Abstract: Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex). METHODS Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. RESULTS The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age 〉 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or 〉 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles. CONCLUSION Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance.

Abstract: 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.

Abstract: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P 〈 .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P 〈 .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Abstract: Primary cardiac lymphoma (PCL), a rare disease, often presents with symptoms resembling other cardiac diseases. The correct diagnosis is crucial, as cardiac lymphoma can be cured with immuno‐chemotherapy. PCL has a high risk of central nervous system recurrence (CNS); therefore, screening for CNS involvement and even prophylaxis may be necessary.

Abstract: 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 & lt;50% of expected and a creatinine clearance of & lt;20 ml/minute. We here report the overall response rate (ORR) on induction treatment, progression free survival (PFS) and OS, treatment discontinuation and toxicity of the first 23/65 eligible unfit and 23/65 frail patients during induction therapy. In addition, we present the mortality rate for all patients who were included in the study (65 unfit, 67 frail), with data cut-off June 18, 2019. Results The demographics of the first 23 unfit and 23 frail patients are described in Table 1. Median follow-up of these first 23 unfit and 23 frail patients is 12.7 months (range 9.1-18.3) and 13.4 months (range 9.2-17.7), respectively. ORR during induction was 87% in unfit (48% partial response [PR] and 39% very good partial response [VGPR] ) and 78% in frail (48% PR, 26% VGPR, 4% stringent complete response). Nine months PFS rates were 78% (95% Confidence Interval [CI] 55-90) and 61% (95% CI 38-77), respectively. Nine months OS rates were 100% and 83% (95% CI 60-93), respectively. Sixteen/23 (70%) unfit and 14/23 (61%) frail patients completed induction treatment with Ixa-Dara-dex. Reasons for treatment discontinuation were progressive disease (PD, n=5), toxicity (n=1) and incompliance (n=1) in unfit and intercurrent death (n=3, all within 3 cycles), PD (n=2), incompliance (n=2) and other reasons (n=2) in frail. The median and inter-quartile range of relative dose intensity (RDI) for respectively unfit and frail were 0.96 and 0.91 for Ixa, 0.98 and 0.96 for Dara and 1.0 and 0.99 for dex. Toxicity is described in Table 2. Hematological toxicity was limited, being mainly neutropenia (in unfit both 4% grade 3 and 4; in frail 4% grade 3 and 13% grade 4) and thrombocytopenia occurring only in frail (17% grade 3, 4% grade 4). Non-hematological toxicity was manageable, with grade 3 infections occurring in 9% of both unfit and frail patients. In both arms, there were no infusion related reactions and only 4% grade 3 neuropathy was reported. Additionally, we investigated the mortality rate of all included 65 unfit and 67 frail patients, with a limited follow-up of 7.1 months (range 1-18.3) and 8.8 months (range 0.4-17.7), respectively. The mortality rate was only 2% in unfit (1/65 due to PD). Thirteen/67 (19%) of frail patients died, which was caused by infections (n=6; 3 pneumonia, 1 influenza B, 1 erysipelas), sudden death (n=2), organ dysfunction (n=2), incompliance (n=1) and PD (n=2). Early death rate (≤3 months of registration) was 0% in unfit and 8/67 (12%) in frail. Conclusion Ixa-Dara-dex is an effective therapeutic regimen in unfit patients with limited toxicity, not giving rise to (early) mortality. Additionally, in the majority of frail patients this regimen is active and feasible. However, better identification and support of those patients is warranted, as we observed early mortality due to vulnerability and infections. Disclosures Van De Donk: Janssen Pharmaceuticals: 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; 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. 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. Levin: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; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Zweegman: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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Response to the CD38-targeting antibody daratumumab is significantly associated with CD38 expression levels on the tumor cells. Resistance to daratumumab is accompanied by increased expression of complement-inhibitory proteins.

