An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study)
Abstract
Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.
Plain language summary
Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 28(5), 1122–1128 (2014).
- 2. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 67(13), 6383–6391 (2007).
- 3. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 12(5), 431–440 (2011).
- 4. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114(16), 3439–3447 (2009).
- 5. US Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin. Cancer Res. 19(17), 4559–4563 (2013).
- 6. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 372(2), 142–152 (2015).
- 7. Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: a phase 1 study in Japan. Cancer Sci. 108(3), 461–468 (2017).
- 8. Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone. Blood Adv. 3(23), 4095–4103 (2019).
- 9. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 17(1), 27–38 (2016).
- 10. CHAMPION-1: a phase 1/2 study of once weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood 127(26), 3360–3368 (2016).
- 11. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 19(7), 953–964 (2018). •• The phase III trial (ARROW study) comparing the efficacy and safety of once-weekly carfilzomib and dexamethasone therapy with twice-weekly carfilzomib and dexamethasone therapy in patients with relapsed and refractory multiple myeloma.
- 12. Once-weekly vs. twice-weekly carfilzomib dosing in a subgroup of Japanese relapsed and refractory multiple myeloma patients from a randomized phase 3 trial (ARROW) and comparison with ENDEAVOR. Int. J. Hematol. 113(2), 219–230 (2021). •• A subgroup analysis focused on the Japanese patients with multiple myeloma enrolled in the ARROW study comparing with ENDEAVOR study.
- 13. Real-world effectiveness and safety analysis of carfilzomib–lenalidomide–dexamethasone and carfilzomib–dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis. Ther. Adv. Hematol. 13, 1–16 (2022). • A retrospective analysis demonstrating the real-world effectiveness and safety of carfilzomib in combination with lenalidomide and dexamethasone and twice-weekly carfilzomib with dexamethasone therapies in Japanese patients.
- 14. Real-world use and effectiveness of carfilzomib plus dexamethasone in relapsed/refractory multiple myeloma in Europe. Cancers 14(21), 5311 (2022).
- 15. International uniform response criteria for multiple myeloma. Leukemia 20(9), 1467–1473 (2006).
- 16. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117(18), 4691–4695 (2011).
- 17. . Post-marketing surveillance of carfilzomib in Japanese patients with relapsed or refractory multiple myeloma. Future Oncol. 18(24), 2661–2674 (2022).
- 18. Prognostic impact of resistance to bortezomib and/or lenalidomide in carfilzomib-based therapies for relapsed/refractory multiple myeloma: the Kyoto Clinical Hematology Study Group, multicenter, pilot, prospective, observational study in Asian patients. Cancer Rep. 5(2), e1476 (2022).
- 19. . Once-weekly (70 mg/m2) vs twice-weekly (56 mg/m2) dosing of carfilzomib in patients with relapsed or refractory multiple myeloma: a post hoc analysis of the ENDEAVOR, ARROW, and CHAMPION-1 trials. Cancer Med. 9(9), 2989–2996 (2020). • Post hoc crosstrial comparisons demonstrating the efficacy and safety profiles of once-weekly versus twice-weekly dosing schedules using data from three trials of patients with relapsed or refractory multiple myeloma.
- 20. Outcomes for Asian patients with multiple myeloma receiving once- or twice-weekly carfilzomib-based therapy: a subgroup analysis of the randomized phase 3 ENDEAVOR and ARROW trials. Int. J. Hematol. 110(4), 466–473 (2019). • A subgroup analysis focused on the outcomes of Asian patients with multiple myeloma enrolled in the randomized phase III ENDEAVOR and ARROW trials.
- 21. Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 ARROW study subgroup analysis. Blood Cancer J. 10(3), 35 (2020).
- 22. Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: a network meta-analysis of randomized clinical trials. Hematol. Oncol. 40(2), 233–242 (2022).
- 23. Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: a retro-prospective observational study. Eur. J. Haematol. 109(4), 373–380 (2022).
- 24. Clinical impacts of frailty, poor performance status, and advanced age in carfilzomib-containing treatment for relapsed/refractory multiple myeloma: post hoc investigation of the KOTOSG multicenter pilot prospective observational study. Int. J. Hematol. 115(3), 350–362 (2022).
- 25. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. Eur. J. Heart Fail. 22(11), 1945–1960 (2020). • Baseline cardiovascular risk assessment and baseline risk stratification proformas in cancer patients prior to receiving the following cancer therapies, such as anthracycline chemotherapy, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs).