A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma

References

• Siegel RL, Miller KD, Jemal A, et al. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.
   PubMed Web of Science ®Google Scholar
• Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31:2443‐ 48.
   Web of Science ®Google Scholar
• Lancman G, Tremblay D, Barley K, et al. The effect of novel therapies in high- molecular- risk multiple myeloma. Clin Adv Hematol Oncol. 2017;15(11):870–879.
   PubMed Web of Science ®Google Scholar
• Orlowski RZ, Lonial S. Integration of novel agents into the care of patients with multiple myeloma [published correction appears in Clin Cancer Res. 2017; 23(10):2605]. Clin Cancer Res. 2016;22(22):5443–5452.
   PubMedGoogle Scholar
• Gay F, Jackson G, Rosiñol L, et al. Maintenance treatment and survival in patients with myeloma: a systematic review and network meta-analysis. JAMA Oncol. 2018;4(10):1389–1397.
   PubMed Web of Science ®Google Scholar
• Moreau P, Joshua D, Chng WJ, et al. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia. 2017;31(1):115–122.
   PubMed Web of Science ®Google Scholar
• Miguel JS, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055–1066.
   PubMed Web of Science ®Google Scholar
• Richardson PG, Oriol A, Beksac M, et al. OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781–794.
   PubMed Web of Science ®Google Scholar
• Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017;130(8):963–973.
   PubMed Web of Science ®Google Scholar
• Spencer A, Hungria VTM, Mateos MV, et al. Daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy analysis of CASTOR. Haematologica. 2018;103(12):2079–2087.
   PubMed Web of Science ®Google Scholar
• Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014;32(25):2712–2717.
   PubMed Web of Science ®Google Scholar
• Facon T, Kumar S, Plesner T, et al. Daratumumab, plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104–2115.
   PubMed Web of Science ®Google Scholar
• Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–1791.
   PubMed Web of Science ®Google Scholar
• Pulte ED, Dmytrijuk A, Nie L, et al. FDA approval summary: lenalidomide as maintenance therapy after autologous stem cell transplant in newly diagnosed multiple myeloma. Oncologist. 2018;23:734–739.
   PubMed Web of Science ®Google Scholar
• Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomized, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27–38.
   PubMed Web of Science ®Google Scholar
• Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–1219.
   PubMed Web of Science ®Google Scholar
• Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment‐refractory multiple myeloma (SIRIUS): an open‐label, randomised, phase 2 trial. Lancet. 2016;387:1551‐60.
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319‐31.
   Web of Science ®Google Scholar
• Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974‐81.
   PubMed Web of Science ®Google Scholar
• Palumbo A, Chanan‐Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754‐66.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Overdijk MB, Verploegen S, Bögels 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.
   PubMed Web of Science ®Google Scholar
• Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcgamma receptor-mediated cross-linking. J Immunol. 2016;197(3):807–813.
   PubMed Web of Science ®Google Scholar
• 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.
   Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Chiu C, Casneuf T, Axel A, et al. Daratumumab in combination with lenalidomide plus dexamethasone induces clonality increase and T-cell expansion: results from a phase 3 randomized study (POLLUX). Blood. 2016;128(22):4531.
   Web of Science ®Google Scholar
• Adams III HC, 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.
   PubMedGoogle Scholar
• Konopleva M, Rissling I, Andreeff M. CD38 in hematopoietic malignancies. Chem Immunol. 2000;75:189–206.
   PubMedGoogle Scholar
• Malavasi F, Deaglio S, Funaro A, et al. Evolution and function in the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88:841–886.
   PubMed Web of Science ®Google Scholar
• 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;7:311‐21.
   PubMed Web of Science ®Google Scholar
• Horenstein AL, Quarona V, Toscani D, et al. Adenosine generated in the bone marrow niche through a CD38- mediated pathway correlates with progression of human myeloma. Mol Med. 2016;22:694–704.
   PubMed Web of Science ®Google Scholar
• Chatterjee S, Daenthanasanmak A, Chakraborty P, et al. CD38 NAD(+)axis regulates immunotherapeutic anti-tumor T cell response. Cell Metab. 2018;27(1):85–100.
   PubMed Web of Science ®Google Scholar
• Dizon MF. The challenges of daratumumab in transfusion medicine. Lab Med. 2017;48:6–9.
   PubMed Web of Science ®Google Scholar
• Daratumumab injection, for intravenous use (package insert). Horsham, PA: Janssen Biotech, Inc; 2018.
   Google Scholar
• Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4(5):349–360.
   PubMed Web of Science ®Google Scholar
• Kubiczkova L, Pour L, Sedlarikova L, et al. Proteasome inhibitors – molecular basis and current perspectives in multiple myeloma. J Cell Mol Med. 2014;18:947–961.
   PubMed Web of Science ®Google Scholar
• Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal. 2011;5:101–110.
   PubMed Web of Science ®Google Scholar
• Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281–3290.
   PubMed Web of Science ®Google Scholar
• Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17(9):2734–2743.
   PubMed Web of Science ®Google Scholar
• Waxman AJ, Clasen S, Hwang W-T, et al. Carfilzomib-associated cardiovascular adverse events: a systematic review and meta-analysis. JAMA Oncol. 2018;4(3):e174519.
   PubMed Web of Science ®Google Scholar
• Chen-Scarabelli C, Corsetti G, Pasini E, et al. Spasmogenic effects of the proteasome inhibitor carfilzomib on coronary resistance, vascular tone and reactivity. EBiomedicine. 2017;21:206–212.
   PubMed Web of Science ®Google Scholar
• Rosenthal A, Luthi J, Belohlavek M, et al. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J. 2016;6:e384.
   PubMed Web of Science ®Google Scholar
• Hasinoff BB, Patel D, Wu X. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted drugs bortezomib and carfilzomib. Cardiovasc Toxicol. 2017;17(3):237–250.
   PubMed Web of Science ®Google Scholar
• KYPROLIS® (carfilzomib) prescribing information, Onyx Pharmaceuticals, an Amgen, Inc. Subsidiary.
   Google Scholar
• Boxhammer R, Steidl S, Endell J, et al. Effect of IMiD Compounds on CD38 expression on multiple myeloma cells: MOR202, A human CD38 antibody in combination with pomalidomide.[abstract] J Clin Oncol. 2015;15(33) suppl. abstract 8588.
   Google Scholar
• Daratumumab investigator brochure, Janssen research and development, Edition 15; 2018.
   Google Scholar
• Carfilzomib investigator brochure, Onyx Therapeutics, Edition 16.1; 2016.
   Google Scholar
• Demo SD, Kirk CJ, Aujay MA, et al. Anti-tumor activity of PR 171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383–6391.
   PubMed Web of Science ®Google Scholar
• Chauhan D, Singh AV, Aujay M, et al. A novel orally active proteosome inhibitor ONX0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood. 2010;116(23):4906–4915.
   PubMed Web of Science ®Google Scholar
• Nooka AK, Kaufman JL, Hofmeister CC, et al. Daratumumab in multiple myeloma. Cancer. 2019;125:2364–2382.
   PubMed Web of Science ®Google Scholar
• Plesner T, Arkenau HT, Gimsing P, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016;128:1821‐ 28.
   Google Scholar
• Dimopoulos MA, White DJ, Benboubker L, et al. Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of POLLUX [abstract]. Blood. 2017;130(suppl 1):739.
   Google Scholar
• Facon T, Lonial S, Weiss BM, et al. Daratumumab in combination with pomalidomide and dexamethasone for relapsed and/or refractory multiple myeloma (RRMM) patients with ≥2 prior lines of therapy: updated analysis of MMY1001 [abstract]. Blood. 2017;130(suppl1):1824.
   Google Scholar
• Sanchez L, barley K, Richter J, et al. Immunomodulatory drug- and proteasome inhibitor-backbone regimens in the treatment of relapsed multiple myeloma: an evidence-based review. Expert Rev Hematol. 2020;13(9):943–958.
