Page 217 - Haematologica Vol. 109 - July 2024

ARTICLE - Carfilzomib, thalidomide and dexamethasone (KTd) in RRMM S. Ninkovic et al.
count ≥1.0x109/L independent of growth factor support for at least 1 week, platelet count ≥50x109/L or ≥30x109/L if >50% plasma cell burden on bone marrow biopsy), renal function (calculated or measured creatinine clearance of ≥15 mL/min), and hepatic function (serum bilirubin <1.5 times the upper limit of normal, aspartate aminotransferase and alanine aminotransferase <3 times the upper limit of normal) at the time of screening. Patients with New York Heart Association class III or IV cardiac failure, or grade 3 or 4 peripheral neuropathy (or grade 2 with pain) were ex- cluded. The study protocol was approved by the relevant human research ethics committee at all participating in- stitutions. All patients provided written informed consent.
Study design
Patients were treated on a 28-day cycle for a pre-defined period of 18 months, consisting of 12 induction and six maintenance cycles, unless prior disease progression, un- acceptable adverse events, or withdrawal of consent. The first ten patients from each of the ALLG and AMN cohorts were treated on a lead-in safety phase. Intravenous carfil- zomib was given at a dose of 20 mg/m2 in cycle 1 on days 1 and 2, followed by dose escalation to 27 mg/m2 on days 8, 9, 15, and 16 (i.e., carfilzomib 20/27 mg/m2). Providing that four or fewer patients in each cohort experienced grade 4 treatment emergent adverse events attributed by investi- gators to carfilzomib exposure during the first two cycles, all subsequent patients <75 years were escalated to 56 mg/m2 from day 8 onwards (i.e., carfilzomib 20/56 mg/m2), while those ≥75 years were escalated to 36 mg/m2 from day 8 onwards (i.e., carfilzomib 20/36 mg/m2). Additionally, patients not achieving at least a partial response after the first two cycles during the lead-in safety phase and provid- ing they did not experience ≥ grade 3 carfilzomib-related toxicity, were escalated to either carfilzomib 20/56 mg/m2 (<75 years) or 20/36 mg/m2 (≥75 years). For comprehensive insights into both hematologic and non-hematologic tox- icities necessitating dose adjustments, further details are provided in Online Supplementary Table S1. Oral dexameth- asone 40 mg was administered on days 1, 8, 15, and 22 (20 mg for patients ≥75 years) together with oral thalidomide 100 mg on day 1 to day 28. During the maintenance phase of treatment, carfilzomib was administered on days 1, 2, 15, and 16, dexamethasone on days 1 and 15, while thalido- mide was omitted. Concomitant medication and supportive care, including venous thromboembolism prophylaxis, were prescribed at the discretion of investigators, following in- stitutional practices, which included options such as low dose aspirin (100 mg daily), low molecular weight heparin, direct acting oral anticoagulants or vitamin K antagonists. Local response assessments were performed in National Association of Testing Authorities (NATA)/Royal College of Pathologists Australasia (RCPA) accredited laboratories prior to day 1 of each treatment cycle, and interpreted, according to the International Myeloma Working Group
Uniform Response Criteria, by local investigators with au- tomated sponsor oversight and resolution of discrepancies in response assessment by the coordinating principal in- vestigator.15 Patients were followed up monthly for disease progression and survival until 1 year after the completion of the last patient’s last cycle of treatment or induction therapy, whichever occurred earlier. The primary endpoint was to assess the PFS in patients with RRMM, who had received one to three prior lines of therapy, when treated with the fixed-duration KTd. The secondary endpoints were overall response rate, OS, duration of response, time to pro- gression and safety and tolerability. Additionally, peripheral blood, bone marrow aspirate and trephine samples were collected at the time of screening, after 6 months of KTd and at the time of either disease progression or complete response, or both, with a view to interrogate changes in the immune system and the bone marrow tumor microen- vironment and correlate findings to treatment outcomes. These translational, exploratory endpoints will be reported on at a later date.
Statistical analysis
The sample size for this study was estimated using a Simon minimax two-stage design, with a minimum of 37 patients per jurisdiction required in order to have an 80% power with a two-sided α of 0.05 to reject the null hypothesis of ≤50% PFS at 6.5 months (based on results from the OPTIMUM study), compared to the alternative hypothesis of ≥70% PFS at 6.5 months.16 PFS and overall survival (OS) were defined as the time, in consecutive days from the start of treatment (day 1 of cycle 1) to disease progression or death from any cause, whichever came first (PFS) or death from any cause (OS). Duration of response was defined as the time in consecutive days from date of first response (partial response or better) to the date of progression or death from any cause. Time to progression was defined as the time from day 1 of cycle 1 to the date of progression with deaths due to causes other than progression censored. Time-to-event analyses were censored by the closeout date or the date of last follow-up for patients lost to follow-up. The influence of prognostic factors (age, cytogenetic abnormalities, lines of prior therapy, previous thalidomide resistance, progression within 6 months vs. >6 months, baseline b2-microglobulin and International Prognostic Scoring System score at baseline) on PFS, time to progression, OS and response were explored using Cox proportional hazard regression or multiple logistic regression, as appropriate. Given the sample size, these analyses are considered hypothesis-generating. Although not specifically powered, comparisons between ethnically Asian and non- Asian populations were pre-specified, post-hoc analyses in the statistical analysis plan which was developed and approved prior to database lock. All hypothesis testing was two-sided, with values of P<0.05 considered statistically significant. Analyses were conducted using Stata MP for Mac v17 (Statacorp, College Station, TX, USA).
Haematologica | 109 July 2024
2231