title: Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.
abstract: Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01615029.
authors.affiliation: Vejle Hospital and University of Southern Denmark, Vejle, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Plesner
authors.affiliation: Sarah Cannon Research Institute, University College London, London, United Kingdom.
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
authors.affiliation: Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Gimsing
authors.affiliation: Vejle Hospital and University of Southern Denmark, Vejle, Denmark.
authors.forename: Jakub
authors.initials: J
authors.lastname: Krejcik
authors.affiliation: Sarah Cannon Research Institute, University College London, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lemech
authors.affiliation: Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Monique C
authors.initials: MC
authors.lastname: Minnema
authors.affiliation: Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Lassen
authors.affiliation: LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.affiliation: Myeloma Unit, Division of Hematology, University of Turin, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: Genmab A/S, Copenhagen, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Lisby
authors.affiliation: Genmab A/S, Copenhagen, Denmark.
authors.forename: Linda
authors.initials: L
authors.lastname: Basse
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: A Kate
authors.initials: AK
authors.lastname: Sasser
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Guckert
authors.affiliation: Janssen Biologics, Leiden, The Netherlands; and.
authors.forename: Carla
authors.initials: C
authors.lastname: de Boer
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Nushmia Z
authors.initials: NZ
authors.lastname: Khokhar
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Howard
authors.initials: H
authors.lastname: Yeh
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Clemens
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Tahamtan
authors.initials: T
authors.lastname: Ahmadi
authors.affiliation: Department of Hematology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.affiliation: LeBow Institute for Myeloma Therapeutics, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003710:Demography; D003907:Dexamethasone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D012008:Recurrence; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C556306:daratumumab; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide