Randomized, Open-Label, Non-Inferiority, Phase 3 Study of Subcutaneous (SC) Versus Intravenous (IV) Daratumumab (DARA) Administration in Patients with Relapsed or Refractory Multiple Myeloma: Columba Update
Authors: Usmani Saad Z. , Mateos Maria-Victoria , Nahi Hareth , Grosicki Sebastian , Vorobyev Vladimir I. , Spicka Ivan , Hungria Vania T.M. , Korenkova Sibirina , Flogegard Max , Bladé Joan , Moreau Philippe , Kaiser Martin F. , Iida Shinsuke , Laubach Jacob P. , Masterson Tara , Lantz Kristen Anne , O'Rourke Lisa , Heuck Christoph , Qin Xiang , Parasrampuria Dolly A. , Qi Ming , Bahlis Nizar 
Published: November 2019

INTRODUCTION: Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38, is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma (MM).To improve safety and reduce patient and healthcare provider burden, a subcutaneous (SC) formulation of DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label, non-inferiority COLUMBA study (NCT03277105) evaluated the efficacy, PK, and safety of DARA SC vs DARA IV in patients (pts) with RRMM. The results, showing the study met both co-primary endpoints (overall response rate [ORR] and Ctrough) at a median follow-up of 7.5 months, were previously presented. Here, we present updated data with longer follow-up.
METHODS: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV infusion) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR; analyzed by Farrington-Manning test, with non-inferiority defined as 60% retention of ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1; non-inferiority defined as the lower bound of 90% confidence interval [CI] for the ratio of the geometric means [GM] ≥80%). Secondary endpoints included rates of infusion-related reactions (IRRs), progression-free survival (PFS), very good partial response or better (≥VGPR), and complete response or better (≥CR).
RESULTS: A total of 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median age was 67 yrs (20% ≥75 yrs). Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% of pts were previously treated with both PI(s) and IMiD(s). 82.2% of pts were refractory to the last line of prior therapy, and 49.4% were refractory to both PI and IMiDs. 26.3% and 17.3% of pts had a high-risk cytogenetic abnormality at baseline in the DARA SC and DARA IV groups, respectively. After a median follow-up of 13.8 months, ORR was improved from 41.1% to 43.7% for DARA SC and 37.1% to 39.4% for DARA IV (Figure). ORR were comparable across all subgroups, including body weight. Rates of deep responses (≥VGPR, ≥CR) were similar between DARA SC and DARA IV, and deeper with longer follow-up (Figure). Median duration of treatment (~5.5 months) was similar for DARA SC and DARA IV. A significantly lower rate of IRRs was observed with DARA SC vs DARA IV. At the time of data cutoff, 118 pts (evenly distributed across both arms) continued treatment on study.
CONCLUSIONS: With longer follow-up, safety and efficacy data continue to support that DARA SC and DARA IV have similar safety profiles with a statistically significant reduction in IRR rates. DARA SC has a reduced treatment burden due to a considerably shorter administration duration, and DARA SC pts reported higher treatment satisfaction. Collectively, the data demonstrate a favorable benefit/risk profile for the use of an 1800 mg flat dose of DARA SC.

Disclosures
Usmani: Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Mateos:Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hungria:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Teijin Pharma: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Astellas: Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Bahlis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

OffLabel Disclosure:
This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.