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Introduction As lenalidomide (Len) has become an integral part of therapy for newly diagnosed MM patients, most will have been either exposed or refractory to Len at the time of first or second relapse. The monoclonal antibody, Daratumumab, in combination with the more potent IMID pomalidomide (Pom) demonstrates good responses in patients previously exposed to lenalidomide. Low dose weekly cyclophosphamide has been shown to enhance the potency of pomalidomide in association with dexamethasone. In this clinical trial, we set out to compare the combination of daratumumab, weekly low dose cyclophosphamide, dexamethasone and pomalidomide (DCdP) to daratumumab, cyclophosphamide and dexamethasone (DCd) with pomalidomide added only at disease progression. Although we expected that a four-drug regiment would give superior clinical results, we hypothesized that a significant number of patients would not necessarily need all four drugs but could benefit from the addition of pomalidomide at treatment failure. Patients/Methods In this phase II clinical trial 120 patients with relapsed refractory myeloma, after at least one line of therapy, were randomized to receive either daratumumab (16mg/kg) weekly IV C1-2, every 2 weeks C3-6, monthly C7+, dexamethasone 40mg po weekly, cyclophosphamide 400mg po weekly and pomalidomide 4mg po days 1-21 of 28 day cycles (Arm A) or the same doses and dosing regimen of daratumumab, cyclophosphamide and dexamethasone but with pomalidomide added only after confirmed disease progression (Arm B). All patients had to be exposed to proteasome inhibitors and len prior to study entry. The primary endpoint of this study is the comparison of the PFS of Arm A and the PFS of Arm B after the addition Pom (PFS2) at 36 months while secondary endpoints included overall responses, duration of responses, survival and safety. Correlative laboratory studies are also planned. Results As of 1 April 2019 all 120 patients have been enrolled in 11 sites across Canada. The patient characteristics were: median age 65 (range 39-82); median 2 prior lines of therapy (range 1-8); 70% had a previous ASCT; 95% lenalidomide exposed; 93% proteasome inhibitor exposed; 90% lenalidomide and PI exposed; 25% carfilzomib exposed, len was the last line of therapy in 65%. Median follow-up was 8.2 months (range 1-15.6), median number of cycles 8 (range 1-17). The overall response rates (ORR) were 88.5% for arm A compared with 50.8% for arm B, with 57.4% and 25.4% of patients achieving ≥VGPR in arm A and B respectively. Among the 20 patients in Arm B that had progressed by data cutoff, the ORR after adding pomalidomide was 40% albeit with the short follow up time of 3.4 months. Although the median PFS of Arm A has not yet been reached, it was 10.9 mo. in Arm B prior to the addition of pom and 14.3 mo. from trial entry in the smaller group in whom pom was added after first progression (PFS2). In Arm A the 9- month PFS was 83%. Rates of grade 3/4 hematologic toxicities included a high incidence of neutropenia, 74% in Arm A and 30% in Arm B; however the rates of febrile neutropenia were low at 8.2% and 6.8% respectively. Grade 3/4 thrombocytopenia were 4.9% and 13.6%, respectively. The most common non-hematologic toxicity was pneumonia in 18% and 16.9% in arms A and B, respectively. Conclusions The results of this randomized phase II trial demonstrate that in a moderately pretreated MM population (median 2 lines of therapy but range 1-8) that the four-drug combination (DCdP) confers impressive response rates (ORR 88.5%) and a 9-month PFS of 83%. Although the three-drug combination (DCd) showed an inferior response rate of 50%, this is superior to Daratumumab used as a single agent in a similar patient population and so far at least 40% of patients who have progressed appear salvageable showing responses upon addition of Pom. Moreover, the addition of low dose cyclophosphamide, an alkylator with recognized immune properties, appears to enhance ORR and produce a durable PFS even when compared to Dara-pom-dex combinations used after two lines of therapy. Toxicities were principally hematologic and few resulted in treatment discontinuations. Disclosures Sebag: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bahlis:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Venner:Celgene: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria. McCurdy:Celgene: Honoraria; Janssen: Honoraria. Shustik:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. White:Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kotb:Karyopharm: Equity Ownership; Amgen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Stakiw:Roche: Research Funding; Lundbeck: Honoraria; BMS: Honoraria; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria. Laferriere:Celgene: Honoraria; Taiho: Honoraria; Teva Pharm: Honoraria; ROCHE: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria. Camacho:Abbvie: Consultancy; Janssen: Consultancy; Baush-Health: Consultancy. Reece:Otsuka: Research Funding; BMS: Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

