Introduction: A vast majority of multiple myeloma (MM) patients requires subsequent lines of therapy following relapses. The choice of regimen following relapse is influenced by response, tolerance to prior therapies, as well as by disease and patient features. Treatment options are limited for those who develop triple-class refractory disease. In this setting, the role of a salvage autologous stem cell transplantation (sAHCT) is controversial. This unmet need has driven the development of new therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of nuclear export (SINE) compound, was recently approved by the FDA and EMA for use in heavily pretreated relapse refractory (RRMM) patients, including triple-class refractory RRMM and FDA has also approved the agent in patients with first relapse. In the absence of head-to-head studies, comparison of treatment options among triple-class treated patients is based on real world experience. Here we performed a retrospective comparison between outcomes following sAHCT versus Selinexor combinations administered among RRMMs. Patients & Methods: Between January 2015 and April 2021, 22 patients at our center underwent sAHCT for treatment of refractory relapse. A transplant was defined as salvage if the patient had already received one prior AHCT and underwent a further AHCT after evidence of disease progression not responding to second generation proteasome inhibitors (PI), İmmunomodulating agents (IMID) or antiCD38 monoclonal antibody. We compared the outcomes of these patients with 10 RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive Selinexor, dexamethasone in combination with either bortezomib (n=7) (XVd) or carfilzomib (n=3) (XCd) as a part of a Karyopharm Expanded Access Program (KEAP). Selinexor was administered 80-100 mg po weekly in combination. Response and disease progression were assessed according to the IMWG criteria. Results: Patients' characteristics and the outcome of treatments are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 6 prior lines of therapy (4-9) and 2 out of 10 carried high-risk cytogenetics in SVd group. Seven (31.8%) patients with high-risk cytogenetics underwent sAHCT. All patients were treated with or refractory to immunomodulators and proteasome inhibitors. Five patients responded to DCEP bridging therapy prior to sAHCT. Five patients received Selinexor after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In sAHCT group, 68.2% of patients relapsed within a median of 6.3 months (Figure-1). Figure-2 shows the impact of the prior lines of therapy and selinoxor on PFS.Adverse events on selinexor regimens included fatigue, nausea, thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. Two patients eventually transitioned to new therapies, while 4 still remain on SVd due to continued response. Conclusion: Our results based on a small number of patients, compared with outcomes post sAHCT reflects comparable duration of response and disease control rates with Selinexor-PI regimens among selected patients. Hospitalization and prolonged infusions are not required with the selinexor regimens, and prolonged treatment is possible with advance in lines of therapy duration of response lessens with any treatment modality. Despite of a DCEP bridging therapy prior to sAHCT, Selinexor combos have achieved similar PFS even among triple class refractory MM patients. For countries where CAR-T therapies are not accessible, sAHCT and Selinexor combinations may be considered as a valid clinical option after failing CD38 monoclonal antibodies, PI and IMIDs. These data support the use of selinexor-based regimens in the treatment of relapsed MM, and given the potency of the combinations, in earlier lines of therapy including in patients who have received anti-CD38 mAbs. Figure 1 Figure 1. Disclosures Kashyap: Karyopharm: Current Employment. Niblock: Karyopharm: Current Employment. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. OffLabel Disclosure: Selinexor has not been approved for myeloma patients in Turkey. It could be used as a part of Karyopharm Expanded Access program (KEAP).

