Page 164 - 2021_04-Haematologica-web

R. Mina et al.
Introduction
Multiple myeloma (MM) is a plasma cell dyscrasia with a heterogeneous prognosis ranging from a few years to over a decade, according to both disease-related factors (such as albumin and β-2 microglobulin levels, cytoge- netic abnormalities [CA] or presence of extramedullary disease) and patient-related factors (age, comorbidities, frailty status).1-3 To date, one of the most powerful prog- nostic markers in MM is the presence of either primary (translocations) or secondary (deletions or amplifications) recurrent CA detected by fluorescence in situ hybridiza- tion (FISH). Deletions of chromosome 17p and TP53 have been reported in 5-20% of MM patients according to the cut-off adopted by laboratories and have been clearly associated with a dismal prognosis.4 Another adverse CA is t(4;14), which is carried by 12-15% of MM patients and leads to the deregulation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET).5,6 Eventually, the occurrence of t(14;16) has been associated to worse progression-free survival (PFS) and overall survival (OS) in a study published by the Mayo Clinic,7 although some doubts have been cast by another study by Intergroupe Francophone du Myélome (IFM)8 and conflicting results have been thereafter report- ed even in patients treated in the novel agent era. The presence of at least one of these three abnormalities iden- tifies a subgroup of patients at high risk of relapse and death.9
MM is mainly a disease of the elderly, with a median age at diagnosis of 69 years.10 Older patients are usually considered not eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT). In this patient population, the initial therapeutic approach includes either a triplet proteasome inhibitor (PI)-based regimen (bortezomib-melphalan-prednisone, VMP), a two-drug regimen containing an immunomodulatory agent (IMiD; lenalidomide-dexamethasone, Rd), or a combination of both a PI and an IMiD (bortezomib- lenalidomide-dexamethasone, VRD).11 In the VISTA study that led to the approval of the VMP combination, the median PFS was 19.8 months in high-risk (HiR) patients by FISH and 23 months in standard-risk (SR) patients (HR:1.29).12,13 In the FIRST study, among patients receiv- ing continuous Rd, the median PFS was 8.4 months in HiR patients versus 31.1 in SR patients.14,15
Carfilzomib is a second-generation PI currently approved for relapsed and/or refractory (RR)MM patients. In the phase III ENDEAVOR trial comparing carfilzomib-dexamethasone (Kd) to bortezomib-dexam- ethasone (Vd), the PFS and OS advantage of Kd observed in the overall population was also retained in HiR patients (median PFS in HiR patients treated with Kd vs. Vd: 8.8 vs. 6.0 months; P=0.007).16 Similarly, in the phase III ASPIRE trial, the triplet carfilzomib-lenalidomide-dexam- ethasone (KRd) proved to be superior to Rd also in patients with HiR CA (median PFS in HiR patients treated with KRd vs. Rd: 23.1 vs. 13.9 months; P=0.08).17 Taken together, these results suggest that carfilzomib-based reg- imens might at least partially overcome the negative impact of HiR cytogenetics in MM patients.
We previously published the results of two phase I/II trials showing that the combination carfilzomib- cyclophosphamide-dexamethasone (KCyd), followed by carfilzomib maintenance, was effective and well tolerated
in newly diagnosed (ND) elderly MM patients (NDMM).18,19 Here we report the results of a pooled analysis of patient data from the two trials aiming at eval- uating the efficacy of a carfilzomib-based therapy in SR and HiR patients.
Methods
Study design and treatment
We pooled together data from two phase I/II (IST-CAR-561; clinicaltrials.gov identifier: NCT01857115) and phase II (IST-CAR- 506; clinicaltrials.gov identifier: NCT01346787) studies. Both trials enrolled NDMM patients over 65 years of age or younger but not eligible for ASCT. Ethics committees or institutional review boards at the study sites approved both studies, which were car- ried out in accordance with the Declaration of Helsinki. All patients provided written informed consent.
Details of study procedures have been published previously.18- 20 Briefly, in both trials treatment consisted of nine 28-day cycles of KCyD followed by maintenance with single-agent carfil- zomib until disease progression or intolerance. Carfilzomib was administered once weekly (70 mg/m2) in the IST-CAR-561 study and twice weekly (36 mg/m2) in the IST-CAR-506 study. The same doses and schedules of cyclophosphamide (oral 300 mg on days 1, 8 and 15) and dexamethasone (40 mg on days 1, 8, 15 and 22) were used in both studies.
Endpoints
The aim of our analysis was to compare treatment efficacy, in terms of response to therapy, PFS, PFS-2 and OS in patients with SR versus HiR cytogenetics receiving carfilzomib-based regi- mens.
Cytogenetic risk was centrally assessed by FISH analysis and t(4;14), t(11;14), t(14;16), del13 and del17p were evaluated in both studies. A 15% cut-off point was used for detection of translocations and a 10% cut-off point for deletions. FISH analy- sis was performed on CD138+ purified plasma cells. According to the Revised International Staging System (R-ISS) criteria pro- posed by the International Myeloma Working Group (IMWG) in 2015, high cytogenetic risk was defined by the presence of at least one CA among del17p, t(4;14) or t(14;16).21 Patients’ fitness was defined according to the IMWG frailty score,2 and patients were classified as either fit, intermediate fit or unfit.
Statistical analysis
Data from the two trials were pooled together and analyzed. Comparisons between different patient groups were performed using Fisher’s exact test. PFS was calculated from the date of enrollment to the date of progression or death, or the date the patient was last known to be in remission. PFS-2 was calculated from the date of enrollment to the date of second relapse/pro- gression or death or the date the patient was last known to be in remission. OS was calculated from the date of enrollment to the date of death or the date the patient was last known to be alive.
Time-to-event data were analyzed using the Kaplan-Meier method; survival curves were compared with the log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) values and the 95% confidence intervals (CI). All reported P-values were two-sided at the conventional 5% significance level. In order to account for potential confounders, the comparison SR versus HiR was adjusted for age, International Staging System (ISS), IMWG Frailty Score and trial (once- vs. twice-weekly carfilzomib).
Data were analyzed using R software (version 3.5.1).
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haematologica | 2021; 106(4)