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Phase II CARTHADEX Study in NDMM
Assessments
Treatment responses and disease progression were assessed by study investigators and were classified according to International Myeloma Working Group (IMWG) Uniform Response Criteria, with categories for CR, VGPR, and partial response (PR).18 Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria of Adverse Events version 4.0.19 Bone mar- row analysis was performed at diagnosis to quantify myeloma cell involvement. Molecular, cytogenetic and fluorescence in situ hybridization (FISH) studies were performed on these samples. CD138+ purified MM cells were used to determine the presence of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q32), del(13q), del(17p), 1p/q abnormalities, numerical abnormalities of chromosome 9 or 11, and complex cytogenetic abnormalities.11
Statistical analysis
This study was designed to investigate whether induction treat- ment with KTd warrants further investigation in future trials. The intention-to-treat principle was used for all analyses, restricted to eligible patients. A CR + VGPR rate lower than 25% after induc- tion treatment, was considered too low to warrant further investi- gation in future trials; however, if the CR + VGPR rate was higher than 45%, therapeutic activity was considered sufficiently high to support further investigation. To reject the null hypothesis in favor of the alternative hypothesis with power 1 - β=0.80 (two-sided sig- nificance level α=0.05), a minimum of 41 patients should be included. A 95% confidence interval (CI) was constructed around the CR + VGPR rate after induction treatment and the null hypoth- esis was rejected if the lower boundary was larger than 25%.
Predefined subgroup analyses were performed to investigate the effect of risk status, using cytogenetic/FISH criteria, International Staging System (ISS) stage and revised (R)-ISS stage, on response and survival. In this trial, patients were considered to be high-risk if they had t(4;14) and/or del(17p) and/or add(1q) and/or ISS stage III.
Continuous and categorical data were summarized with descriptive statistics. Survival end points were estimated using the Kaplan-Meier method, and 95%CI were constructed. The log- rank was used to evaluate differences in PFS and OS between sub- groups. Statistical analysis was performed using Stata v15.1 soft- ware (StataCorp, College Station, TX, USA).
Results
Patients and treatment
One hundred and eleven patients were enrolled between September 16th, 2010 and December 30th, 2013. The analysis was based on data available as of February 27th, 2018 with a median follow up of 58.7 months (range: 25.1-88.0 months). Four different dose levels were investigated (27 mg/m2, n=50; 36 mg/m2, n=20; 45 mg/m2, n=21; 56 mg/m2, n=20). Baseline demographics and disease characteristics are shown in Table 1. Median age was 58 years (range: 29- 66 years) and the male/female distribution 61%/39%. Nine percent of patients had an R-ISS stage 3 and in 9% of patients R-ISS stage was unknown, mainly due to missing cytogenetics. A total of 39% of patients were classified as high-risk based on cytogenetics and ISS stage; 41% of patients were classified as standard risk. In 20% of patients, risk status was unknown, mainly due to missing cytogenet- ics. Seven patients had a history of grade 1/2 PN and two patients a grade 3 PN at diagnosis; in nine patients, baseline assessment of PN was missing at enrollment. A total of 5% of patients had renal insufficiency with a creatinine ≥ 177
mmol/L at diagnosis.
All 111 patients started induction therapy with KTd
(Figure 1). Six patients discontinued treatment because of the following adverse events (AE): grade 3 rash (carfilzomib 27 mg/m2), grade 2 fever with sepsis (carfilzomib 27 mg/m2), grade 1 hyponatremia (carfilzomib 27 mg/m2), grade 2 exanthema (carfilzomib 27 mg/m2), grade 3 conges- tive heart failure (carfilzomib 27 mg/m2), grade 3 pneu- monitis (carfilzomib 36 mg/m2), grade 3 drug reaction with eosinophilia and systemic symptoms (Dress syndrome) (carfilzomib 56 mg/m2). One patient appeared not eligible for further treatment and two patients discontinued treat- ment due to progressive disease. Out of 111 patients, 102 (92%) continued treatment with high-dose cyclophos- phamide and stem cell collection. Stem cell collection was successful in 100 of 102 patients with a median CD34+ yield of 5.5x103. A total of 98 patients (88%) continued treatment with a single HDM (200 mg/m2) and ASCT. Four patients were not eligible for HDM: one because of insufficient CD34+ yield and three because of progression of disease after stem cell collection. After treatment with HDM and ASCT, 94 patients (85%) initiated consolidation therapy. Four patients were not eligible for consolidation treatment because of progression of disease (n=1), a delayed hemato- logic recovery after ASCT (n=1), non-related disease (n=1), and uncontrolled pain after ASCT (n=1). Nine patients dis- continued consolidation treatment because of progressive disease (n=2), thrombotic thrombocytopenic purpura (TTP) (n=1), a TTP-like syndrome (n=1), overall worsening of condition (n=1), grade 3 fatigue (n=1), refusal of further treatment (n=2), and persisting PN (n=1). A total of 83 patients (75%) completed all four consolidation cycles.
Efficacy
Table 2 shows response to induction, HDM/ASCT and consolidation therapy. Response according to risk group and R-ISS is shown in Table 3. Overall response after induction therapy in all 111 patients was 93% with a CR rate of 18%. The ≥ VGPR rate after induction therapy was 65% (95%CI: 55-74%) leading to rejection of the null hypothesis, as the 95%CI is above 25%. The ≥ VGPR rate increased to 77% after HDM/ASCT and to 86% after con- solidation therapy. ORR increased to 94% after consolida- tion therapy. CR rate after induction therapy between the four different dose levels was comparable and increased after consolidation therapy. At the three highest dose lev- els, CR rate after consolidation therapy was higher in com- parison to the lowest dose level (75%, 67% and 65% vs. 56%, respectively); however, this was not statistically sig- nificant (test for trend, P=0.39; χ2 test, 27 mg/m2 vs. 36-56 mg/m2, P=0.16). Response after consolidation treatment between standard risk patients and high-risk patients (defined by ISS stage and cytogenetics) was similar with CR rates of 67% versus 58%. Response after consolidation therapy according to R-ISS stage (I, II and III) was compa- rable with CR rates of 73%, 57% and 60%, respectively.
Median PFS in all 111 patients was 58 months (95%CI: 45-67 months). Dose level was not associated with PFS. Median PFS in high-risk patients was worse compared to standard risk patients (42 vs. 60 months; P=0.006), while a higher R-ISS stage was also associated with a worse PFS (P=0.04) (Figure 2).
Median OS was 83 months and 5-year OS was 76% (95%CI: 66-83%) (Figure 3). Dose level and risk status were not associated with OS.
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