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

Abstract: 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 ( 〈 50% tumor cell lysis), including cell lines with lower expression of CD38 or higher expression of the complement inhibitory protein CD59. Importantly, in pilot experiments that are part of an ongoing larger study, HexaBody-CD38 was able to effectively kill MM cells from patients in CDC assays ex vivo, including in one patient that had relapsed from daratumumab (Figure 1). In addition to superior CDC, HexaBody-CD38 was shown to induce comparable antibody-dependent cell mediated cytotoxicity (ADCC) and antibody-dependent cell mediated phagocytosis (ADCP) as daratumumab. HexaBody-CD38 demonstrated more efficient inhibition of CD38 cyclase activity, which has been postulated to contribute to immune suppression in the tumor microenvironment. Importantly, in the presence of monocytes, HexaBody-CD38 treatment resulted in the removal of CD38 from the cell membrane of CD38 expressing cells, including T regulatory cells. This suggests downmodulation of CD38 as another potential mechanism to reduce CD38-generated metabolites and associated immune suppression. Finally, HexaBody-CD38 induced promising anti-tumor activity in vivo in PDX models of diffuse large B cell lymphoma in nude mice. Anti-tumor activity was associated with CD38 expression levels. In conclusion, HexaBody-CD38 is a novel CD38 antibody that shows superior capacity to induce CDC-mediated tumor cell kill compared to daratumumab, including in tumor samples from MM patients. Furthermore, HexaBody-CD38 induces FcγR-mediated effector functions and effectively inhibits CD38 enzymatic activity, either directly or indirectly by removal of CD38 from the cell membrane, thereby potentially contributing to immune activation. Targeting CD38 with HexaBody-CD38 could have therapeutic potential in daratumumab-naïve and -refractory MM patients, as well as in CD38-positive tumors in which daratumumab does not have single agent efficacy, such as DLBCL and AML. The promise of HexaBody-CD38 warrants further clinical investigation in CD38-positive hematological malignancies, including MM, B cell lymphoma and AML. Disclosures De Goeij: Genmab BV: Employment, Other: stock and/or warrants. Janmaat:Genmab BV: Employment, Other: stock and/or warrants. Andringa:Genmab BV: Employment, Other: stock and/or warrants. Kil:Genmab: Employment, Other: stock and/or warrants. Van Kessel:Genmab: Other: stock and/or warrants. Lingnau:Genmab: Employment, Other: stock and/or warrants. Freidig:Genmab BV: Employment, Other: stock and/or warrants. Mutis:Onkimmune: Research Funding; BMS: Research Funding; Janssen Pharmaceuticals: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Aduro: Research Funding. Sasser:Genmab: Employment, Other: stock and/or warrants. Breij:Genmab: Employment, Other: stock and/or warrants. Van De Donk: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; Novartis: 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; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Roche: Membership on an entity's Board of Directors or advisory committees. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Satijn:Genmab BV: Employment, Other: stock and/or warrants.

Abstract: 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 〈 75x109/L, absolute neutrophil count 〈 1.0x109/L, FEV1 〈 50%, significant hepatic or renal dysfunction (CrCl 〈 30 mL/min), or active autoimmune disease or inflammatory disorder. All patients gave written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki. In this first planned interim analysis we report on efficacy (overall response rate (ORR)) and safety of part A of the study. Results: Between February 2018 and January 2019, 40 patients were enrolled in part A of this study. The demographics are described in Table 1. At data cut-off (July 1st 2019), 13 patients were still on treatment. Median follow-up of surviving patients is 8.6 months (range 5.0-16.1). The ORR was 50% in both treatment groups (Figure 1); the disease control rate (≥ stable disease) was 85% for ND and 80% for NDc. Ten patients (25%) died due to progressive disease, which was equally distributed over treatment arms. Two patients died during NDc treatment: one (2.5%) due to a cardiac arrest and one (2.5%) due to an Aspergillus fumigatus infection. Non-hematologic toxicity was manageable: daratumumab-associated infusion related reactions (IRRs) occurred in 8 (20%) patients, all during the first administration and all grade ≤3. No IRRs related to nivolumab were reported. Two immune-mediated adverse events occurred: both concerned grade 2 hypothyroidism. The infection rate was higher in patients treated with NDc (24 infections in 12 patients; CTC grade ≥3 in 25% of infections), compared to ND treatment (13 infections in 9 patients; CTC grade ≥3 in 8%). A higher need for supportive care in the form of granulocyte-colony stimulating factor, erythrocyte- and/or platelet transfusion was found in the NDc arm (n=10; 50%), compared to ND treatment (n=6; 30%). Conclusion: Here we show for the first time that, although follow-up is still short, the combination of daratumumab and nivolumab may be a new therapeutic regimen with an acceptable safety profile in RRMM. Addition of low-dose cyclophosphamide did not improve ORR, but increased the frequency of infections and hematologic toxicity, when compared to ND alone. Therefore, the nivolumab-daratumumab regimen was selected for further evaluation in part B. Disclosures Minnema: Gilead: Honoraria; Amgen: Honoraria; Jansen Cilag: Honoraria; Servier: Honoraria; Celgene Corporation: Honoraria, Research Funding. Bos:Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Mutis:Genmab: Research Funding; Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, 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. Levin:Abbvie: 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; Janssen: 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 ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Van De Donk: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; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Takeda: 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; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab: off-label treatment for Multiple Myeloma