Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma.

The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2: C1D1, C1D2; 36 mg/m2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m2; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m2) and prednisone (60 mg/m2) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease-negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a ≥5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade ≥3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade ≥2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP. This trial was registered at www.clinicaltrials.gov as #NCT01818752.

Semiparametric bayesian testing procedure for noninferiority trials with binary endpoints.

A semiparametric testing approach based on the Bayes factor is developed for non-inferiority trials with binary endpoints. The proposed method is shown to work for a broad class of hypotheses by accommodating a variety of dissimilarity measures between two binomial parameters. Two of the unique features of the proposed testing procedure include: (i) construction of a flexible class of conjugate priors using a mixture of beta densities to maintain approximate equality of prior probabilities of the competing hypotheses; and (ii) automatic determination of the cutoff value of the Bayes factor to facilitate the decision making process. In contrast to the use of Jeffreys's rule of thumb, two forms of total weighted average error criteria are used to determine the cutoff value. Through several simulation studies it is demonstrated that the proposed Bayesian procedure has competitive frequentist properties of controlling type I error as compared to the default frequentist test and meanwhile the proposed criterion improves the statistical power, especially in small samples. The method is further illustrated using the data from a streptococcal pharyngitis clinical trial.