Abstract: Microgrids with distributed generation (DG) are rapidly coming into distribution networks to supply load demand in order to preserve ecological balance and reduce greenhouse gas emissions. Power electronic advancements are making renewables dispatchable to loads while turning passive networks to active with bidirectional power flow. The IEEE-1547-2018 regulations enforced certain standards on microgrids, including the ability to detect unintended failures, island the microgrid in less than 2 seconds, and feed connected loads while maintaining voltage, frequency, and power quality. There are numerous islanding techniques accessible, including passive, active, hybrid, and communication techniques. The active techniques degrade power quality due to injection of deviations, passive type leaves larger nondetection zone (NDZ), and communication type are costly. The hybrid type combines both passive and active methods. To get away from all these issues, a passive technique is formulated in this paper, which measures the differential phase angle of voltage and current at DG output, to detect islanding. This approach reliably identifies islanding in 20 ms at nearly zero NDZ. This approach is also stable during transient conditions such as load switching and throwing off. There is also no power quality issue because there are no injections during testing. This method is tested in MATLAB/Simulink and evaluated using the differential frequency technique to get performance indices in accordance with UL-1741 testing standards.

Abstract: The addition of brivanib to cetuximab in patients with K‐ RAS wild‐type, chemotherapy‐refractory, metastatic colorectal cancer was found to shorten time to worsening of quality of life on the Physical Function and Global scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. Compared with a randomized control group receiving cetuximab and placebo, patients treated with the 2‐drug combination experienced higher rates of grade 3 or greater fatigue and gastrointestinal adverse events.

Abstract: The treatment of multiple myeloma has dramatically improved due to the availability of novel therapies that are highly effective and are quickly moving into first-line therapy. The Canadian Agency for Drugs and Technologies in Health (CADTH) recently recommended that patients who receive daratumumab should only be eligible to receive either carfilzomib or pomalidomide but not both, for relapsed MM. In order to assess the efficacy of these two agents in the relapsed setting, we utilized our national myeloma database. A total of 121 patients were reviewed, 49 patients received CAR- before POM-based (CAR-POM), and 73 patients received POM- before CAR-based (POM-CAR) therapy. In the groups selected, the median PFS was 4.93 months (95% CI, 2.76–7.07) and 5.36 months (95% CI, 3.75–6.94) for CAR-POM and POM-CAR, respectively. The median OS for patients treated with CAR-POM was 11.01 months (95% CI, 4.50–19.13), and for patients treated with POM-CAR the median OS was 10.98 months (95% CI, 8.98–19.17). In this real-world observational study, we demonstrated that both CAR- and POM-based therapies, irrespective of the order in which they were used, were effective treatment options for patients with advanced relapsed MM.

Abstract: Background: Belantamab mafodotin (belamaf) is a first-in-class antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) that has shown clinically meaningful activity as a single agent in relapse/refractory multiple myeloma (RRMM). Pre-clinical studies demonstrate that the immune mediated anti-myeloma activities of belamaf are enhanced by immunomodulatory drugs (IMiDs) providing the rationale for combining Belamaf with pomalidomide (POM). The Algonquin study is an ongoing Phase 1/2 trial designed to evaluate the recommended Part 2 dose (RP2D), safety, and preliminary efficacy of belamaf in combination with POM and dexamethasone (DEX) (B-Pd) in patients (pts) with RRMM. The initial data from the dose-escalation phase of the study identified 2.5 mg/kg in combination with standard dosing of POM/DEX as the maximum tolerated dose (MTD) (Trudel et al. ASH 2020). Here we report updated safety and efficacy data and additional dosing cohorts used to identify the RP2D. Methods: Eligibility required & gt; 1 prior lines of treatment (LoT), lenalidomide (LEN) and proteasome inhibitor (PI) exposure and refractoriness to the last LoT. POM was administered at 4 mg days 21/28 days, DEX 40 mg (20 mg age & gt; 75 years) weekly in conjunction with IV belamaf SINGLE (1.92 or 2.5 mg/kg) Q4W, 2.5 mg/kg LOADING dose followed by 1.92 mg/kg Q4W from cycle 2+, 2.5 mg/kg dosed Q8W (BIMONTHLY) or Q12W (TRIMONTHLY), or belamaf SPLIT (2.5 or 3.4 mg/kg), split equally on days 1 and 8 Q4W. Dose escalation was accomplished using a standard 3+3 dose escalation design. Responses were assessed by International Myeloma Working Group (IMWG) criteria and adverse events (AEs) were graded by CTCAE criteria except for corneal findings which were also graded by the pre-specified keratopathy and visual acuity (KVA) scale. Up to 12 pts could be enrolled at dose levels not exceeding the MTD to inform the R2PD. Results: At cut-off (July 15, 2021), 60 pts had been enrolled in the following dose levels and schedules: 1.92 SINGLE (n=12), 2.5 SINGLE (n=7), 2.5 LOADING (n=5), 2.5 BIMONTHLY (n=12), 2.5 TRIMONTHLY (n=11), 2.5 SPLIT (n=8) and 3.4 SPLIT (n=5). The median age was 65 years (range 36-81) and median prior LoT was 3 (1-5). Prior therapies (exposed/refractory) included stem cell transplant (57%), PI (100%/82%), LEN (100%/90%) and daratumumab (DARA) (58%/100%). 76% were refractory to LEN and a PI and 48% to LEN, a PI and DARA. The most frequent AEs regardless of attribution were keratopathy (an ophthalmologic finding) (96.9%), blurred vision (87.5%), fatigue (59.4%), neutropenia (62.5%), thrombocytopenia (50%), fever (46.9%), diarrhea (34.4%), constipation (34.4%), and dry eye (28.1%). Grade 3/4 AEs reported in & gt;20% of pts across all cohorts, were keratopathy (56.7%), neutropenia (38.3%), thrombocytopenia (35%) and blurred vision (30%). Corneal safety profile by dosing cohort as well as dose reductions and dose delays used to manage corneal AEs are listed in Table 1. Two patients discontinued treatment due to AEs (one G4 decreased visual acuity and one G3 elevated ALT) while no grade 5 AEs were observed. At cut-off, 54/60 patients were evaluable for response. Across all cohorts the ORR was 88.9% (11 PR, 24 VGPR, and 13 sCR). Responses by dosing cohort are summarized in Table 1. At a median follow up of 8.6 months (range 0.9-27.9) the median PFS was 24.2 months (95% CI: 14.1, NYR). Conclusions: The safety profile of B-Pd is consistent with that observed for Pd or Belamaf individually. All dosing cohorts demonstrate deep and durable responses however the 2.5 mg/kg dose appears to have better efficacy. The 2.5 BIMONTHLY dosing schedule has been selected for the Part 2 cohort expansion based on optimized safety and efficacy. Figure 1 Figure 1. Disclosures Trudel: Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. McCurdy: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy. Louzada: Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; BMS: Research Funding; GSK: Research Funding; Sanofi: Research Funding. Mian: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kotb: Pfizer: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Celgene: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Akcea: Honoraria; BMS: Honoraria. Othman: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Camacho: Janssen: Consultancy; AbbVie: Consultancy; Bausch-Health: Consultancy. Reece: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; Amgen: Consultancy, Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. White: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. OffLabel Disclosure: belantamab and pomalidomide in combination

Abstract: Background: Overexpression of the nuclear export protein exportin 1 (XPO1) mediates the functional inactivation of tumor suppressor proteins (TSPs), facilitates the export of oncogene mRNA thus facilitating oncoprotein expression, is associated with poor prognosis in multiple myeloma (MM), and contributes to immunomodulatory drug (IMiD) resistance. Selinexor is an oral, first-in-class, selective inhibitor of nuclear export (SINE) compound that by blocking XPO1 forces the nuclear retention and activation of TSPs and nuclear retention and inactivation of oncoproteins. 1 Selinexor is approved with low-dose dexamethasone ± bortezomib for patients with previously treated MM. Pomalidomide plus dexamethasone (Pd) has an overall response rate (ORR) of ~30% and median PFS (mPFS) of ~4 months in patients with MM refractory to bortezomib and lenalidomide. We hypothesized that selinexor could be safely combined with Pd (XPd) and would improve the combination's efficacy. Methods: In the XPd arm of the multi-arm Phase 1b/2 STOMP study, selinexor was evaluated at 60, 80, or 100 mg in combination with Pd. Study objectives were to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) and to assess the safety and activity of the XPd regimen. The dose of selinexor 60 mg once weekly (QW), pomalidomide 4 mg once daily (days 1-21), dexamethasone 40 mg QW (XPd-60) was the lowest evaluated dose of selinexor in combination with the approved dose of Pd, and in light of the marked efficacy of that dose (ORR 65%), Phase 2 cohorts at a lower (40 mg weekly) dose of selinexor (XPd-40), were evaluated. Of the 19 patients enrolled at XPd-40 and evaluable for efficacy, 12 patients were enrolled into STOMP and 7 patients were enrolled at the same dose level and similar inclusion criteria into a parallel study XPORT-MM-028. Results: As of 14 July 2021, 39 patients were enrolled into the 60 (N=20) and 40 (N=19) mg selinexor dose levels in combination with Pd: 19 males, median age 66.0 years (range 37-85 years), median number of prior lines of therapy 2 (range 1-9). 