinflammatory cytokines (i.e., IL-6) correlated with onset of cytokine release syndrome symptoms (median time to onset of 7 days [range 2-12]). Findings from the ongoing CARTITUDE-1 trial suggest that JNJ-4528 is a differentiated CAR-T cell therapy that is highly active at a relatively low dose, potentially related to a preferential and consistent in vivo expansion of CD8+ CAR+ T cells displaying a central memory phenotype. Disclosures Zudaire: Janssen R&D: Employment, Equity Ownership. Madduri:Foundation Medicine: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Patents & Royalties, Research Funding; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Skyline DX: Consultancy; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau. Jakubowiak:Adaptive Biotechnologies: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Geng:Legend Biotech: Employment, Equity Ownership. Rizvi:Legend Biotech: Employment, Equity Ownership. Nesheiwat:Legend Biotech: Employment, Equity Ownership. Schecter:Janssen R&D, LLC: Employment, Equity Ownership. Goldberg:Janssen R&D: Employment, Equity Ownership. Banerjee:Janssen R&D: Employment, Equity Ownership. Allred:Janssen R&D: Employment, Equity Ownership. Singh:Janssen R&D: Employment, Equity Ownership. Verona:Janssen R&D: Employment, Equity Ownership. McCaffery:Janssen R&D: Employment, Equity Ownership. Jagannath:Celgene Corporation: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Merck & Co.: Consultancy.

Description: Introduction: Daratumumab (DARA) is a human IgGκ mAb targeting CD38 with both direct on-tumor and immunomodulatory mechanisms of action, and has been approved as monotherapy for RRMM and in combination with standard of care (SOC) regimens for RRMM and newly diagnosed MM (NDMM). Across three phase 3 DARA studies in RRMM and NDMM, DARA plus SOC reduced the risk of progression or death by ≥50%, enabled a doubling of CR rates, and elicited a ≥3-fold increase in MRD-negative rates. Among MRD-negative RRMM pts, pts treated with D-Rd or D-Vd rapidly achieved MRD negativity and demonstrated prolonged progression-free survival (PFS) vs MRD-positive pts (Avet-Loiseau H, et al. ASH 2016. Abstract 246). MRD assessment is being investigated as a potential surrogate for established endpoints such as overall survival (OS). When measured sequentially, sustained MRD-negativity provides an index of deep clinical responses that may provide a more robust assessment of disease control (Kumar S, et al. Lancet Oncol 2016. 17[8]:e328-e346). Here, we evaluate sustained MRD negativity with DARA plus SOC regimens and its association with PFS/OS outcomes in RRMM. Methods: Eligible pts in POLLUX and CASTOR received ≥1 prior line of therapy and were randomized (1:1) to receive SOC treatment regimens ± DARA. Pts in the POLLUX study were given lenalidomide (25 mg PO) on Days 1-21 and dexamethasone (40 mg) once per week in each 28-day cycle ± DARA (16 mg/kg IV) given weekly for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. CASTOR pts received 8 cycles (21 d/cycle) of bortezomib (1.3 mg/m2 SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± DARA (16 mg/kg IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. MRD was assessed at the time of suspected CR and at 3 and 6 months following confirmed CR in POLLUX, and at time of suspected CR and 6 and 12 months following the first treatment dose in CASTOR. Additional MRD evaluation was required in both studies every 12 months post-CR. MRD was assessed via next generation sequencing using the clonoSEQ® assay V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as the maintenance of MRD negativity in the bone marrow confirmed ≥6 or ≥12 months apart and was evaluated in the intent-to-treat (ITT) population. Sustained MRD negativity was also evaluated among ≥CR pts to account for different sustained MRD negativity rates between treatment arms. Results: A total of 569 (D-Rd, n = 286; Rd, n = 283) pts in POLLUX and 498 pts (D-Vd, n = 251; Vd, n = 247) in CASTOR were randomized; median (range) number of prior lines received was 1 (1-11) and 2 (1-10), respectively. Median duration of follow up was 39.5 months in POLLUX and 31.3 months in CASTOR for this analysis. Using the ≥6-month sustained MRD cutoff, a significantly higher proportion of pts achieved sustained MRD negativity for ≥6 months when treated with D-Rd vs Rd (16% vs 0.7%; P

Description: Background: Proteasome inhibitors (PIs) are important agents against myeloma, but innate and acquired resistance limit their effectiveness. We previously found Tight junction protein (TJP)-1 to be a modulator and potential biomarker of PI sensitivity, via studies of bortezomib resistant models and clinically annotated gene expression profiling (GEP) databases of patient samples. Also, we showed that its expression reduced EGFR/JAK1/STAT3 pathway activation and proteasome capacity. However, the molecular mechanisms by which TJP1 expression suppressed EGFR signaling and enhanced PI sensitivity were not understood. Methods: We performed co-immunoprecipitation (co-IP) studies to understand interactions of TJP1 with EGFR, and evaluated the impact of various cytokines on proteasome capacity. Also, genetic and pharmacologic approaches were used to modulate EGFR/JAK/STAT activity to determine the effects on PI sensitivity. Finally, gene set enrichment analyses (GSEA) were performed to determine if EGFR activation signatures could be identified in primary samples, and if they correlated with outcomes. Results: Previous studies of TJP1 focused on myeloma models, but since bortezomib is also approved for mantle cell lymphoma, we sought to determine if TJP1 influenced sensitivity here as well. Suppression of TJP1 using shRNAs reduced the sensitivity of JeKo-1 and MINO cells to bortezomib. In addition, murine embryonic stem cells (mESCs) with TJP1 knockout were more resistant to PIs than was the case for wild-type mESCs. Moreover, the TJP1 knockout mESCs expressed higher levels of both activated EGFR and immunoproteasome subunits PSMB8 and 9, and had greater levels of proteasome chymotrypsin-like (ChT-L) activity. Also, re-introduction of TJP1 into the knockout mESCs ehanced their PI sensitivity, and reduced the ChT-L activity. Co-IP studies showed that IP of TJP1 also led to detection of EGFR, and vice versa. Phospho-specific antibodies showed that TJP1 precipitated predominantly the non-phosphorylated, inactive EGFR. Indeed, when cells were treated with EGF and extracts were subjected to IP for TJP1, reduced levels of EGFR were precipitated. Evaluating other receptor tyrosine kinases, we found that TJP1 precipitated IGF-1R but not IL-6R. Therefore, we treated myeloma cells with EGF, IL-6, or IGF-1; all reduced PI sensitivity, but only EGF enhanced proteasome ChT-L activity and capacity. Moreover, shRNA-mediated EGFR knockdown, or pharmacologic inhibition with erlotininb in myeloma cells reduced JAK1/STAT3 activity, levels of PSMB8 and 9, and ChT-L activity, and enhanced the activity of bortezomib. Since the PSMB8 and PSMB9 promoters have consensus STAT3 binding sites, we knocked down STAT3 and found that this also reduced PSMB8 and 9 and ChT-L activity, and enhanced the efficacy of bortezomib. In a mouse model of lytic bone destruction by xenografted RPMI 8226 cells, the ability of bortezomib to increase bone trabecular volume was blunted by TJP1 suppression, consistent with a lower anti-myeloma effect. Lastly, we used publically available EGF-stimulated and EGFR inhibitor gene signatures to examine the clinically annotated GEP data from myeloma patients. This showed that: 1) TJP1 expression in myeloma samples from patients on the University of Arkansas Total Therapy studies was positively correlated with known signatures of inhibitors of EGFR signaling; 2) in GSEA, signatures of EGF and EGFR signaling were significantly positively enriched when genes were ranked by correlation with TJP1; and 3) an EGFR-related gene set had significant negative correlation with survival duration in the Total Therapy 3 dataset. Conclusions: Taken together, our data support the role of TJP1 as a negative regulator of EGFR signaling through its ability to specifically bind, and possibly stabilize the non-phosphorylated form of EGFR. Furthermore, they demonstrate that TJP1 influences proteasome capacity through EGFR/JAK/STAT signaling, and that approaches to suppress this pathway hold promise to overcome PI resistance and achieve PI sensitization. Finally, they validate a heretofore underappreciated role for EGF/EGFR signaling in myeloma pathobiology and patient outcomes. Disclosures Mulligan: Millennium Pharmaceuticals: Employment. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Advances in novel agents and treatment combinations have improved prognosis and increased disease-free and overall survival for patients (pts) with multiple myeloma (MM). However, currently available data on disease presentation, treatment patterns, and outcomes for real-world MM pts at the global level are limited. This is due to several factors, including the overrepresentation of medically fit pts in clinical trials making generalization of outcomes challenging, the large number of treatment combinations, and varying global access/practice patterns. INSIGHT-MM (NCT02761187) is a global, prospective, non-interventional, observational study which aims to further understand disease and pt characteristics at presentation, treatment and clinical outcomes of real-world MM pts, as well as the association of treatment with tolerability, effectiveness, health-related quality of life (HRQoL), and healthcare resource utilization (HRU), on both a country-specific and global basis. As this is an observational study, no formal hypothesis will be tested. The INSIGHT-MM objectives are summarized in the Table. At least 5000 pts aged ≥18 yrs with newly diagnosed or relapsed/refractory MM will be enrolled over a 3-yr period and followed prospectively for ≥5 yrs, until death or end of study, whichever comes first. Pts not available for data collection for 〉9 mos will have follow-up for survival. No study drug or medications will be provided; no modification of standard of care pt management will be assigned per protocol. Choice of therapy for all pts will be decided by the treating healthcare provider independent of study participation. Baseline pt and MM-specific characteristics, diagnosis, comorbidities, and prior therapies will be recorded based on review of hospital/clinic records. MM management, disease status and safety data will be obtained as part of routine office visits and recorded quarterly by each site in electronic case report forms. Quarterly assessment of MM management will be done based on prior and current treatment and recorded reason for treatment changes. Effectiveness of therapy will be assessed based on response, progression status, time to next therapy, vital status, and date and cause of death. Treatment tolerability will be assessed based on serious and non-serious adverse events leading to treatment discontinuation or dose modification. Incidence of second primary malignancies will be recorded. HRQoL, a specific type of patient reported outcome (PRO), will be collected at study entry and at predefined intervals following initiation of therapy using a secure electronic data collection system. HRQoL will be collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the MM module (EORTC QLQ-MY20). To capture pt satisfaction with MM-directed therapy, including the dimension of convenience, the 9-item Treatment Satisfaction Questionnaire for Medication will be used. The 5-dimension, 5-level EuroQol (EQ-5D-5L) PRO instrument will capture self-reported preference-based measures of health status suitable for calculating quality-adjusted life year (QALY) data to inform health economic evaluations. Frailty will be assessed using the Charlson Comorbidity Index, the Katz Index of Independence in Activities of Daily Living, and the Lawton Instrumental Activities of Daily Living. HRU will be evaluated using inpatient and intensive care unit admissions, length of stay, outpatient clinic visits, and emergency room visits. Data for all participating pts will be extracted by healthcare professionals at the site level and entered into a central database; descriptive statistical analyses will be done to address the study objectives. Interim analyses are planned after 1000 and 5000 pts have been enrolled and a final analysis will be conducted within 1 year after the last pt entered has completed ≥5 yrs follow-up. Data will be analyzed biannually to address emerging clinical questions identified by investigators to increase understanding of real-world treatment patterns. INSIGHT-MM aims to promote better understanding of contemporary demographics, patterns of care, and outcomes for real-world MM pts to inform treatment practice, supportive care, and pt outcomes. The study is currently ongoing and recruiting pts; further details regarding study rationale and protocol will be provided. Table 1 Table 1. Disclosures Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Zonder:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Girnius:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Array: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: 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; Onyx: 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; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Omel:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Member of Takeda's "Patient Leadership Council". Token payment. Thompson:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: MDS/AML Registry; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AIM Specialty Health: Membership on an entity's Board of Directors or advisory committees; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Multiple Myeloma International Registry; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shah:Array: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schwartz:Bayer: Consultancy; Blue Cross and Blue Shield Associations: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Hungria:Takeda: Consultancy; Roche: Consultancy; International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy; Amgen: Consultancy. Mateos:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Pashos:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Cacioppo:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Yu:Takeda Restricted Stock Unit (RSU), a publicly traded company: Equity Ownership; Takeda