   PubMed Web of Science ®Google Scholar
• O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009 15;15(22):7085–7091.
   PubMed Web of Science ®Google Scholar
• Alsina M, Trudel S, Furman RR, et al. A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18(17):4830–4840.
   PubMed Web of Science ®Google Scholar
• Jagannath S, Vij R, Stewart AK, et al. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012;12(5):310–318.
   PubMed Web of Science ®Google Scholar
• Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817–2825.
   PubMed Web of Science ®Google Scholar
• Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753–1761.
   PubMed Web of Science ®Google Scholar
• Papadopoulos KP, Lee P, Singhal S, et al. A phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma: updated efficacy and tolerability from the completed 20/56mg/m2 expansion cohort of PX-171-007. Blood. 2011;118(21):2930.
   Web of Science ®Google Scholar
• Siegel DS, Berdeja JG, Infante JR, et al. Updated results from a Phase 2 extension study of patients with multiple myeloma or solid tumors previously enrolled in carfilzomib company-sponsored Phase 1 and 2 clinical trials (PX-171-010). Blood. 2014;124(21):2134.
   Web of Science ®Google Scholar
• Berenson JR, Cartmell A, Bessudo A, et al. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016;127(26):3360–3368.
   PubMed Web of Science ®Google Scholar
• Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013;122(18):3122–3128.
   PubMed Web of Science ®Google Scholar
• Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015;126(20):2284–2290.
   PubMed Web of Science ®Google Scholar
• Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(5):421–431.
   PubMed Web of Science ®Google Scholar
• Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomized, multicentre, open-label, phase 3 study. Lancet. 2020;396:186–197.
   PubMed Web of Science ®Google Scholar
• Yong K, Hinsley S, Auner HW. Carfilzomib, cyclophosphamide, and dexamethasone (KCD) versus bortezomib, cyclophosphamide and dexamethasone (VCD) for treatment of first relapse or primary refractory multiple myeloma (MM): first analysis of the phase 2 MUK five study. Blood. 2017;130:835.
   Web of Science ®Google Scholar
• Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol. 2017;177(3):404–413.
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Goldschmidt H, Nietvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomized, phase 3 trial. Lancet Oncol. 2017;18(10):1327–1337.
   PubMed Web of Science ®Google Scholar
• Moreau P, Mateos M-V, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19(7):953–964.
   PubMed Web of Science ®Google Scholar
• Dimopoulos M, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811–1822.
   PubMed Web of Science ®Google Scholar
• San-Miguel JF, Hungria VTM, Yoon -S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomized, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–1206.
   PubMed Web of Science ®Google Scholar
• Moreau P, Harrison S, Cavo M, et al. Updated analysis of Bellini, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood. 2019;134(Suppl 1):1888.
   Google Scholar
• Leleu X, Beksac M, Chou T, et al. Efficacy and safety of carfilzomib, dexamethasone, and daratumumab (KdD) twice-weekly at 56 mg/m2 and once weekly at 70 mg/m2 in relapsed or refractory multiple myeloma (RRMM): a cross-study comparison of the CANDOR and MMY1001/EQUULEUS studies. Presented Poster Session ASCO. 2020;38(15):Abstract 8526.
   Google Scholar
• Facon T, Lee JH, Moreau P, et al. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019;133(18):1953–1963.
   PubMed Web of Science ®Google Scholar
• Chari A, Stewart K, Russell SR, et al. Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. Blood Adv. 2018;2(13):1633–1644.
   PubMed Web of Science ®Google Scholar
• Piedra KM, Hassoun H, Buie LW, et al. VTE rates and safety analysis of newly diagnosed multiple myeloma patients receiving carfilzomib-lenalidomide-dexamethasone (KRD) with or without rivaroxaban prophylaxis. Blood. 2019;134(Supplement_1):1835.
   Google Scholar
• Mateos M-V, 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, randomized, phase 3 trial. Lancet Haematol. 2020;7(5):e370–80.
   PubMed Web of Science ®Google Scholar