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Introduction: Extramedullary disease (EMD) in patients (pts) with multiple myeloma (MM) is a poor prognostic feature which is not curable with currently approved treatments. Consequently, there is a significant unmet need for effective therapies with good safety profiles. Daratumumab with cyclophosphamide, bortezomib and dexamethasone (daraVCD) is a novel treatment combination with a good efficacy profile in pts with EMD based on preclinical synergistic data. Methods: EMN19 is a phase 2, open-label, multicenter study which aims to enroll 40 MM pts presenting with EMD either at diagnosis or following one line of treatment but not refractory to bortezomib-based regimens, from 8 sites in Turkey, Greece and Italy. Pts with bortezomib or daratumumab hypersensitivity, who received previous autologous stem cell transplant (ASCT) ≤12 weeks before Day 1 of treatment Cycle 1, or with previous allogenic stem cell transplant were excluded. Daratumumab was initially administered intravenously at 16 mg/mL, and since July 2020 has been administered subcutaneously at a fixed dose of 1800 mg, weekly during Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Intravenous bortezomib 1.5 mg/m 2 and oral/intravenous cyclophosphamide 300 mg/m 2 is administered weekly, and oral/intravenous dexamethasone 20 mg is administered on Days 1, 2, 8, 9, 15, 16, 22 and 23. DaraVCD will be administered until progression or unacceptable toxicity unless refractory disease is detected by the end of Cycle 3 (progressive disease [PD] or failure to achieve a confirmed partial response [PR] or better). The present analysis includes pts who initiated study treatment ≥3 months prior to the cut-off date (01 June 2021). Results: In total, 34 patients were screened, 27 patients were enrolled, 2 relapsing patients died during the screening phase due to severe COVID-19 infection, 22 pts were analyzed (59% female; median age 56 years, range 44-77); 14 pts (64%) were still on treatment and 8 (36%) discontinued; due to inadequate response after 3 cycles of treatment (n=3, 38%), PD (n=4, 50%), death (n=1, 13%). Fourteen pts (64%) were newly diagnosed and 8 (36%) first relapsed. International Staging System stage at baseline was I, II and III for 8 (36%), 9 (41%) and 5 (23%) pts, respectively. Eastern Cooperative Oncology Group performance status was 0, 1 and 2 for 14 (64%), 7 (32%), and 1 patient (5%), respectively. On average, 3.0 (range 1-20) extramedullary plasmacytomas were observed per patient; most commonly reported sites were thorax (6 pts, 27%), brain, head and lower extremities (4 pts, 18% each). Twenty (91%) pts had ≥1 serious or non-serious treatment-emergent adverse event (TEAE); 8 pts (36.4%) experienced ≥1 sTEAEs; COVID-19 infection (n=3, 14%) urinary tract infection (n=2, 9%), infectious myocarditis, hip arthroplasty, pneumonia, cytomegaloviral pneumonia and thrombocytopenia (n=1 each, 4.5%). Thirteen (59%) pts ≥1 Grade 3/4 TEAE; neutropenia observed in 8 pts (36%), followed by thrombocytopenia (n=4, 18%) and COVID-19 infection (n=3, 14%). Overall, 16 (73%) pts missed ≥1 dose of any of the study drugs; 2 (9%) pts missed ≥1 dose due to COVID-19 infection (7 doses), 8 (36%) due to COVID-19 vaccination (37 doses), 2 (9%) due to other COVID-19-related issues (65 doses), 10 (46%) due to other safety events (104 doses) and 9 (41%) due to other reasons (25 doses). Overall, 20 cycle delays were observed in 13 (59%) pts, with median (range) delay of 12.0 (4-133) days. Two pts (9%) had a cycle delay due to COVID-19 infection (2 cycles), 1 (5%) due to COVID-19 vaccination (1 cycle), 5 (23%) due to adverse events (8 cycles), 2 (9%) due to ASCT (2 cycles) and 7 (32%) due to other reasons (7 cycles). Total number of missed doses (missed doses due to COVID-19-related issues) were 17 (3) for daratumumab, 53 (11) for bortezomib, 45 (9) for cyclophosphamide and 123 (86) for dexamethasone; 238 doses missed in total. No fatalities occurred due to any infection. Conclusions: DaraVCD was associated with a good safety profile in this high risk MM with EMD patient population. The COVID-19 impact on missed doses was greater for dexamethasone (>60% of missed doses) than other components (~20%), however overall, the pandemic did not significantly affect the patients' safety and data integrity of the study. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Tuglular: GSK: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Genesis Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: 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, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria. Gay: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Membership on an entity's Board of Directors or advisory committees. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Merante: EMN Italy Medical Monitor: Research Funding. Manousou: Health Data Specialists: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos: GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

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