Development Center Americas, Inc., Deerfield, IL, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Luptakova:Takeda Oncology: Employment. Niculescu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Noga:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Chari:Array Biopharma: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Description: Introduction: Daratumumab (DARA) is a human monoclonal IgG1κ CD38-targeting antibody that functions through several mechanisms of action (MOA), including CDC, ADCC, ADCP and induction of apoptosis. An additional, novel role of immune modulation and increased adaptive immune response was revealed from translational studies of DARA (16 mg/kg) in single-agent, phase 1/2 studies (SIRIUS [MMY2002] and GEN501; Krejcik J et al, Blood 2016;128:384-94). To further explore the ability of DARA to promote adaptive T-cell responses, we profiled T-cell repertoires (TCR) to evaluate T-cell clonality, expansion, and diversity from samples collected in POLLUX (MMY3003), a phase 3, randomized, open-label, multicenter study for patients with relapsed/refractory MM, in which DARA was tested in combination with lenalidomide plus dexamethasone versus lenalidomide plus dexamethasone alone (DRd vs. Rd; Dimopoulos MA et al, N Engl J Med 2016; in press). Methods: T-cell receptor beta (TCRβ) sequencing for repertoire profiling was conducted on whole blood samples collected at baseline and eight weeks after DARA treatment (cycle 3 [C3]) from subjects on both arms using the ImmunoSEQ assay (Adaptive Biotechnologies. Seattle, WA, USA). 133 subjects in DRd and 124 subjects in Rd treatment groups were included in this analysis and represented a balanced subgroup of the POLLUX clinical trial subjects. T-cell metric changes were compared between arms with ANOVA, including the treatment arm and visit interaction term. Within treatment-arm changes were evaluated with a Wilcoxon signed-rank test comparing baseline to on-treatment values per patient. Results: Consistent with the randomized treatment groups, no baseline differences were observed in T-cell repertoire metrics between the treatment arms, including T-cell clonality, diversity (or richness), and T-cell fraction. Similar to prior findings from DARA monotherapy studies, significantly larger increase of TCRβ clonality was observed in the DRd arm (median of 0.166 at baseline to 0.263 at C3). Interestingly, there was no increase in TCRβ clonality in the Rd arm (median of 0.175 at baseline to 0.175 at C3). The change in TCRβ clonality between C1 and C3 was significantly different between DRd and Rd (p=3.26E-10), demonstrating that the addition of DARA to Rd induces a specific clonal expansion of T cells. Estimated richness (diversity), on the other hand, slightly decreased with DRd treatment but not with Rd treatment (median of 503,951 at baseline to 427,096 at C3 [p= 1.01E-04] vs 572,182 to 532,806 [p= 3.58-01]). Among patients in both treatment groups, a bigger increase in T-cell fraction was observed in DRd vs Rd (median of 0.231 at baseline to 0.278 at C3 [p= 2.62E-3] vs 0.228 to 0.249 [p= 1.91E-01]). Although there were no significant differences in baseline characteristics in T-cell clonality, richness, and T-cell fraction, quartile analysis demonstrated that high baseline TCR richness predicted for better PFS with DRd but not for Rd. Conclusion: DARA in combination with lenalidomide plus dexamethasone specifically induced robust increases in T-cell clonality, which was not observed within the control lenalidomide plus dexamethasone arm. Interestingly, baseline TCR richness was associated with improved PFS in DRd subjects. This observation is similar to results with immune checkpoint inhibitors (Postow MA et al, J Immunother Cancer 2015;3:23), and together with the significant increase in T-cell clonality, provides further evidence for the immunomodulatory activity of DARA, even in combination therapy. These data support DARA's immune-modulatory MOA and provide additional insights into DARA's effect on the TCR in combination with standard of care treatment. Figure Figure. Disclosures Chiu: Janssen: Employment. Casneuf:Janssen R&D, Beerse, Belgium: Employment; Johnson & Johnson: Equity Ownership. Axel:Janssen Pharmaceuticals Research and Development: Employment. Lysaght:Immuneering Corp: Employment; Janssen: Research Funding. Bald:Janssen: Employment. Khokhar:Janssen: Employment. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding. Goldschmidt:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: 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, Research Funding; 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Ahmadi:Janssen: Employment. Chan:Adaptive Biotechnologies: Employment; University of Washington: Other: Visiting scholar. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment.

Description: BACKGROUND: The immune system plays an essential role in both promoting and inhibiting the growth of MM. Loss of anti-myeloma immunity involves altered activation and polarization of effector cells as well as immunosuppressive cytokines. Immune dysfunction associated with MM can be partially or totally reversed when patients achieve clinical remission. Detection of MRD has become an achievable goal in MM, and is a powerful predictor of progression-free survival and overall survival. We hypothesized that the immune profile of MRDpos patients is distinct from MRDneg patients. PATIENTS AND METHODS : We studied peripheral NK, NK-T and T cell distribution/activation, and measured bone marrow MRD status by flow cytometry in 30 newly diagnosed MM patients 60+ days after ASCT. Patients were divided in 2 groups based on κ/λ ratio and MM-plasma cell (MM-PC) distribution: MRDneg (n=6), with κ/λ ratio ≤1.8 and MM-PC≤15 per million or MRDpos (n=24), with MM-PC〉15 per million. Plasma was also collected from 17 of these patients (5 MRDneg and 12 MRDpos) 60+ days after ASCT to quantify inflammatory cytokines, chemokines and growth factors by multiplex protein assay. Linear regression was used to determine association between each tested variable (25 by flow cytometry and 27 by multiplex protein assay) and MRD status. Unsupervised hierarchical cluster analysis was then applied to post-ASCT samples with selected variables that were differentially expressed between MRDneg and MRDpos patients (p

Description: Background Multiple groups of pts, including elderly/frail pts and those with comorbidities, are typically under-represented in randomized controlled trials (RCTs). A recent study found an average of 16 eligibility criteria per cancer trial, 60% of which were related to comorbidity or performance status (PS; Unger, JNCI 2014). Phase 3 RCTs in MM have similar extensive eligibility criteria, resulting in populations that are not reflective of RW MM pts. Data from CONNECT-MM (Shah, CLML, 2017) and CoMMpass (Fiala, IMW 2017) suggest that 22-40% of RW pts are ineligible for MM RCTs, and an analysis of US RW relapsed/refractory MM (RRMM) pts showed that only 25-47% of pts would have been eligible for the phase 3 ASPIRE, TOURMALINE-MM1, ELOQUENT-2, and POLLUX studies, based on their differing eligibility criteria (Chari, EHA 2018). Further, data from CONNECT MM show that clinical trial ineligibility is associated with poorer long-term outcome (Shah, CLML, 2017). Thus, it is important to characterize RW MM pts and understand the discrepancies vs RCT populations. INSIGHT MM (NCT02761187) is the largest prospective, observational study in MM to date, following ~4,200 pts from 15 countries. Here we analyze RCT eligibility in INSIGHT MM pts, with a focus on the treatment of frail MM pts in the real world. Methods INSIGHT MM is following newly diagnosed (≤3 mos since treatment initiation) MM (NDMM) and RRMM (≤3 prior lines) pts. Demographics and disease characteristics, including medical history, comorbidities, PS, and frailty status (per IMWG Frailty Index criteria, Palumbo, JCO 2015), are collected using electronic case report forms at study baseline visit. For this analysis, pt data were reviewed vs 20 standard RCT eligibility criteria, using a conservative approach of classifying 'not available' data as 'eligible'; laboratory/PS and medical history exclusion criteria are summarized in the Table. Presence of hypertension was reviewed but omitted, as INSIGHT MM only collected data on 'hypertension requiring treatment' vs the standard RCT exclusion criterion of 'uncontrolled hypertension'. Results Data from 3,201 pts (1,761 NDMM, 1,440 RRMM) were analyzed. The proportions of pts who would be ineligible for RCTs based on each individual parameter, and the overall rate of ineligible pts, are shown in the Table. Overall, 39.2% of pts would have been ineligible for RCTs based on not meeting at least one of the 20 standard eligibility criteria included in this analysis, including 38.8% of NDMM and 39.7% of RRMM pts. The most common criteria excluding pts overall were another prior malignancy (7.5%), CrCl ≤30 mL/min (6.4%), cardiac arrhythmias (5.4%), platelets ≤75,000/mm3 (5.1%), and hemoglobin

