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Multiple myeloma (MM) is a plasma cell (PC) malignancy of terminally differentiated B lymphocytes that is typically associated with the secretion of partial and/or complete monoclonal immunoglobulins and a constellation of particular symptoms and signs. MM is a treatable condition, and timely diagnosis is essential to limit or avoid irreversible target-organ damage and to prolong survival. The Myeloma Canada Research Network Consensus Guideline Consortium (MCRN-CGC) proposes national consensus recommendations for the diagnosis of MM and associated PC neoplasms. The focus is on widely available tests but also highlights recent advancements that are important to include in the diagnostic paradigm. By clarifying and updating the required laboratory, radiographic, and bone marrow investigations, the MCRN-CGC hopes to address the needs of Canadian physicians and people living with MM across the country through accurate and timely diagnosis of MM, as well as appropriate initial stratification to improve treatment selection and outcomes. The MCRN-CGC will periodically review the recommendations herein and update as necessary. Recommendations on the therapeutic approaches and associated monitoring of MM will follow.

Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM)with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of Methods- Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with pomalidomide (pom)3 or 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. The primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the combination of selinexor, pomalidomide, and low dose dex (SPd) in pts with RRMM. Results- As of July 20th2018, 34 pts (16 male / 18 female) have been enrolled. The median age is 61 years and patients received a median of 4 (range, 2 - 9) prior treatment regimens. Thirty-two patients were IMiD refractory (21 len, 11 pom/len). Six dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (80 mg QW, pom 4), G3 thrombocytopenia (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common SPd treatment related adverse events included (all grades, grades 3/4): neutropenia (62%, 56%), thrombocytopenia (59%, 32%), anemia (53%, 29%), anorexia (56%, 0%), fatigue (50%, 9%), nausea (47%, 0% ). Thirty pts were evaluable for response, which is outlined in Table 1. Median PFS is 10.3 months with a median follow up of 9.4 months. Conclusions- Enrollment is ongoing to evaluate once weekly selinexor in combination with Pd , (SPd). This all-oral SPd combination has clinical activity with an ORR 55% in pom-naive pts with heavily pretreated MM compared to previously published data of 30% ORR for Pd alone. Similarly, the PFS on SPd is 10.3 months vs. Disclosures Chen: Amgen: 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. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau. Gasparetto:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Leblanc:Amgen 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; Celgene 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. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lipe:Celgene: Consultancy. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bahlis:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells. Methods - Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM Results - As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 - 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW. Conclusions - Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented. Disclosures Gasparetto: Takeda: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Sebag: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; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc: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; Celgene 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. Chen:Amgen: Honoraria. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy.

Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (dex) has demonstrated potent anti-cancer activity in patients with heavily pretreated MM. While the development of proteasome inhibitors (PIs) has transformed the treatment of MM, acquired resistance to PIs limit their efficacy. Preclinical studies have shown that selinexor, when combined with bortezomib, can restore sensitivity of bortezomib-resistant MM to this drug, inducing tumor growth inhibition and increasing survival in MM models in mice. In this clinical trial (NCT02343042), we investigated the safety, tolerability and efficacy of the combination of selinexor, bortezomib and low dose dex (SdB) in patients (pts) with refractory MM. Methods - This phase 1b/2 dose escalation study using a standard 3+3 design, was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for SdB. The study included pts with refractory MM, after ≥ 1 prior therapy. Pts with prior PI relapsed and/or refractory disease were included, provided the patient's MM was not refractory to bortezomib as last therapy. Selinexor was independently dosed escalated in once-weekly (QW, starting at 80 mg; N=7, 100 mg N=6 pts) or twice-weekly (BIW, starting at 60 mg; N=3, 80 mg N=6 pts) regimens. Bortezomib (1.3 mg/m2 sc) was administered either once-weekly or twice-weekly and dex was given orally 40 mg QW or 20 mg BIW. Results - As of July 25th, 2016, enrollment in the dose escalation cohorts has been completed with 22 pts (12 male /10 female). The median age is 65 years (range, 46 - 74), with a median of 4 (range, 1 - 12) prior treatment regimens. One dose limiting toxicity (Grade 4 thrombocytopenia without bleeding) in the 80 mg BIW cohort was observed but the MTD has not been reached. Common related grade 1/2 adverse events (AEs) include: fatigue 41%, nausea 41%, anorexia 36%, and weight loss 18%. Grade 3/4 AEs include: thrombocytopenia 41%, anemia 18%, and neutropenia 18%. One case of grade 1 peripheral neuropathy in the 80 mg BIW cohort was reported. All pts were evaluable for response. The ORR (≥partial response, PR) was 77% with ≥VGPR 27% (1 pt in CR and 5 pts in VGPR) and 11 PRs. There were 3 minor responses (14%), 1 stable disease, 1 progressive disease (5% each). Seven of the 12 pts with PI-refractory MM responded (ORR 58%). A summary of response by PI treatment history is shown in Table 1. Ten patients have remained on study >4 months, including 7 patients still on trial (longest >9 months). Based on tolerability and anti-MM activity, RP2D of SdB is selinexor 100 mg, bortezomib 1.3 mg/m2 and dex 40 mg, all given once weekly. At the RP2D, all six pts achieved ≥PR (ORR 100%). Conclusions - Selinexor in combination with bortezomib and dex is well tolerated and highly active in refractory MM. Toxicities are manageable and similar to selinexor or bortezomib monotherapy. Peripheral neuropathy is uncommon, consistent with the use of weekly bortezomib sc and the lack of neuropathy with selinexor. Overall, the SdB regimens induced an ORR of 77% with ≥VGPR of 27%. In patients with PI-refractory MM, the ORR was 58%, indicating that the addition of selinexor restores sensitivity to bortezomib. These results confirm the preclinical data supporting synergistic effects of selinexor when combined with PIs. This promising, once-weekly treatment regimen may provide deeper and more durable responses in pts with relapsed / refractory MM, including those with PI-refractory disease. Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Table 1. Best Response by Prior Proteasome Inhibitor (PI) Treatment Status Disclosures Bahlis: Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; BMS: Honoraria. Sebag:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Sutherland:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Amgen: Honoraria; J+J: Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Kouroukis:Amgen: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acetylon: Research Funding; Takeda: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding.