Daratumumab Plus Carfilzomib: An Optimistic Approach in Relapsed/ Refractory Multiple Myeloma

Abstract

Background: Although with the introduction of novel agents, clinical outcomes have significantly improved in patients of multiple myeloma (MM); however, nearly all relapse, requiring subsequent treatment. Patients who have been heavily treated for relapsed/refractory MM (RRMM) have limited options and poor survival outcomes. Carfilzomib plus daratumumab combination have been evaluated in a phase 1b study in patients of RRMM progressing after 1–3 lines of therapies including bortezomib and an immune-modulatory drug. However, data are lacking evaluating the efficacy of this combination in RRMM patients who have progressed or have suboptimal response on either of these drugs (carfilzomib or daratumumab). Methods: Prospective analysis of data of 19 RRMM patients who progressed after multiple lines of therapy (including bortezomib and lenalidomide/pomalidomide) and had suboptimal response/stable/progressive disease after receiving carfilzomib or daratumumab based combination as last therapy. All patients received combination of carfilzomib plus daratumumab along with dexamethasone (DKd) after prior consent. Daratumumab (16 mg/kg IV) was administered weekly (days 1, 8, 15, and 22) during cycles 1 and 2, every 2 weeks (days 1 and 15) during cycles 3–6, and every 4 weeks thereafter. Carfilzomib was administered weekly on days 1, 8, and 15 of each 28-day cycle. Patients received an initial carfilzomib dose of 20 mg/m2 on day 1,2; 27 mg/m2 on day 8, 9, 15, 16 of cycle 1, which increased to 70 mg/m2 on day 1, 8, 15 from cycle 2 onwards if deemed tolerable. Dexamethasone was given as fixed-dose of 40 mg weekly. Results: Eighteen of 19 patients (including 3 high risk cytogenetics) to DKd (CR-4, very good partial response-10, partial response-02). After median follow-up of 16 months, progression-free survival (PFS) was 95%. Median PFS was not reached. Three patients who were transplant eligible received high-dose chemotherapy followed by autologous stem-cell transplantation and achieved minimal residual disease negativity. The most frequent all grade side effects were hematological, which included neutropenia 30%, anemia 70%, and thrombocytopenia 42%. Most frequent non hematological side effects were nausea 40%, vomiting, cough, respiratory tract infections, asthenia, and loss of appetite. Conclusion: Carfilzomib plus daratumumab based combination in RRMM patients has shown promising results in phase Ib study, where patients with prior exposure to either of these drugs were excluded. Our data show similar or better response of this combination in patients who had progressive disease/stable disease/minimal response to either of carfilzomib or daratumumab. This combination can be a better option in heavily treated RRMM (with prior exposure to either of carfilzomib or daratumumab) producing deeper and durable responses. A larger study may be required to prove this benefit.

Keywords

Carfilzomib - daratumumab - multiple myeloma - relapsed/refractory

Publication History

Received: 27 February 2020

Accepted: 02 October 2020

Article published online:
14 May 2021

• References

• 1 Orlowski RZ, Lonial S. Integration of novel agents into the care of patients with multiple myeloma. Clin Cancer Res 2016; 22: 5443-52
• 2 Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J. et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study. Leukemia 2012; 26: 149-57
• 3 Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375: 1319-31
• 4 Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K. 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: 953-64
• 5 Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S. et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 2018; 378: 518-28
• 6 Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I. et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: Updated analysis of CASTOR. Haematologica 2018; 103: 2079-87
• 7 Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375: 754-66
• 8 Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A. et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: A meta-analysis. JAMA Oncol 2017; 3: 28-35
• 9 Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF. et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 1996; 335: 91-7
• 10 Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P. et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: A randomised, multicentre, phase 3 trial. Lancet Oncol 2015; 16: 1617-29
• 11 Lahuerta JJ, Mateos MV, Martínez-López J, Rosiñol L, Sureda A, de la RubiaJ. et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: Sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 2008; 26: 5775-82
• 12 Moreau P, Attal M, Pégourié B, Planche L, Hulin C, Facon T. et al. Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial. Blood 2011; 117: 3041-4
• 13 Harousseau JL, Avet-Loiseau H, Attal M, Charbonnel C, Garban F, Hulin C. et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: Long-term analysis of the IFM 99-02 and 99-04 Trials. J Clin Oncol 2009; 27: 5720-6
• 14 Quach H, Mileshkin L, Seymour JF, Milner A, Ritchie D, Harrison S. et al. Predicting durable remissions following thalidomide therapy for relapsed myeloma. Leuk Lymphoma 2009; 50: 223-9