85% of patients had MM refractory to a proteasome inhibitor (PI; bortezomib or carfilzomib or ixazomib), 79% to an IMiD (thalidomide or lenalidomide or pomalidomide), 33% to an anti-CD38 mAb (daratumumab or isatuximab); 26% had triple class refractory disease. Common hematologic, treatment-emergent adverse events (TEAEs) consisted of (all grades, grade ≥3) neutropenia (72%, 59%; and two cases of grade 3 [G3] febrile neutropenia one in each of the dose levels), and anemia (51%, 15% all G3). Non-hematologic TEAEs were reversible and included fatigue (56%, 10% all G3) and nausea (49%, 0%). On XPd-60, the RP2D (N=20), ORR was 65% (1 stringent complete response [sCR] , 5 very good partial responses [VGPR], 7 PR); mPFS was 8.9 months (95% CI, 7.6 - NE, median follow-up 8.3 months). In patients treated at XPd-40 (N=19), ORR was 42% (3 VGPR, 5 PR); mPFS was not reached (95% CI, 5.7 - NE, median follow-up 2.8 months). Among patients who had received anti-CD38 mAb, the ORR was 64% overall and 100% at the RP2D (1 sCR, 2 VGPR, 3 PR). All patients who had MM refractory to pomalidomide (N=3; all at the 60 mg dose level) responded with 1 VGPR and 2 PR. For the 21 responders across both dose levels, median time to response was 1.0 months (95% CI 1.0 - 2.0) and median duration of response was not reached (95% CI: 8.0, NE). Conclusions: Selinexor, once weekly, can be safely combined with Pd in patients with relapsed MM. The all-oral combination of XPd is highly active with an ORR of 65% at XPd-60, the RP2D, and an ORR of 42% at XPd-40 dose level (compared to expected ORR ~30% for Pd). The high ORR that was achieved at the RP2D, including in patients previously treated with anti-CD38 mAb, supports XPd-60 as a promising therapy with no significant cross-resistance to anti-CD38, PIs or lenalidomide. No new safety signals were identified. The most common TEAE, neutropenia, is a common AE of Pd and was managed effectively with standard G-CSF. The regimen leverages the concept of mechanism switching from an anti-CD38 mAb-based regimen to a selinexor-based regimen. These data support the new Phase 3 study (XPORT-MM-031) with an all-oral combination of XPd vs elotuzumab-Pd in patients who have been previously treated with lenalidomide, a PI, and an anti-CD38 mAb. Figure 1 Figure 1. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. Chen: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Baljevic: BMS/Celgene: Consultancy; Exelixis: Research Funding; Karyopharm: Other: Advisory Board; BMS/Celgene: Other: Advisory Board; Amgen: Research Funding; Janssen Research: Other: Advisory Board; Oncopeptides: Other: Advisory Board. Tuchman: Caelum: Consultancy, Research Funding; Sanofi / Genzyme: Consultancy, Research Funding; Shattuck Labs: Consultancy; Karyopharm: Research Funding; Oncopeptides: Consultancy. Bahlis: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Schiller: Eli Lilly: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ambit: Research Funding; MedImmune: Research Funding; Cyclacel: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Trovagene: Research Funding; Gamida Cell Ltd.: Research Funding; Bio: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Deciphera: Research Funding; Regimmune: Research Funding; Delta-Fly: Research Funding; FujiFilm: Research Funding; Tolero: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Daiichi-Sankyo: Research Funding; Celator: Research Funding; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Elevate: Research Funding; Samus: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Onconova: Research Funding; Novartis: Consultancy, Research Funding; Ono-UK: Consultancy, Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Sangamo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Pharma: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Kotb: Akcea: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Amgen: Honoraria; Pfizer: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; BMS: Honoraria. Sutherland: Celgene: Consultancy; Karyopharm: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy. Bensinger: Amgen, BMS, Janssen, Sanofi: Speakers Bureau; BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding. Madan: Amgen: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Sebag: Janssen: Research Funding; Takeda: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Venner: GSK: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria. Leblanc: BMS/Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Canada: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Research Funding. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Zhang: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Mishal: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Gasparetto: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Connect Registry: 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.

Abstract: Background: Selinexor (SEL) is a novel, first-in-class oral selective inhibitor of nuclear export (SINE) which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. The SVd regimen with once weekly (QW) oral SEL (100 mg), dexamethasone (dex) and QW bortezomib (BOR) had significantly increased progression free survival (PFS) and overall response rate (ORR) with significantly reduced peripheral neuropathy as compared to standard twice weekly BOR/dex (Vd) in the phase III BOSTON study. Pomalidomide (POM) plus dex (Pd) achieved an ORR of 31% and PFS of 4 months in patients (pts) with disease refractory to BOR and lenalidomide (LEN). We hypothesize that the all oral Pd combination with the addition of QW SEL (SPd) would demonstrate improved activity and acceptable tolerability as compared with Pd. Methods: STOMP is a multicenter, open-label, phase 1b/2, dose escalation study with an expansion phase. Pts with RRMM who received ≥ 2 prior therapies including LEN and a proteasome inhibitor (in separate or the same regimens) were eligible for enrollment. Oral SEL was evaluated in 2 different dosing schedules in 28 days cycle: QW 60, 80 or 100 mg or twice weekly (BIW) 60 or 80 mg, with escalating doses of POM 2, 3 or 4 mg (days 1-21), and dex 20 mg BIW or 40 mg QW. The primary objectives of the study were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and to assess the safety, tolerability, ORR and PFS of the combination of SPd in pts with RRMM. Results: As of June 1 2020, 52 pts (28 male and 24 female) were enrolled. The median age was 64 (range: 43-85) years. Pts received a median of 3 (range: 1-10) prior therapies including 44 (84.6%) with autologous stem cell transplantation. During the escalation phase, eight dose limiting toxicities (DLTs) were observed (Table 1). Common hematologic treatment related adverse events (TRAE) included (All Grades, Grades ≥3) neutropenia (62%, 56%), anemia (60%, 37%), and thrombocytopenia (56%, 35%). Common non-hematologic TRAE included nausea (62%, 2%), fatigue (56%, 12%), decreased appetite (48%, 2%), weight loss (42%, 0%), diarrhea (35%, 0%), vomiting (23%, 2%). Rates of ≥ Grade 3 hematological TRAEs were lower in QW vs BIW schedules of SEL: thrombocytopenia (29% vs 44%) and anemia (32% vs 44%). Based on all of the safety data, the RP2D was SEL 60 mg QW, POM 4 mg (days 1-21), and DEX 40 mg QW. Out of 52 pts, 47 were evaluable for response. Previously treated / refractory rates were as follows (N=47 pts evaluable for efficacy): LEN (100% / 96%), BOR (94%, 45%), carfilzomib (38%, 34%), POM (30%, 30%), daratumumab (21%, 21%). Among POM naïve pts (N=33), all pts (100%) received prior LEN and 31 pts (94%) had MM documented LEN refractory. Among pts who were POM naive (N=33), the ORR was 58% (1 CR, 5 very good partial responses and 13 partial responses) and the median PFS and OS were 12.3 and 19.0 months, respectively. Amongst pts who received POM previously (N=14), the ORR was 36% (1 VGPR and 4 PR), and the median PFS and OS were 8.8 and 8.0 months, respectively. Conclusions: The RP2D is SEL 60 mg QW, POM 4 mg QD and dex 40 mg QW. The ORR was 58% in pts in LEN treated or refractory and POM naïve MM compared to previously published data of 31% ORR with Pd in a similar population. The median PFS on SPd of 12.3 months in POM naïve pts is longer than that historically observed with Pd (~4 months). All TRAEs were expected and manageable with appropriate supportive care (eg, G-CSF) and/or dose modifications. The all oral SPd combination appears to confer relatively high ORR with good durability and promising PFS in pts with heavily pretreated MM. Disclosures Chen: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bahlis:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding. Tuchman:Caelum: Honoraria; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Honoraria, Research Funding. Lipe:Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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. Baljevic:Coleman: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Honoraria; Amgen: Research Funding; Exelixis: Research Funding; Celgene Corporation / BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Putnam Associates: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gerson Lehrman Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlphaSights: Consultancy, Membership on an entity's Board of Directors or advisory committees; MediCom Myeloma CME: Honoraria; NCCN Hematologic Malignancies Congress: Honoraria. Kotb:Celgene: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current equity holder in publicly-traded company; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Amgen: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Amgen: Consultancy. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. LeBlanc:Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Schiller:Kite Pharma: Research Funding; Ariad: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; DeltaFly: Research Funding; MedImmune: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Abbvie: Research Funding; Jazz Pharmaceuticals: Research Funding; Forma: Research Funding; Novartis: Consultancy, Research Funding; Cyclacel: Research Funding; AstraZeneca: Consultancy; Mateon: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Gamida: Research Funding; FujiFilm: Research Funding; Geron: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Constellation: Research Funding; Genentech-Roche: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Deciphera: Research Funding. Lentzsch:Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sorrento: Consultancy; Celularity: Consultancy; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Sanofi: Research Funding; Magenta: Current equity holder in private company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Sheehan:Karyopharm Therapeutics Inc: Current Employment. Van Domelen:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Kazuharu:Karyopharm Therapeutics Inc.: Current Employment. Wang:Karyopharm: Current Employment; Curis: Ended employment in the past 24 months. Shah:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. White:Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

Abstract: Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effect of BCRs and Ld for the treatment of TIMM using the newly-formed Myeloma Canada Research Network Multiple Myeloma Database (MCRN-MM-DB) project. This web-based centralized platform can track and characterize real-world outcomes of patients treated at major Canadian institutions and includes both legacy data dating back to 2007 (from 4 centres) as well as ongoing prospective data collection (from 11 centres) analyzed up to 01/07/18. Patients and Methods: The primary objective was to assess the ORR, PFS and OS for TIMM patients treated with CyBorD/CyBorP, Ld, VMP or VD/VP, each given as reported previously but with dose-adjustments at the discretion of the treating physician to maintain patients on therapy. The two-sided Fisher exact test was used to test for differences between categorical variables. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test; a p value of 〈 0.05 was considered significant. Results: 842 TIMM patients were evaluated. Clinical characteristics are shown in Table 1. Median OS and PFS for the entire cohort were 54.1 and 20.4 months, respectively. ORR and ≥VGPR better rates were 83% and 52% for the entire cohort. A ≥VGPR rate of 53%, 46%, 56% and 51% were observed for patients treated with CyBorD/P, VMP, Ld and VD/VP, respectively (p=0.3). The median PFS was longer for Ld patients (25 months) compared to CyBorD/CyBorP, VMP and Vd/VP (19.3, 20.5 and 13.7 months, respectively), (p=0.03, Fig 1a); there was no significant difference in PFS between the 2 different alkylating-agent containing regimens when combined with bortezomib + steroids (CyBorD/P vs VMP, p =0.9). Median OS was 51, 59.5, 29.4 and 66.5 months for those patients treated with CyBorD/CyBorP, VMP, VD/VP and Ld, respectively (p=0.07, Fig 1b). When the OS and PFS for CyBorD/P (typically given for a fixed duration of 9 cycles) were compared with Ld in a subset analysis, the p-values were 0.08 and 0.008, respectively. Conclusions: 1) OS was not significantly different in patients treated with either a bortezomib-containing triplet that includes an alkylator + steroid or continuous Ld. 2) The BCR triplets and Ld were more efficacious than the bortezomib + steroid doublet (VD/VP) for both OS and PFS although, the small sample size and adverse factors, such as frailty and comorbidities, may have influenced the findings. 3) The results in the real-world setting, i.e., a median PFS in the range of 1.5-2 years and median OS of 4.5-5.5 years, confirm triplet-based BCRs and Ld as current valid standards of care for frontline therapy in TIMM. 5) This study confirms the utility of a large comprehensive national database to benchmark current results for comparison with newer regimens as they are introduced into the Canadian therapeutic landscape. Disclosures Arleigh: Celgene: Honoraria; Janssen: Honoraria. Sebag:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Leblanc:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Louzada:Janssen: Honoraria; Celgene: Honoraria; amgen: Honoraria; pfizer: Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria.

