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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

ABSTRACT: BACKGROUND:Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS:A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ?3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ?3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS:Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ?3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS:The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.

SUBMITTER: Chari A

PROVIDER: S-EPMC6587745 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

Chari Ajai A Lonial Sagar S Mark Tomer M TM Krishnan Amrita Y AY Stockerl-Goldstein Keith E KE Usmani Saad Z SZ Londhe Anil A Etheredge Delores D Fleming Sarah S Liu Baolian B Ukropec Jon J Lin Thomas S TS Jagannath Sundar S Nooka Ajay K AK

Cancer 20181105 22

<h4>Background</h4>Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM).<h4>Methods</h4>A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients re ...[more]

PMID: 30395359

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Project description:IntroductionDaratumumab is a human IgGκ monoclonal antibody targeting CD38. Despite the demonstrated benefit of daratumumab in multiple myeloma, not all patients have access to commercially available daratumumab. Here we report a pooled analysis of patients from the UK, Spain, Italy, and Russia enrolled in an open-label, early access treatment protocol (EAP) that provided daratumumab (16 mg/kg) monotherapy to patients with heavily pre-treated relapsed or refractory multiple myeloma (RRMM).MethodsIntravenous daratumumab 16 mg/kg was administered to patients who had received ≥ 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or who were double refractory to both a PI and an IMiD. Safety and patient-reported outcomes data were collected.ResultsA total of 293 patients received ≥ 1 dose of daratumumab. The median duration of daratumumab exposure was 4.2 (range 0.03-24.1) months, with a median number of 13 (range 1-37) infusions. The overall response rate was 33.1%, and the median progression-free survival was 4.63 months. Grade 3/4 treatment-emergent adverse events occurred in 60.1% of patients, of which the most common were thrombocytopenia (18.8%), anemia (11.9%), and neutropenia (11.6%). The most common serious adverse events were pneumonia (4.4%) and pyrexia (4.1%). Infusion-related reactions occurred in 45.1% of patients. The median change from baseline in all domains of patient-reported outcome instruments (European Quality of Life Five Dimensions Questionnaire [EQ-5D-5L], European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ-C30], and EORTC Multiple Myeloma Module [QLQ-MY20]) was generally 0 or close to 0.ConclusionThese EAP results are consistent with those from previous trials of daratumumab monotherapy and confirm its safety in patients from Europe and Russia with heavily pre-treated RRMM.Trial registrationClinicalTrials.gov identifier, NCT02477891.

Project description:Immunotherapy is changing the paradigm of multiple myeloma (MM) management and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved for the treatment of this malignancy. Daratumumab exerts anti-myeloma activity by different mechanisms of action as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), direct apoptosis, and immunomodulation. After GEN501 and SIRIUS trials showed efficacy of daratumumab monotherapy in heavily pretreated relapsed-refractory multiple myeloma (RRMM), in patients with at least two previous line of therapy, two phase III trials demonstrated superior overall response rate (ORR) and progression free survival (PFS) using triplets daratumumab-bortezomib-dexamethasone (DVd) vs Vd (CASTOR) or daratumumab-lenalidomide-dexamethasone (DRd) vs Rd (POLLUX) in relapsed-refractory MM patients; so these combinations have been approved and introduced in clinical practice. The ongoing phase III CANDOR is evaluating the triplet daratumumab-carfilzomib-dexamethasone (DKd) vs Kd whereas phase III APOLLO trial is exploring daratumumab-pomalidomide-dexamethasone (DPd) vs PD. Many other trials exploring daratumumab combinations in relapsed-refractory MM are ongoing, and they will provide other interesting results. In newly diagnosed transplant-eligible patients, phase III CASSIOPEIA trial found the combination daratumumab-bortezomib-thalidomide-dexamethasone (Dara-VTd) significantly improves stringent Complete Response (sCR) rate and PFS compared with VTD, whereas in the phase II GRIFFIN study, comparing daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) vs VRD, sCR rate was significantly higher using quadruplet combination. Many studies are evaluating daratumumab in consolidation and maintenance therapy after autologous stem cell transplantation (ASCT). As regard patients ineligible for ASCT, a great efficacy of daratumumab-containing combinations was reported by the phase III trials ALCYONE and MAIA, exploring daratumumab-bortezomib-melphalan-prednisone (DVMP) vs VMP and daratumumab-lenalidomide-dexamethasone (DRd) vs Rd, respectively. These studies provided results never seen before in this setting. The aim of this paper is to critically review the results obtained with regimens containing daratumumab both in relapsed-refractory and in newly diagnosed MM.

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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

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Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma.

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