Page 216 - Haematologica Vol. 109 - July 2024

ARTICLE - Carfilzomib, thalidomide and dexamethasone (KTd) in RRMM S. Ninkovic et al.
gression-free survival was 22.3 months (95% confidence interval: 15.7-25.6) and the 2-year progression-free survival was 46.3% (95% confidence interval: 35.1-52.8). The median overall survival was not reached and the 2-year overall survival was 73.8% (95% confidence interval: 62.9-81.9). The overall response rate was 88% (73% had a very good partial response or better). There was no difference in the depth of response, progression-free survival or overall survival comparing Asian and non-Asian cohorts (P=0.61). The safety profile of KTd was consistent with that of each individual drug. KTd is well tolerated and effective in patients with relapsed and/or refractory multiple myeloma irrespective of Asian or non-Asian ethnicity and provides an alternative treatment option, particularly in circumstances in which the use of carfilzomib, lenalidomide, and dexamethasone (KRd) is limited by access, cost, or renal impairment.
Introduction
Multiple myeloma is a neoplasm of clonal plasma cells, characterized by a vicious cycle of response and relapse with ultimate development of resistance to therapy in most patients. The steadfast introduction and approval of novel agents, including first- and second-generation proteasome inhibitors, immunomodulatory drugs and monoclonal anti- bodies, in both the newly diagnosed and relapsed/refractory settings, has translated into progressive improvements in survival, especially for the elderly and patients with favor- able-risk disease.1-3 We are currently entering an even more promising era of cellular- and immune-based therapies with remarkable responses seen even in heavily pre-treated patients.4,5 In parallel, however, the associated healthcare costs are steadily increasing and while treatment-related drug costs account for less than a third of the total, the increased dependency on inpatient and outpatient ser- vices required for delivery of novel therapies is expected to further jeopardize their affordability and accessibility for all patients.2,6
The management of relapsed or refractory multiple my- eloma (RRMM) is complex, taking into consideration pri- or drug exposure, response, and toxicity profile, as well as disease- and patient-related factors. The challenge of managing RRMM is compounded by limited access to novel agents outside of clinical trials. In the late 2000s, the combination of lenalidomide and dexamethasone (Rd) was a well-established and utilized standard of care in early RRMM.7 With contemporary practice, however, most patients receive upfront lenalidomide as part of either a triplet or even quadruplet therapy with continuous or main- tenance treatment until disease progression.8 For patients who are not refractory to lenalidomide, re-treatment at relapse with the Rd backbone in combination with novel agents including carfilzomib, ixazomib, daratumumab, or elotuzumab is effective, and was instrumental in the regis- trational approval of these agents.9-13 Most patients at first relapse will have been exposed to bortezomib, but are not necessarily refractory to the drug. However, the ENDEAVOR study demonstrated that for these patients, switching to a second-generation proteasome inhibitor, carfilzomib, is superior to re-treatment with bortezomib across a variety of subgroups of patients.14
The phase III ASPIRE study compared fixed-duration car- filzomib, lenalidomide, and dexamethasone (KRd) followed by Rd against Rd until disease progression in a cohort of patients who had received one to three prior lines of therapy, including 20% lenalidomide-exposed patients. The triplet KRd significantly improved overall response rate (87.1 vs. 66.7%; P<0.001) and progression-free survival (PFS; 26.3 vs. 17.6 months; hazard ratio [HR]=0.69; 95% confidence interval [95% CI]: 0.57-0.83; P=0.0001) compared to Rd alone. At the time of this study design, in certain jurisdictions including the Asia-Pacific region, thalidomide, a first-generation im- munomodulatory drug, was a more affordable alternative to lenalidomide. This single-arm, multicenter, phase II study conducted jointly by the Australasian Leukemia and Lymphoma Group (ALLG) and the Asian Myeloma Network (AMN) evaluated the safety and efficacy of fixed-dura- tion carfilzomib, thalidomide, and dexamethasone (KTd) in patients with RRMM who had received one to three prior lines of therapy. The study was registered with the Australian New Zealand Clinical Trials Registry (identifier: ACTRN12615000818538) and ClinicalTrials.gov (identifier: NCT03140943)
Methods
Patients
Adults (≥18 years of age from the ALLG or ≥21 years of age from the AMN) with RRMM, evidence of measurable disease and a history of one to three prior lines of therapy were eligible. Measurable disease was considered as a serum M-protein ≥5 g/L, or urine M-protein ≥200 mg/24 h or, in patients without detectable serum or urine M-protein, se- rum free light chains >100 mg/L (involved light chain) and an abnormal κ/λ ratio or for IgA patients, whose disease can only be reliably measured with serum quantitative IgA immunoglobulin, a value ≥7.5 g/L. Induction therapy followed by stem cell transplant and consolidation/maintenance therapy was considered as one line of treatment. Patients with prior exposure to any immunomodulatory drug (thalid- omide, lenalidomide or pomalidomide) or bortezomib, but not carfilzomib, were eligible. All patients had an Eastern Cooperative Oncology Group performance status 0 to 2, with adequate hematologic function (absolute neutrophil
Haematologica | 109 July 2024
2230