MOR202 with Low-Dose Dexamethasone (Dex) or Pomalidomide/Dex or Lenalidomide/Dex in Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis of a Phase I/IIa, Multicenter, Dose-Escalation Study
Authors: Raab Marc S , Chatterjee Manik , Goldschmidt Hartmut , Agis Hermine , Blau Igor , Einsele Hermann , Engelhardt Monika , Ferstl Barbara , Gramatzki Martin , Rollig Christoph , Weisel Katja , Jarutat Tiantom , Weinelt Dominika , Winderlich Mark , Peschel Christian 
Published: October 2019

Abstract
Background: CD38 is a type II transmembrane glycoprotein widely expressed in many hematological malignancies including multiple myeloma. MOR202, a human IgG1 CD38 monoclonal antibody demonstrates cytotoxic activity. The main mode of action for MOR202-induced cell lysis is through antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis. MOR202 does not induce complement-dependent cytotoxicity, a suspected major contributor to infusion-related reactions (IRRs) observed with other monoclonal antibodies. MOR202 has demonstrated activity as monotherapy and synergy in combination with the immunomodulatory drugs lenalidomide (LEN) and pomalidomide (POM) in preclinical models of multiple myeloma.
Methods: The primary objectives of this multicenter, dose-escalation phase I/IIa study in patients with RRMM (NCT01421186) are to evaluate the safety, and to determine the maximum tolerated dose (MTD)/recommended phase II dose of MOR202. We present the primary analysis of safety and efficacy data from patient cohorts treated with MOR202 at doses of 4, 8 and 16 mg/kg q1w plus Dex (≤40 mg), or MOR202 at 8 or 16 mg/kg q1w plus LEN/Dex or POM/Dex. MOR202 infusion time was 2 hours for all three regimens, which was successfully reduced to 30 minutes for the majority of patients at the time of primary analysis (cutoff 31 Dec 2017).
Results: As of 31 December 2017, 91 patients had been treated, 56 at the doses previously described: 18 patients were treated with MOR202 + Dex, 17 with MOR202 + LEN/Dex and 21 with MOR202 + POM/Dex. Before entering the study, patients had undergone a median of 3, 2 and 3 prior treatment lines, respectively. Notably all patients in the MOR202 + POM/Dex group were refractory to lenalidomide. The MTD of MOR202 was not reached. The combinations were generally well tolerated. In the 56 patients, grade ≥3 adverse events (AEs) were mainly hematological in nature. Two patients discontinued due to a MOR202-related AE (one a grade 4 thrombocytopenia and one a grade 3 bacterial infection complicated by acute kidney failure). IRRs to MOR202 (all grade 1 or 2) were observed in 4/56 (7%) patients. These mainly occurred during the first infusion. Twelve of 16 patients remaining on study at the time of primary completion received MOR202 as a 30 minute infusion without obvious safety concerns. In patients treated with MOR202 + Dex, 28% (5/18) showed a response: 3 partial responses (PRs) and 2 very good PRs (VGPRs). Higher response rates of 65% and 48% were observed in patients treated with MOR202 + LEN/Dex (11/17, 7 PRs, 2 VGPRs, 2 complete responses [CRs]) and MOR202 + POM/Dex (10/21, 5 PRs, 3 VGPRs and 2 CRs) respectively. Median time on study was 3.8 months for patients treated with MOR202 + Dex, 9 months for patients who received MOR202 + LEN/Dex and 4.7 months for those treated with MOR202 + POM/Dex. Longest response duration was 27.6 months (MOR202 + POM/Dex). Median progression-free survival was 8.4 months in patients treated with MOR202 + Dex, was not reached in those receiving MOR202 + LEN/Dex and was 17.5 months in those receiving MOR202 + POM/Dex.
Conclusions: MOR202 administered as infusions as short as 30 minutes at doses up to 16 mg/kg with Dex or in combination with LEN/Dex or POM/Dex in heavily pretreated patients with RRMM showed a favorable safety profile, including good infusion tolerability. Promising efficacy and long-lasting tumor control were observed for MOR202 + Dex and in particular for MOR202 combined with LEN/Dex or POM/Dex.

Disclosures
Raab: Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Goldschmidt:Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy. Agis:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Prothena: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Ferstl:Janssen Cilag: Honoraria, Other: Travel EHA. Gramatzki:Affimed: Research Funding. Rollig:Bayer: Research Funding; Janssen: Research Funding. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jarutat:Morphosys AG: Employment. Weinelt:Morphosys AG: Employment. Winderlich:Morphosys AG: Employment. Peschel:Morphosys AG: Honoraria.