Jan Straub

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study

BACKGROUND Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. FINDINGS Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). INTERPRETATION For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. FUNDING Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Subcutaneous Bortezomib in Multiple Myeloma Patients Induces Similar Therapeutic Response Rates as Intravenous Application But It Does Not Reduce the Incidence of Peripheral Neuropathy

Objective Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM) patients treated using either intravenous (IV) or subcutaneous (SC) route of administration. Patients and methods During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly – 63% or twice weekly – 27%) in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration. Results The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥2 was present in 20% vs 18% and PN grade ≥3 was present in 6% vs 4%. Conclusions We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.

Intrapleural Bortezomib for the Therapy of Myelomatous Pleural Effusion: A Case Report

Myelomatous pleural effusion (MPE) is an extremely rare manifestation of multiple myeloma (MM). We present a case of MPE in a patient with IgG-κ MM treated with intrapleural bortezomib with systemic bortezomib-based therapy. Although we observed good local response, the patient succumbed due to systemic myeloma progression.

Multicentered patient-based evidence of the role of free light chain ratio normalization in multiple myeloma disease relapse

The normalization of free light chain ratio (FLCr) has been introduced as a marker of stringent complete remission (CR) of multiple myeloma (MM). There is currently a lack of literature assessing the role of FLCr on MM disease progression and remission status.

10 years of experience with thalidomide in multiple myeloma patients: Report of the Czech Myeloma Group

We analyzed 1156 multiple myeloma (MM) patients treated with thalidomide. The overall response rate was 63.6%, with complete remission in 13.4%. Combined regimens had better outcomes than thalidomide plus dexamethasone or single agent thalidomide. Thalidomide was not able to overcome adverse cytogenetics. Superior results were seen in patients undergoing subsequent autologous stem cell transplantation. The rate of adverse events was low. Thalidomide has a strong potential to improve response and survival measures in patients with standard risk MM. Combined regimens should be used, with lower doses of thalidomide. High risk myelomas should be treated individually.

A first Czech analysis of 1887 cases with monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition with a risk of malignant conversion.