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Lenalidomide (Len) has become the standard first line therapeutic choices for Multiple Myeloma (MM), whether as first line for transplant ineligible patients or as maintenance post transplant. Therapies that are designed to overcome lenalidomide refractory disease are few and often give disappointing results. We previously reported the efficacy of daratumumab in combination with low dose weekly cyclophosphamide and dexamethasone with and without pomalidomide (Pom). In patients previously treated with both Proteosome Inhibitors (PIs) and Len the combination of Dara, Cyclophosphamide, Dex and pomalidomide (DCdP) produced impressive response rates. Although the same combination without the Pom had appreciably lower response rates and initial progression free survival (PFS), most patients were salvageable after the addition of Pom. Here we report an update on this trial. Patients/Methods In this phase II clinical trial, 120 patients with relapsed refractory MM, after at least one line of therapy, were randomized to receive either daratumumab (16mg/kg) weekly IV C1-2, every 2 weeks C3-6, monthly C7+, dexamethasone 40mg po weekly, cyclophosphamide 400mg po weekly and pomalidomide 4mg po days 1-21 of 28 day cycles (Arm A) or the same doses and dosing regimen of daratumumab, cyclophosphamide and dexamethasone but with Pom added only after confirmed disease progression (Arm B). All patients were exposed to PIs and Len prior to study entry. The primary endpoint of this study was the comparison of the PFS of Arm A to that of Arm B after the addition Pom (PFS2) at 36 months while secondary endpoints included overall responses, duration of responses, survival and safety. Correlative laboratory studies will be reported separately. Results As of 1 June 2020 all 120 patients have been enrolled in 11 sites across Canada. The patient characteristics were: median age 65 (range 39-82); median 2 prior lines of therapy (range 1-8); 70% had a previous ASCT; 95% Len exposed; 93% PI exposed; 90% Len and PI exposed; 25% carfilzomib exposed, Len was the last line of therapy in 65%. Median follow-up was 19 months (range 1-28), median number of cycles 16 (range 1-31). The overall response rates (ORR) were 88.6% for arm A compared with 50.8% for arm B, with 62.4% and 28.8% of patients achieving ≥VGPR in arm A and B respectively. 43 patients in Arm B have progressed by data cut-off and the ORR after adding pomalidomide was 55.8% with a median follow up time 6.6 months. The response rates for both Arm A and B (prior to Pom) did not vary much in patients in whom Len was the last line of therapy (94.5% vs 55.7%), compared to the ITT population. The response rate after the addition of Pom to Arm B patients after first progression was also similar in patients in whom Len was used last (58.3%). The median PFS of Arm A was an impressive 20.5 months (regardless of previous Len exposure) while it was considerably shorter for Arm B prior to addition of Pom at 11.5 months and 16.7 months overall after addition of Pom. Median OS has not yet been reached, however, time to subsequent therapies from randomization was similar in both groups at 18.1 (Arm A) and 20.2 months (Arm B). Rates of grade 3/4 hematologic toxicities included a high incidence of neutropenia, 85.2% in Arm A and 50.8% in Arm B overall; however, the rates of febrile neutropenia were low at 13.1% and 16.9% respectively. The most common infection was pneumonia, seen in 13% of Arm A and 6.8% of Arm B prior to Pom and 20.3% overall for Arm B. Conclusions The results of this randomized phase II trial demonstrate that in a highly pretreated MM population (2 lines of therapy but range 1-8) that the four-drug combination (DCdP) confers impressive ORR (88.6%) and a median PFS (20.5 months) that compares favourably to other studies with anti-CD38 antibodies combined with Pomalidomide (11.5 months for Isatuximab-Pom-Dex, albeit in patients with 3 median lines of prior therapy). In Len exposed patients, DCdP demonstrates an ORR of 93% and a PFS of 20.5 months which is similar to what has been reported recently in Len exposed patients with Dara-pom-dex but after only one previous line of therapy. Although the 3 combination (DCd) showed an inferior initial response rate, over half of patients recaptured a response after the addition of Pom. Finally, while the overall PFS is lower in Arm B, the times to subsequent therapies are so far similar in both arms of this study opening a sequential-based approach as a feasible and economic option for further study. Disclosures Sebag: Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Bahlis:Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. McCurdy:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Honoraria. Shustik:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Kotb:Amgen: Honoraria; Celgene: Honoraria; Sanofi: Research Funding; Karyopharm: Current equity holder in publicly-traded company; Merck: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria. White:Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Stakiw:BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Roche: Research Funding; Lundbeck: Honoraria. Laferriere:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Camacho:Janssen: Consultancy; AbbVie: Consultancy; Bausch-Health: Consultancy. Reece:Otsuka: Research Funding; Merck: Honoraria, Research Funding; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria.

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