Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma

Saad Z Usmani, Hareth Nahi, Wojciech Legiec, Sebastian Grosicki, Vladimir Vorobyev, Ivan Spicka, Vania Hungria, Sibirina Korenkova, Nizar J Bahlis, Max Flogegard, Joan Bladé, Philippe Moreau, Martin Kaiser, Shinsuke Iida, Jacob Laubach, Hila Magen, Michele Cavo, Cyrille Hulin, Darrell White, Valerio De Stefano, Kristen Lantz, Lisa O'Rourke, Christoph Heuck, Maria Delioukina, Xiang Qin, Ivo Nnane, Ming Qi, Maria-Victoria Mateos, Saad Z Usmani, Hareth Nahi, Wojciech Legiec, Sebastian Grosicki, Vladimir Vorobyev, Ivan Spicka, Vania Hungria, Sibirina Korenkova, Nizar J Bahlis, Max Flogegard, Joan Bladé, Philippe Moreau, Martin Kaiser, Shinsuke Iida, Jacob Laubach, Hila Magen, Michele Cavo, Cyrille Hulin, Darrell White, Valerio De Stefano, Kristen Lantz, Lisa O'Rourke, Christoph Heuck, Maria Delioukina, Xiang Qin, Ivo Nnane, Ming Qi, Maria-Victoria Mateos

Abstract

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) μg/mL for DARA SC and 496 (SD, 231) μg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice. (Clinicaltrials gov. Identifier: NCT03277105.

Figures

Figure 1.
Figure 1.
Response rates over time. Response rates from the primary COLUMBA analysis (median follow-up, 7.5 months) and the final COLUMBA analysis (median follow-up, 29.3 months) for patients in the intent-to-treat population. Response rates are shown for the DARA SC and DARA IV groups. ORR: overall response rate; VGPR: very good partial response; PR: partial response; DARA SC: daratumumab by subcutaneous administration; DARA IV: daratumumab by intravenous administration; CR: complete response; sCR: stringent complete response.
Figure 2.
Figure 2.
Kaplan-Meier estimates for progression-free survival in the intent-to-treat population. Data included all patients who underwent randomization. Estimated 12-month progression-free survival (PFS) rates are shown. DARA SC: daratumumab by subcutaneous administration; DARA IV: daratumumab by intravenous administration; CI: confidence interval.
Figure 3.
Figure 3.
Kaplan-Meier estimates for overall survival in the intent-to-treat population. Data included all patients who underwent randomization. Estimated 24-month overall survival (OS) rates are shown. DARA SC: daratumumab by subcutaneous administration; DARA IV: daratumumab by intravenous administration; CI: confidence interval.
Figure 4.
Figure 4.
Kaplan-Meier estimates for progression-free survival in the intent-to-treat population. Data included all patients who underwent randomization. PFS2: time from randomization to progression on next line of therapy or death, based on investigator assessment; DARA SC: daratumumab by subcutaneous administration; DARA IV: daratumumab by intravenous administration; CI: confidence interval.
Figure 5.
Figure 5.
Plot of mean (standard deviation) daratumumab serum peak and trough concentrations over time. Data represented as mean with error bars denoting standard deviation for patients who received ≥1 administration of study therapy and had ≥1 pharmacokinetics sample concentration value after the first dose administration. C: cycle; D: day; Pre: pre-dose; EOD: end of dose; PK: pharmacokinetics; DARA SC: daratumumab by subcutaneous administration; DARA IV: daratumumab by intravenous administration.

References

    1. de Weers M, Tai YT, van der Veer MS, et al. . Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840-1848.
    1. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. . Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124(21):3474.
    1. Overdijk MB, Verploegen S, Bogels M, et al. . Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-321.
    1. Overdijk MB, Jansen JH, Nederend M, et al. . The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking. J Immunol. 2016;197(3):807-813.
    1. Krejcik J, Casneuf T, Nijhof IS, et al. . Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384-394.
    1. Adams HC III, Stevenaert F, Krejcik J, et al. . High-parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action. Cytometry A. 2019;95(3):279-289.
    1. Casneuf T, Adams HC III, van de Donk NWCJ, et al. . Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab. Leukemia. 2020;35(2):573-584.
    1. DARZALEX® (daratumumab) injection, for intravenous use [packet insert]. Horsham, PA: Janssen Biotech, Inc.; October 2021.
    1. European Medicines Agency. Darzalex 20 mg/mL concentrate for solution for infusion. Summary of product characteristics. . Accessed 11 March 2021.
    1. Mateos MV, Nahi H, Legiec W, et al. . Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370-e380.
    1. DARZALEX FASPRO™ (daratumumab and hyaluronidase-fihj) [package insert]. Horsham, PA: Janssen Biotech, Inc; November 2021.
    1. Xu XS, Yan X, Puchalski T, et al. . Clinical implications of complex pharmacokinetics for daratumumab dose regimen in patients with relapsed/refractory multiple myeloma. Clin Pharmacol Ther. 2017;101(6):721-724.
    1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. . International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548.
    1. Rajkumar SV, Harousseau JL, Durie B, et al. . Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691-4695.
    1. Lokhorst HM, Plesner T, Laubach JP, et al. . Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207-1219.
    1. Lonial S, Weiss BM, Usmani S, et al. . Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-1560.
    1. Usmani SZ, Nahi H, Plesner T, et al. . Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020;7(6):e447-e455.
    1. Mateos MV, Usmani SZ, Grosicki S, et al. . Randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (Pts) with relapsed or refractory multiple myeloma (RRMM): body weight subgroup analysis of COLUMBA. Blood. 2019;134(Suppl 1):S1906.
    1. Usmani SZ, Mateos MV, Hungria V, et al. . Greater treatment satisfaction in patients receiving daratumumab subcutaneous vs. intravenous for relapsed or refractory multiple myeloma: COLUMBA clinical trial results. J Cancer Res Clin Oncol. 2021;147(2):619-631.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe