A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma: First Report of Efficacy and Safety
Authors: Nadeem Omar , Redd Robert , Stampleman Laura V. , Matous Jeffrey V. , Yee Andrew J. , Zonder Jeffrey A. , Kin Andrew , Rosenblatt Jacalyn , Bustoros, MD Mark , Prescott Julia , Savell Alexandra , Guimond Kathleen , Frey Erin , Styles Rachel , Bielawski Adrienne , Boehner Cody J , Su Nang Kham , Multiple Myeloma Research Foundation Multiple Myeloma Research Foundation , The Leukemia & Lymphoma Society The Leukemia & Lymphoma Society , Blood Cancer Research Partnership BCRP , Sperling Adam S , Bianchi Giada , Laubach Jacob P. , Castillo Jorge J. , Munshi Nikhil C. , Anderson Kenneth C. , Richardson Paul G. , Trippa Lorenzo , Ghobrial Irene M. 
Published: November 2019

Introduction: Daratumumab (DARA) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with DARA in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. This is a single-arm, phase II study evaluating efficacy and safety of using DARA in patients with HR-MGUS and LR-SMM.
Methods: Patients enrolled on this study met eligibility for either: 1) HR-MGUS defined as <10% bone marrow plasma cells and <3g/dL M protein and at least 2 of the following 3 criteria: Abnormal serum free light chain ratio (SFLC) of <0.26 or >1.65, M protein ≥ 1.5g/dL or non-IgG M protein or 2) LR-SMM with one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio <0.125 or >8. DARA (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine proportion of patients who are in VGPR or greater after 20 cycles of DARA. Secondary objectives included duration of response, safety, and rates of MRD negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease.
Results: A total of 31 patients were enrolled on this study from January 2018 to June 2019 with participation of five sites. The median age for all patients enrolled was 59 years (range 41 to 76), with 16 males (52%) and 15 females (48%). Majority of patients enrolled were classified as LR-SMM (n = 29; 94%) and the remaining 2 patients had HR-MGUS (6%). Twenty-eight patients have started treatment and are included in toxicity assessment and 15 patients have at least completed cycle 6 (range 1-19). Grade 3 toxicities were rare and only experienced in 2/28 patients including diarrhea (n =1) and flu like symptoms (n = 1). Most common toxicities of any grade included fatigue (n = 13/28, 46%), cough (n = 11/28, 39%), nasal congestion (n = 10/28, 36%), headache (n = 8/28, 29%), hypertension (n = 8/28, 29%), nausea (n = 8/28, 29%), and white blood cell decreased (n = 8/28, 29%). All patients remain on treatment and none have discontinued therapy due to toxicity. Best overall responses were CR (n = 1, 3%), VGPR (n = 3, 11%), PR (n = 9, 32%, 2 unconfirmed), MR (n = 10, 36%), SD (n = 5, 18%, 1 unconfirmed), PD (n = 0, 0%), and NE (n = 1, 4%). Minimal response or better was observed in 82% of patients (23/28) and PR or better was observed in 46% of patients (13/28). In the 15 patients who completed at least 6 cycles, response rates were as follows: MR or better 93% (14/15), PR or better 73% (11/15) and VGPR or better 20% (3/15). Median time to VGPR was 3.2 months. Median overall survival and progression-free survival have not been reached. Thus far, no patients have progressed to MM.
Conclusion: DARA is very well tolerated among patients with HR-MGUS and LR-SMM. Responses are seen in majority of patients and there has been no observed progression to MM to date. Early therapeutic intervention in this precursor patient population appears promising.

Disclosures
Nadeem: Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Yee:Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Zonder:Celgene Corporation: Consultancy, Honoraria, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; Celgene: Research Funding; BMS: Research Funding; Parexel: Consultancy; Merck: Other: Advisory Board; BMS: Other: Advisory Board ; Amgen: Other: Advisory Board; Imaging Endpoint: Consultancy. Bustoros, MD:Takeda: Honoraria. Prescott:Janssen: Equity Ownership. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Munshi:Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Adaptive: Consultancy. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Oncopeptides: 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; Bristol-Myers Squibb: Research Funding. Ghobrial:Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy.

OffLabel Disclosure:
Daratumumab has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.