ALBERT

Description: Introduction Elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies, however, overall survival (OS) is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index. This is caused by a high discontinuation rate due to toxicity. Therefore, a less toxic effective treatment for unfit and frail patients is needed. In view of the favorable safety profile of ixazomib (Ixa) and daratumumab (Dara), we investigated the efficacy and feasibility of treatment with Ixa and Dara plus low dose dexamethasone (Ixa-Dara-dex) in unfit and frail patients. This trial was registered at www.trialregister.nlwww.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial, treatment consisted of nine 28 day-induction cycles consisting of Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dex (in combination with Dara; cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with Ixa (days 1, 8, 15, 29, 36, 43) and Dara (day 1) of 8-week cycles, until progression for a maximum of 2 years. A pre-specified efficacy analysis was planned for the first eligible 23 unfit and 23 frail patients separately at the time the data of the first 9 cycles induction therapy was available. Inclusion criteria were unfit or frail NDMM patients according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1

Description: Key Points REP is an active combination in MM patients refractory to lenalidomide. REP is an all-oral and generally well-tolerated regimen.

Description: Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell proliferative disorder with a very poor prognosis and with distinct biologic, clinical, and laboratory features. Compared with multiple myeloma, pPCL presents more often with extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, elevated serum β2-microglobulin and lactate dehydrogenase levels, as well as impaired renal function. Many of the genetic aberrations observed in newly diagnosed pPCL are typically found in advanced multiple myeloma. These cytogenetic abnormalities and mutations lead to increased proliferation, enhanced inhibition of apoptosis, escape from immune surveillance, and independence from the BM microenvironment, with changes in expression of adhesion molecules or chemokine receptors. The outcome of pPCL has improved with the introduction of autologous stem cell transplantation and combination approaches with novel agents, including bortezomib and immunomodulatory drugs, such as lenalidomide. In this review, we provide an overview of currently available therapeutic options with recommendations of how these treatment modalities can best be used to improve outcome for plasma cell leukemia patients.

Description: Key Points In a multicenter, randomized phase 3 trial, MPR-R was not superior over MPT-T with respect to response rate, PFS, and OS. Grade 3/4 hematologic toxicity requiring growth factor support occurred with MPR-R vs clinically significant neuropathy with MPT-T.

Description: Background: Substantial improvements in both progression free survival (PFS) and overall survival (OS) have been observed in patients with multiple myeloma over recent years. Despite these therapeutic advances, multiple myeloma remains incurable, and most patients eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies (mAbs) and others. Understanding the effectiveness of current standards of care in heavily pretreated patients with relapsed and / or refractory multiple myeloma (RRMM) remains an area of unmet need, and there are currently no prospective data reflecting real-world practice in this patient population progressing after PIs, IMiDs and anti-CD38 mAbs. Study design: This prospective multinational efficacy and safety study of real-life current standards of care (real-life SOC) will be conducted in the USA and Europe in approximately 230 adult patients with RRMM who received at least 3 prior lines of therapy or are double refractory to PI & IMiD and have received at least a PI, an IMiD, and CD38 mAbs and with documented progressive disease (PD) since their last line of therapy and have an ECOG score of 0-1. Also, subjects with documented evidence of PD (as above) within the previous 6 months and who are refractory or non-responsive to their most recent line of treatment are eligible. There are no exclusion criteria due to the observational nature of the study. The treatments that these patients receive in real life will be assessed for safety and efficacy over a two-year period. Real-life SOC treatments are defined as the treatment used in local clinical practice by the investigator for adult subjects with RRMM, who meet the eligibility criteria. Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase up to 24 months from day 1, cycle 1 of the treatment. The Follow-up Phase will continue until study completion, which is defined as 24 months after the last subject receives the first dose of real life SOC treatment. Subjects will be treated until disease progression, unacceptable toxicity, or other reasons. The primary objective of the study is to evaluate the overall response rate (ORR) of real-life SOC treatments in participants with RRMM patients. The secondary and exploratory objectives of the study are the further evaluation of the clinical benefit, patient-reported outcomes (PROs), safety and the potential correlation of rate of minimal residual disease (MRD) negativity with duration of response (DOR), PFS and OS. Methods: Demographic and patient characteristics, clinical response parameters, PRO measures, health care resource utilization, and safety data will be descriptively summarized. Due to the observational nature of the study, there is no direct hypothesis being tested. Therefore, the sample size is based on the clinically acceptable precision of the 95% confidence interval for the primary objective of describing ORR under real-life current SOC treatment. For the primary endpoint exact 95% confidence intervals by the Clopper-Pearson method will be calculated. For therapies available to treat participants with RRMM the reported ORR is 30% or less. When the sample size is 230, using the large sample normal approximation, the width of a two-sided 95% confidence interval for the observed proportion will vary from 0.107 to 0.130 for an expected proportion varying from 0.20 to 0.40. Disclosures Moreau: AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Juno: Consultancy. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Goldschmidt:ArtTempi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Takeda: 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, Other, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. Cavo:Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen, Celgene: Speakers Bureau; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Gay:Janssen: 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; 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; Roche: 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: Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Van De Donk:AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: 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, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Potamianou:Janssen-Cilag: Employment. Sakabedoyan:Janssen-Cilag: Employment. Strulev:Jansen Pharmaceutica NV: Employment. Nesheiwat:Legend Biotech: Employment, Equity Ownership. Bergmans:Janssen-Cilag: Employment. Rizvi:Legend Biotech: Employment, Equity Ownership. Pilatowicz:Janssen-Cilag: Employment. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.

Description: Introduction: Chimeric Antigen Receptor (CAR) based cellular-immunotherapies have demonstrated significant clinical efficacy in haematological malignancies. However, the progress of cellular-immunotherapy for the treatment of Acute Myeloid Leukaemia (AML) has failed to gain momentum due to the lack of targetable tumour specific antigens. CD38 is a transmembrane glycoprotein expressed in lymphoid and myeloid cells with high expression in plasma B-cells, and is a well validated target for anti-CD38 therapy in Myeloma. A recent study has furthermore shown that a proportion of AML patients express CD38 on their leukemic blasts. TNF-related apoptosis-inducing ligand (TRAIL) receptor DR4 is another targetable antigen which has been shown to be expressed in 70% of AML patients. In this study, we investigate the therapeutic efficacy of "affinity-optimized" variant(s) of CD38 CAR and membrane bound TRAIL on NK-cell based platforms which can target AML blasts with high expression of CD38 (CD38high AML). The CAR variant is a CAR which binds with lower affinity to CD38 expressed on healthy immune cells such as CD38positive NK cells, while targeting CD38high AML. The membrane bound TRAIL variant (TRAIL4c9) is a mutant which binds with higher affinity to TRAIL-DR4 on AML cells, whilst avoiding binding to decoy receptors. We hypothesize that genetically modifying NK cells to express "affinity optimized" CD38 CARand/or TRAIL4c9 can effectively eliminate CD38high AML cells. Methods: AML cell lines THP-1, U937, and KG1a were immunophenotyped for CD38 and TRAIL-DR4 expression. Retrovirally transduced CD38 CAR-KHYG1 NK cells were used as immune effector cells and were co-cultured with AML cell lines in cytotoxicity assays. CD38low AML cell line KG1a was pre-treated with 10nM all-trans-retinoic acid (ATRA) to upregulate CD38 expression and were subsequently co-cultured with CD38 CAR-KHYG1 in cytotoxicity assays. CD38 CAR-KHYG1 was also co-cultured with n=4 patient derived AML cells in cytotoxicity assays. Using Maxcyte GT electroporation system primary donor derived IL-2 activated NK cells were either mock electroporated, or electroporated with TRAIL4c9 m-RNA orCD38 CAR m-RNA and subsequently co-cultured with THP-1 or ATRA pre-treated KG1a in a cytotoxicity assay. Expression of pro-apoptotic, anti-apoptotic and ligands for checkpoint inhibitory receptors was analysed by immunoblotting or flowcytometry. Results: Based on immunophenotyping, we classified AML cell lines as CD38high (THP-1), CD38moderate (U937) and CD38low (KG1a). CD38 CAR-KHYG1 was significantly more cytotoxic than MOCK KHYG1 against CD38high THP-1, at E:T ratios of 2.5:1, 5:1 and 10:1. CD38 CAR-KHYG1 were also more cytotoxic than MOCK KHYG1 against CD38moderate U937 at multiple E:T ratios; albeit the increase in cytotoxicity was at a much lower level in comparison to THP-1 (Fig 1a). Pre-treatment of CD38low KG1a cells with 10nM ATRA upregulated the cell surface expression of CD38, which were subsequently eliminated by CD38 CAR KHYG1 at E:T ratios of 2.5:1, 5:1 and 10:1. KG1a was intrinsically resistant to NK cells as compared to THP-1 and U937 (Fig 1b). This could partly be explained by the high intracellular expression of Bcl-xL, and higher cell surface expression of Nectin-1 and Sialic acid which are the ligands for checkpoint inhibitory receptors CD96 and Siglec-7/9 respectively on NK cell (Fig 1c). CD38 CAR-KHYG1 mounted a potent cytotoxic response against primary CD45intermediate AML blasts (n=4 patients) at multiple E:T ratios, and the extent of CAR induced cytotoxicity correlated with the cell surface CD38 expression on the primary AML blasts (R2=0.87) (Fig 1d,e). TRAIL4c9 or CD38 CAR m-RNA electroporated primary donor-derived NK cells were also potent in eliminating THP-1 and ATRA pre-treated KG1a at multiple E:T ratios (Fig 1f). This demonstrates the potential of therapeutically treating AML patients, with high CD38 expression, with a combination of NK cells expressing "affinity-optimized" CD38 CAR and membrane bound TRAIL variant. Conclusion: The study demonstrates the therapeutic potential of an "affinity-optimized" CD38 CAR NK cell-based therapy, which can potentially be combined with membrane bound TRAIL expressing NK cells to target CD38high AML. In patients with CD38low expressing AML blasts, patients could be pre-treated with ATRA followed by the combination therapy of CD38 CAR and TRAIL expressing NK cells. Disclosures Stikvoort: Onkimmune Ltd., Ireland: Research Funding. Kirkham-McCarthy:Onkimmune Ltd., Ireland: Research Funding. Van De Donk:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: 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; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Mutis:Celgene: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; BMS: Research Funding; Novartis: Research Funding; Aduro: Research Funding; Onkimmune: Research Funding. Sarkar:Onkimmune: Research Funding. O'Dwyer:Onkimmune: Equity Ownership, 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; GlycoMimetics Inc: Research Funding; AbbVie: Consultancy; BMS: Research Funding.

Description: Introduction: Daratumumab (DARA) has potent single agent activity in relapsed/refractory multiple myeloma (RRMM). The effectivity of DARA is partially dependent on the expression of its target, CD38, on tumor cells. Upregulation of CD38 on MM cells by all-trans retinoic acid (ATRA) improved the ex vivo efficacy of DARA, even in DARA-resistant MM cells. We therefore evaluated the efficacy and safety of DARA combined with ATRA in RRMM patients in the DARA/ATRA study (NCT02751255). Methods: In part A of this prospective, multicenter phase 1/2 trial, DARA was administered according to the approved schedule (16 mg/kg; cycles 1-2: weekly; cycles 3-6: biweekly; cycles ≥7: monthly). In part B, ATRA was given twice daily during 3 days prior to each DARA infusion. DARA dosing was resumed according to the aforementioned schedule. Inclusion criteria were ≥2 prior lines of treatment, WHO performance score 0-2, adequate bone marrow reserve, kidney and hepatic function. Patients were enrolled in part B, after treatment in part A, if they developed disease progression (PD), or if they had insufficient response defined as 〈 minimal response (MR) after cycle 2, or 〈 partial response (PR) after cycle 3, and if they still fulfilled the other inclusion criteria. All patients gave written informed consent. In phase 1 of part B, we determined the maximum tolerated dose (MTD) of ATRA (dose levels: 15, 30 and 45mg/m2) and the recommended dose level (RDL) for phase 2. We here report overall response rate (ORR), progression free survival (PFS(A)), overall survival (OS) and adverse events (AEs) for all patients in part A. For patients treated at the RDL in part B, we report ORR, PFS(A), PFS for part A + B combined (PFS(A+B)) and AEs. Results: Between July 2016 and October 2017, 63 patients were enrolled in part A, baseline characteristics are described in Table 1. At data cut-off (July 1st, 2019), 6 patients were still on treatment in part A. The median duration of follow-up of surviving patients at data cut-off was 26 months (range 18.2 - 39.4 months). The ORR in part A was 41% (22% PR, 14% very good PR [VGPR] and 5% (stringent) complete remission; Figure 1). The median PFS(A) and OS from start of DARA for all enrolled patients were 7.0 months (95% CI 5.3-8.8) and 28.2 months (95% CI 20.4-36.0), respectively. Eight patients did not meet eligibility criteria for part B, and 1 patient refused further treatment in part B. In part B phase 1, 14 patients were treated with ATRA at the 3 dose levels. The MTD was not reached and the RDL for phase 2 was defined as 45mg/m2. At data cut-off, 34 patients were enrolled in part B phase 2, of whom 2 patients were still on treatment. Thirty-two patients stopped treatment due to PD (n=28) or withdrawal of consent (n=4). Next, we focused on all 42 patients who were treated at the RDL in part B (8 patients in phase 1, and 34 patients in phase 2). The ORR in part B was 5% (VGPR n=2). However, 57% achieved MR or stable disease (SD; Figure 1). During part A, median PFS(A) in these patients was 6.7 months (95% CI 2.7-10.6). When stratified by ≥PR vs SD/MR vs PD/not evaluable (NE), median PFS(A) was 9.9 months (95% CI 3.1-16.7) vs 3.2 months (95% CI 2.5-3.9) vs 1.2 months (95% CI 0.8-1.5), respectively. Addition of ATRA and re-intensification of DARA in DARA-refractory patients resulted in a median PFS(A+B) of 7.9 months (95% CI 5.6-10.1 months). When stratified by ≥PR vs SD/MR vs PD/NE in part A, median PFS(A+B) was 17.7 months (95% CI 9.6-25.7) vs 5.4 months (95% CI 3.8-7.0) vs 2.5 months (95% CI 2.1-2.9), respectively. The presence of extramedullary plasmacytomas (P=0.004 and P=0.012) and WHO ≥ 1 (P=0.002 and P=0.005) were associated with lower PFS(A) and PFS(A+B). Importantly, combination of ATRA with DARA did not increase the rate of AEs (Table 2). The incidence of any grade infusion related reactions (IRR) was 34.9%. There were no complications with red blood cell transfusions. Conclusion: Here, we report for the first time on the efficacy of DARA re-intensification, combined with ATRA in DARA-refractory patients. Overall, this approach resulted in a modest prolongation of PFS. Patients with primary DARA-refractory disease did not benefit from the addition of ATRA. However, in patients with ≥PR on DARA monotherapy prior to progression, addition of ATRA and re-intensification of DARA was of marked clinical benefit with an additional 7.8 months of disease control. The combination of DARA and ATRA was well tolerated and safe. Disclosures Minnema: Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Servier: Honoraria; Jansen Cilag: Honoraria. Levin:Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Kersten:Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding; Kite Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria. Mutis:Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding; Genmab: Research Funding. Zweegman:Celgene: 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, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Van De Donk:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: 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; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: 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; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ATRA for treatment of MM

Description: HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superior complement dependent cytotoxicity (CDC) activity, in addition to other effector mechanisms. HexaBody-CD38 carries the E430G mutation and binds a different epitope than the clinically validated CD38 monoclonal antibody daratumumab, which is currently being established as backbone therapy for the treatment of multiple myeloma. Introduction of the E430G mutationfacilitates the natural process of antibody hexamer formation through increased intermolecular Fc-Fc interactions after antigen binding at the cell surface (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). Improved IgG hexamer formation can increase binding of the hexavalent complement component C1q, thereby potentiating or unlocking antibody-mediated complement-dependent cytotoxicity (CDC). Preclinical data demonstrate highly potent CDC-mediated tumor cell kill in vitro in a panel of cell lines derived from hematological malignancies, including multiple myeloma (MM), B cell lymphoma and acute myeloid leukemia (AML). In these cell lines, at the highest dose tested (10 µg/mL), HexaBody-CD38 induced approximately 2-fold more CDC-mediated lysis compared to daratumumab. Of note, in those cell lines that were responsive to daratumumab in CDC assays (〉50% tumor cell lysis), CDC activity of HexaBody-CD38 was superior to daratumumab, with IC50 values for HexaBody-CD38 2.4- to 13-fold lower than for daratumumab. Moreover, HexaBody-CD38 unlocked CDC activity in 17 out of 28 tumor cell lines that were not sensitive to daratumumab in CDC assays (