Description: Background Ixazomib, the first oral proteasome inhibitor, has been approved for 〉3 years in 〉70 countries, for the treatment of RRMM pts who have received ≥1 prior therapy, on the basis of the TOURMALINE-MM1 study, which reported an overall response rate (ORR) of 78% and median progression free survival (PFS) of 20.6 mos. Although outcomes and tolerability in routine clinical practice often differ from data reported in clinical trials, growing evidence suggest that outcomes in patients treated with ixazomib-based regimens are comparable to those in the Phase 3 TOURMALINE-MM1 trial. We report on an expanded pooled analysis with longer follow-up of IRd therapy from the INSIGHT MM study (NCT02761187) and the Czech Registry of Monoclonal Gammopathies (RMG) to evaluate the effectiveness of IRd in RRMM pts in routine clinical practice. Methods INSIGHT MM is a large, prospective, observational study which has enrolled over 4,200 adult pts with MM from Europe (plus Israel, EUR), the US, Asia, and Latin America, with a planned follow-up of ≥5 years. The RMG comprises clinical data for 〉6,000 MM pts enrolled at 19 Czech and 4 Slovak centers. Eligible pts had 1-3 (INSIGHT) or ≥1 prior therapy (RMG) including an IR-based regimen. Individual pt level data on demographics, disease characteristics, treatment history, effectiveness, and safety from INSIGHT and RMG were integrated and analyzed. Best response or time to first response and PFS were determined as per investigator assessment, using IMWG criteria. PFS, duration of treatment (DOT), and overall survival (OS) were estimated using Kaplan Meier (KM) methodology, applying an exclusion criterion to account for immortal time bias (INSIGHT only). Results At data cutoff of 22 Nov 2018, 217 pts (83 in INSIGHT and 134 in RMG) from 11 countries had been included: 191 (88%) from EUR, 17 (8%) from the US, and 9 (4%) from Taiwan; 89% of pts were treated in an academic facility. At diagnosis, 32% of pts had ISS Stage III disease, 78% had bone lesions, 46% had anemia, and 12% had elevated creatinine. At study start, median age was 67 years with 12% 〉75 years; 58%/14% of pts had ECOG performance status 1/2. The distribution of immunoglobulin (Ig) heavy and light chain MM was as expected; 69% of pts had IgG MM. Overall, 21% of pts had extramedullary disease. Prior therapies included: bortezomib (90%), stem cell transplant (60%), thalidomide (47%), lenalidomide (26%), carfilzomib (8%), daratumumab (6%), and pomalidomide (2%). Median time from diagnosis to start of IRd therapy was 42.1 mos; 43%/35%/22% of pts received IRd at 2nd/3rd/≥4th line. The most common reasons for starting IRd were relapse/progression (87%) and insufficient response (10%). The most common CRAB criteria present were bone lesions (48%) and anemia (18%). Median duration of follow-up was 12.6 mos in all pts. At data cutoff, 117 (54%) pts had discontinued IRd; median DOT was 11.9 (95% CI: 9.4-15.2) mos; at 12 mos, 49% (41.3-56.2) of pts were still on treatment (KM estimates). Data on best response to therapy were available for 152 pts. The ORR was 74%, with 36% ≥VGPR; ORR with IRd at 2nd/3rd/ ≥4th-line therapy was 82%/71%/59%, including 43%/37%/17% ≥VGPR. Median time to first response was 1.2 mos (RMG); median time to best response was 3.7 mos (INSIGHT). Median PFS was 21.6 (95% CI: 13.6-26.7) mos across all lines. PFS rate at 12 mos was 62%, and 86 (40%) pts had progressed at data cutoff. Median time to next therapy (TTNT) was 31.5 (95% CI: 24.5-35.9) mos, with a 12-month rate of 74% across all lines. Overall, 60 (28%) pts received subsequent therapies including daratumumab (22%), pomalidomide (22%), bortezomib (20%), carfilzomib (17%), lenalidomide (15%), and thalidomide (12%). At data cutoff, 53 (24%) pts had died. Median OS was 36.7 (95% CI: 24.4-NR) mos, with 79% of pts alive at 12 mos (Figure). Regarding safety, ixazomib and lenalidomide dose reductions were required in 16% and 36% of pts, respectively, including 10% and 21% who required dose reductions due to AEs. Conclusions These findings show that the effectiveness of IRd in routine clinical practice (ORR 74%, median PFS 21.6 mos) is comparable to the efficacy of IRd reported in the registrational TOURMALINE MM1 trial (ORR 78%, median PFS 20.6 mos). IRd is well tolerated with no new safety signals, and low rates of dose reductions due to AEs for ixazomib (10%) and lenalidomide (21%). Outcomes should be interpreted with caution due to limited maturity of data. Disclosures Hajek: Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding. Minarik:Celgene: Consultancy, Honoraria, Research Funding; Amgen, BMS, Janssen-Cilag, Takeda: Consultancy, Honoraria. Straub:Amgen, Takeda, Celgene: Consultancy. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Boccadoro:AbbVie: Honoraria; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Spencer:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Specialised Therapeutics Australia: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. van Rhee:Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; EUSA: Consultancy; Castleman Disease Collaborative Network: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Thompson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties: Myeloma reviewer; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; BMS: Research Funding; Lynx Bio: Research Funding. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: 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. Cook:Karyopharm: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Costello:Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lee:Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Puig:Takeda: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rifkin:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding. Usmani:Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Patents & Royalties, Research Funding, Speakers Bureau; Janssen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Takeda: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Patents & Royalties, Research Funding; Amgen: Consultancy, Patents & Royalties, Research Funding, Speakers Bureau; Array Biopharma: Patents & Royalties, Research Funding; Skyline DX: Consultancy. Weisel:Sanofi: Consultancy, Honoraria, Research Funding; Juno: Consultancy; GSK: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Zonder:Celgene Corporation: Consultancy, Honoraria, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Skacel:Millennium Pharmaceuticals, Inc., subsidiary of Takeda Pharmaceutical Company Limited: Employment. Elliott:Takeda: Employment. Demers:Takeda: Employment. Stull:Takeda: Employment. Ren:Takeda: Employment. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria.

Description: Background Ixazomib (ixa), the first oral proteasome inhibitor, is approved in combination with lenalidomide (len)-dexamethasone in 〉50 countries globally, including the US and EU, for the treatment of relapsed/refractory MM (RRMM) pts who have received ≥1 prior therapy. Outcomes and tolerability in routine clinical practice often differ from data reported in clinical trials for novel-agent-based MM therapies; however, data directly comparing efficacy in clinical trials with effectiveness in routine clinical practice of new MM agents and regimens are currently limited. To evaluate the effectiveness of IRd in RRMM pts in routine clinical practice, we performed a pooled analysis of individual pt-level data for IRd-treated RRMM pts from the ongoing INSIGHT MM (NCT02761187) study and from the Czech RMG. INSIGHT MM is the largest global, prospective, observational MM study conducted to date, which is currently enrolling ~4200 adult pts with newly diagnosed MM or RRMM from Europe (EUR), the US, Asia, and Latin America. The Czech RMG was established by the Czech Myeloma Group in 2007 and comprises clinical data for 〉6000 MM pts enrolled at 19 Czech and 4 Slovak centers. Methods RRMM pts with 1-3 (INSIGHT MM) or ≥1 (RMG) prior therapies who had been treated with IRd were identified. INSIGHT MM pts required prospectively collected data on IRd therapy; pts who received another regimen or additional treatment within the same line of therapy as IRd were excluded. RMG pts from Czech centers who received IRd were included using the same eligibility criteria as the INSIGHT MM study. Individual pt-level data on demographics, disease characteristics, treatment history, effectiveness, and safety for IRd-treated RRMM pts from INSIGHT MM and the Czech RMG were integrated and analyzed. Best response and PFS were determined as per the assessment of the treating physician or local investigator, utilizing IMWG criteria. Descriptive analyses were performed on the integrated data as well as on data from INSIGHT MM and from the Czech RMG. PFS, TTNT, DOT, and OS were estimated using Kaplan Meier methodology. Results Overall, 163 IRd-treated RRMM pts from 9 countries were included in the analysis (50 INSIGHT MM, 113 Czech RMG); of these, 146 (90%) were from EUR, 16 (10%) from the US, and 1 (1%) from Taiwan. Median age was 67 (range 39-84) yrs, with 23 (14%) pts aged 〉75 yrs; 86 (53%) pts were male. At initial diagnosis, 38%/36%/26% of pts had ISS Stage I/II/III disease; median time from diagnosis to initiation of IRd treatment was 42.6 mos; 71% of pts had ECOG PS ≥1. Most pts (65%) had IgG MM, and 14% had extramedullary disease. Overall, 50%/30%/20% of pts received IRd as 2nd/3rd/≥4th-line therapy. The most common reasons for starting IRd therapy were relapse/progression (90%), including bone lesions (53%), and anemia (14%). Overall, 61% of pts had received prior stem cell transplant; prior therapies included bortezomib (bor) in 89% of pts, thalidomide (thal) in 42%, len in 21%, carfilzomib (car) in 11%, daratumumab (dara) in 3%, and pomalidomide (pom) in 2%. Median DOT was 14.0 mos; 101 (62%) pts were on treatment at data cut-off. Data on best response to therapy were available for 105 pts; among these, ORR (partial response or better) was 74%, with 31% ≥VGPR (Table); ORR with IRd as 2nd/3rd/≥4th-line therapy was 91%/57%/47%, including 41%/25%/11% ≥VGPR. Median time to first response was 1.1 mos for Czech RMG pts; median time to best response was 3.7 mos for INSIGHT MM pts. Overall, median PFS was 20.9 (95% CI: 13.0-28.7) mos, with a 12-mo rate of 65% (Table). Median PFS with 2nd/3rd/4th/〉4th-line therapy was NR/23.2/14.2/5.1 mos. Median TTNT was 26.2 (95% CI: 9.6-42.8) mos, with a 12-mo rate of 73% (Table). Overall, 37 (23%) pts received subsequent therapies including bor (24%), pom (24%), thal (16%), dara (16%), car (14%), or len (8%). Median OS was not reached, with 81% of pts alive at 12 mos (Table). Ixa and len dose reductions were required in 15% and 30% of pts, respectively, with 11% and 21% of pts, respectively, requiring dose reductions due to AEs (Table). Conclusions These findings show that the effectiveness of IRd in routine clinical practice, including an ORR of 74% and a median PFS of 20.9 mos, is comparable to the efficacy of IRd reported in the TOURMALINE-MM1 trial (ORR 78%, median PFS 20.6 mos). IRd is well tolerated in RRMM pts treated in routine clinical practice, with low rates of dose reductions due to AEs for ixa (11%) and len (21%). Table. Table. Disclosures Hajek: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: 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, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Array Biopharma: Research Funding. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Puig:Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Leleu:Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Karyopharm: Honoraria. Berdeja:Celgene: Research Funding; Sanofi: Research Funding; Glenmark: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Bluebird: Research Funding; Teva: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Davies:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, 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. Hungria:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Boccadoro:Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding. Rifkin:McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; EMD Serono: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Sandoz: Consultancy; Amgen: Consultancy. Zonder:Takeda: Honoraria; Pharmacyclics: Other: DSMC; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Ren:Takeda Pharmaceuticals International Co.: Employment. Cacioppo:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Maisnar:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.