Petr Kessler

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.

Genomewide profiling of copy-number alteration in monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with an approximate 1% annual risk of symptomatic plasma cell disorder development, mostly to multiple myeloma (MM). We performed genomewide screening of copy‐number alterations (CNAs) in 90 MGUS and 33 MM patients using high‐density DNA microarrays. We identified CNAs in a smaller proportion of MGUS (65.6%) than in MM (100.0%, P = 1.31 × 10−5) and showed median number of CNAs is lower in MGUS (3, range 0–22) than in MM (13, range 4–38, P = 1.82 × 10−10). In the MGUS cohort, the most frequent losses were located at 1p (5.6%), 6q (6.7%), 13q (30.0%), 14q (14.4%), 16q (8.9%), 21q (5.6%), and gains at 1q (23.3%), 2p (6.7%), 6p (13.3%), and Xq (7.8%). Hyperdiploidy was detected in 38.9% of MGUS cases, and the most frequent whole chromosome gains were 3 (25.6%), 5 (23.3%), 9 (37.8%), 15 (23.3%), and 19 (32.2%). We also identified CNAs such as 1p, 6q, 8p, 12p, 13q, 16q losses, 1q gain and hypodiploidy, which are potentially associated with an adverse prognosis in MGUS. In summary, we showed that MGUS is similar to MM in that it is a genetically heterogeneous disorder, but overall cytogenetic instability is lower than in MM, which confirms that genetic abnormalities play important role in monoclonal gammopathies.

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.

Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients

Abstract Objectives: We conducted an adjusted comparison of progression-free survival (PFS) and overall survival (OS) for daratumumab monotherapy versus standard of care, as observed in a real-world historical cohort of heavily pretreated multiple myeloma patients from Czech Republic. Methods: Using longitudinal chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, patient-level data from the RMG was pooled with pivotal daratumumab monotherapy studies (GEN501 and SIRIUS; 16 mg/kg). Results: From the RMG database, we identified 972 treatment lines in 463 patients previously treated with both a proteasome inhibitor and an immunomodulatory drug. Treatment initiation dates for RMG patients were between March 2006 and March 2015. The most frequently used treatment regimens were lenalidomide-based regimens (33.4%), chemotherapy (18.1%), bortezomib-based regimens (13.6%), thalidomide-based regimens (8.0%), and bortezomib plus thalidomide (5.3%). Few patients were treated with carfilzomib-based regimens (2.5%) and pomalidomide-based regimens (2.4%). Median observed PFS for daratumumab and the RMG cohort was 4.0 and 5.8 months (unadjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.94–1.39), respectively, and unadjusted median OS was 20.1 and 11.9 months (unadjusted HR, 0.61; 95% CI, 0.48–0.78), respectively. Statistical adjustments for differences in baseline characteristics were made using patient-level data. The adjusted HRs (95% CI) for PFS and OS for daratumumab versus the RMG cohort were 0.79 (0.56–1.12; p = .192) and 0.33 (0.21–0.52; p < .001), respectively. Conclusions: Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for daratumumab monotherapy.

Real-World Outcomes of Multiple Myeloma: Retrospective Analysis of the Czech Registry of Monoclonal Gammopathies

&NA; The Registry of Monoclonal Gammopathies (RMG) collects long‐term data for patients with hematologic malignancies and is one of the largest registries of its type in Europe. The present noninterventional, observational study analyzed real‐world data from 2446 Czech patients from the RMG to provide insights into the real‐world treatment outcomes of patients with multiple myeloma. Introduction: Real‐world data on patient outcomes and treatment patterns in multiple myeloma (MM) are limited. Materials and Methods: The present noninterventional, observational, retrospective analysis of prospectively collected Czech patient medical record data from the Registry of Monoclonal Gammopathies estimated real‐world outcomes in adults with a diagnosis of symptomatic MM made between May 2007 and June 2014. Results: In total, 2446 patients had initiated first‐line treatment. The median overall survival since the diagnosis (primary endpoint) was 50.3 months (95% confidence interval, 46.1‐54.5 months) and decreased with each successive treatment line. A similar trend was observed for progression‐free survival and the depth of response. In line with European guidelines and clinical practice, bortezomib‐, thalidomide‐, and lenalidomide‐based regimens were most commonly used across all treatment lines (42.3%, 28.9%, and 18.4%, respectively). In the first line, bortezomib and thalidomide were used most often, with lenalidomide the most commonly used agent in the relapse setting (second to fourth lines). Exploratory analyses revealed that younger age (≤ 65 years), lower international staging system stage, and previous stem cell transplantation were associated with significant improvements in overall and progression‐free survival, especially in the early treatment lines. Conclusion: The present study is the first analysis of Czech data from the Registry of Monoclonal Gammopathies, and it provides important insights into the real‐world management of MM for physicians and healthcare providers.

Validation of multiple myeloma risk stratification indices in routine clinical practice: Analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies

This study used data from the Czech Myeloma Group Registry of Monoclonal Gammopathies to validate the International Myeloma Working Group (IMWG) and revised International Staging System (R‐ISS) indices for risk stratification in patients with multiple myeloma (MM) in clinical practice. Patients were included if they had symptomatic MM, complete data allowing R‐ISS and IMWG staging (including cytogenetic information regarding t(4;14), t(14;16), and del(17p)), and key parameters for treatment evaluation. Median overall survival (OS) in included patients (n = 550) was 47.7 (95% CI: 39.5‐55.9) and 46.2 (95% CI: 38.9‐53.5) months from diagnosis and initiation of first‐line therapy, respectively. Patients categorized as higher vs lower risk had reduced survival; median OS from diagnosis was 35.4 (95% CI: 30.5‐40.3) vs 58.3 (95% CI: 53.8‐62.9) months in high‐risk vs other patients (IMWG; P = .001) and 34.1 (95% CI: 30.2‐38.0) vs 47.2 (95% CI: 43.4‐51.0) months in Stage III vs Stage II patients (R‐ISS; P < .001). In conclusion, IMWG and R‐ISS risk stratification indices are applicable to patients with MM in a real‐world setting.