Description: Background. The outcome of multiple myeloma (MM) patients is heterogeneous. In 2015, analyzing 4445 newly diagnosed MM (NDMM) patients enrolled into 11 clinical trials after a median follow-up of 46 months, a risk stratification algorithm named Revised-ISS (R-ISS) was developed combining International Staging System (ISS), chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization and serum lactate dehydrogenase (LDH) (Palumbo et al., JCO 2015). Here we report a mature follow-up of 5584 patients enrolled in 14 clinical trials, providing an updated report on the R-ISS prognostic role and highlighting potential improvements. Methods. Data from different European cooperative groups were collected through the European Myeloma Network (EMN) and registered in a big data platform developed by HARMONY, which is a European public-private partnership focusing on hematologic malignancies with unmet medical needs and providing a legal-ethical framework for international data sharing and analysis. The primary end point of this analysis was overall survival (OS) according to R-ISS. All NDMM patients received immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) as part of their upfront treatment. Results. 5584 NDMM patients with a median age of 65 years were analyzed after a median follow-up of 74 months. 35% of evaluable patients had ISS I disease, 40% ISS II and 25% ISS III. LDH was ≤ the upper limit of normal (ULN) in 87% of evaluable patients, 〉ULN in 13%. To define high-risk CA, we performed a multivariate Cox model for OS individually evaluating del(17p), t(4;14) and t(14;16) positivity. Del(17p) (HR 1.78, p

Description: Introduction: Daratumumab (DARA) monotherapy is effective and well tolerated in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. However, approximately 70% of patients do not respond and eventually all patients will develop progressive disease. DARA treatment results in depletion of CD38+ immune suppressor cells and thereby increased T cell frequencies. A partner drug with immune stimulating activity through a different mechanism of action could further improve the efficacy of DARA. As a single agent, the Programmed Death (PD)-1 checkpoint inhibitor nivolumab induced only stable disease in 67% of RRMM. Immune modulation through targeting CD38 combined with blocking the PD-1/PD-L1 axis may lead to improved T and NK cell activity and therefore better anti-MM efficacy. Preclinical studies showed that cyclophosphamide has synergistic activity with both DARA and PD-1 inhibitors. In this study, we investigate the efficacy and safety of DARA combined with nivolumab, with or without low-dose cyclophosphamide, in RRMM. This trial is registered at ClinicalTrials.gov as NCT03184194. Methods: In part A of this prospective multicenter phase 2 trial, we treated 6 patients with nivolumab-daratumumab (ND), and subsequently 6 patients with nivolumab-daratumumab-cyclophosphamide (NDc) as safety run-in. Next, 28 patients were randomized between both treatment arms at a 1:1 ratio. Twenty additional patients will be treated with either ND or NDc in part B, based on safety and efficacy data as derived in part A. Patients were treated with 28-day cycles until progressive disease. Daratumumab 16 mg/kg i.v. was administered weekly in cycles 1-2, biweekly in cycles 3-6 and every 4 weeks from cycle 7. Nivolumab was administered biweekly (240mg i.v) in cycles 1-6 (in cycle 1 on day 2 and 16) and every 4 weeks (480mg i.v ) thereafter. In the NDc arm, low-dose oral cyclophosphamide (50mg once daily) was given continuously. Inclusion criteria were age ≥18 years, WHO performance score of 0-2, ≥2 prior therapies, lenalidomide-refractory disease, and prior treatment with a proteasome-inhibitor-containing regimen for ≥2 consecutive cycles. Main exclusion criteria were platelet count