Abstract: Background: Multiple myeloma is a heterogenous plasma cell cancer characterized by expression of a monoclonal protein (M-protein) or free light chains (FLC). Although survival has improved over the past 15 years, outcomes are variable and not fully predicted by conventional prognostic markers. Survival is associated with depth and duration of response to treatment but it is not known if the trajectory of response is associated with survival. We hypothesized that the trajectory of M-protein over the first six months of treatment in patients with newly diagnosed multiple myeloma can identify distinct clinical groups and is an independent predictor of overall survival (OS). The objectives of our study are to: 1) Identify groups of patients with different M-protein trajectories using trajectory analysis; 2) Evaluate patient and illness factors associated with different M-protein trajectories; and 3) Determine whether M-protein trajectory is an independent predictor of OS in newly diagnosed multiple myeloma. Methods: We conducted a retrospective cohort review of all patients with newly diagnosed multiple myeloma in Manitoba between 2012 and 2017 who had a measurable M-protein at presentation and who were initially treated with bortezomib-based chemotherapy. Baseline characteristics and monthly response assessments up to six months were collected and analyzed using trajectory analysis. We used latent class mixed models (LCMM) to produce trajectory groups of M-protein response over time. We used the Bayesian Information Criterion and clinical validity characteristics to select the optimal trajectory model. We developed a multinomial logistic model to evaluate the association of patient and illness characteristics with M-protein trajectories. We constructed a multivariable Cox proportional hazard model adjusted for trajectory group, ISS stage, transplant status, LDH, renal failure and platelet count to evaluate the association of M-protein trajectory on OS in multiple myeloma. Results: 266 patients were included in the trajectory analysis. 154 (57.9%) were male. Mean age was 66.4 years (SD 10.1). 29 (10.9%) were classified as ISS stage 1, 80 (30.1%) as ISS stage 2, and 109 (41.0%) as ISS stage 3. The best fit trajectory model identified three trajectory groups representing distinct M-protein trajectories over time (Figure 1). We plotted the trajectory of the absolute value for M-protein as the percentage change from baseline did not separate the population into distinct groups. Baseline bone marrow plasma percentage (p & lt;0.01), albumin (p & lt;0.01), and hemoglobin (p & lt;0.01) were significantly associated with trajectory group membership. The median follow-up was 2.74 years for the OS analysis. The median OS was not reached for the low group, 4.3 years for the moderate group, and 5.4 years for the high group. In a multivariable Cox proportional hazard model, we found that trajectory group was not significantly associated with OS (moderate group HR 1.18, 95%CI 0.48-2.91, high group HR 1.10, 95%Cl 0.62-1.88). Variables significantly associated with OS included ISS stage (p & lt;0.025), LDH (p & lt;0.022), platelet count (p & lt;0.001), and receipt of a stem cell transplant (p & lt;0.001). Discussion and Conclusions: In this retrospective cohort study of patients with newly diagnosed multiple myeloma, we identified three distinct groups based on their M-protein trajectory over time. The identified groups have different mean baseline M-protein values and follow different evolutionary patterns over time. While M-protein trajectory group was not associated with differences in OS, the small sample size and short follow-up may limit interpretation of the results. Our analyses only looked at the M-protein trajectory over the first six months after treatment start, which indicates an early response to treatment. It is possible this early response does not play a large role in the OS of patients with myeloma given the mutliple lines of chemotherapy they may receive. Further studies are planned to assess the achievement of a complete remission at one year or at renal recovery for patients affected with renal involvement. Alternative uses for M-protein trajectory analysis include the trajectory of M-protein prior to relapse or in patients with smoldering myeloma to identify who may benefit from earlier treatment. Disclosures Kotb: Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Karyopharm: Current equity holder in publicly-traded company.