Bortezomib (Velcade) in the Treatment of Relapsed or Refractory Multiple Myeloma: Analysis of Safety and Efficacy of Bortezomib From Registry of Monoclonal Gammopathy of Czech Myeloma Group
Authors: Sandecka Viera , Spicka Ivan , Maisnar Vladimir , Pika Tomas , Gregora Evzen , Starostka David , Walterova Lenka , Gumulec Jaromir , Adamova Dagmar , Wrobel Marek , Vonke Ivan , Zahradova Lenka , Straub Jan , Radocha Jakub , Minarik Jiri , Pavlicek Petr , Kessler Petr , Pour Ludek , Hajek Roman 
Published: October 2019

Abstract
Abstract 1872

Background:
Bortezomib (Velcade) is one of the most effective treatment options in the treatment of relapsed or refractory multiple myeloma (RRMM). In the Czech Republic, it has been available since 2004. Registry of monoclonal gammopathy (RMG) of the Czech Myeloma Group contains information of more than 90% of patients in the Czech Republic treated with novel drugs.Aims: The aim of this retrospective analysis was to verify the therapeutic efficacy and safety of bortezomib in the treatment of RRMM in the Czech Republic.

Methods:
Before inclusion to RMG, all persons signed the informed consent form. In total, 1469 MM patients treated with bortezomib were evaluated from the RMG between June 2004 and December 2011.A total of 51.5% (750/1469) RRMM patients were analyzed with follow-up ≥6 months from the start of first administration of bortezomib. 30.6% (450/1469) patients with newly diagnosed MM were excluded from the analysis as well as 18.2% (267/1469) with a short follow-up. Evaluation of treatment response was performed according to the IMWG criteria. Median patient age was 65 years (range 33.9–88.1), median time since starting therapy was 21.5 months (range 6.1– 86.2), median number of previous treatments was 3.0 (range 1.0–8.0). In total, 92% (690/750) patients finished treatment of bortezomib (cycles length 21–28 days with application on days 1, 4, 8,11 or 1, (4), 8, 15 for frail patients). Median number of bortezomib cycles delivered was 6 (0.5–15.5).

Results:
Assessment of therapeutic response was possible in 92% (690/750) of treated patients. Overall response (ORR) in 57.5% (397/690) patients including 3% sCR, 8% CR, 20.3% VGPR, 26.2% PR. Stable disease was confirmed in 11.4% (79/690) patients and 22.5% (155/690) patients had progressive disease. In 50.1% of responders, first response (≥MR; defined as a ≥25% decrease in the serum MIg) occurred within the first cycle. At the second cycle, 24.2% of responders started to respond. Median time to progression (TTP) for all responders was 12.4 months. Median overall survival after starting bortezomib therapy (OS) was 32.3 months for all responders. Altogether, 692 adverse events (AEs) were documented. The most frequent AEs were: anemia in 62% of patients (462/750); severity of anemia was distributed as follows: 33.3% (250/750) cases of grade 1, 28.3% (212/750) cases of grade 2. Thrombocytopenia grade 3 and 4 was seen in 21.5% (161/750) of patients. Pre-existing peripheral neuropathy (PNP) grade 1–2 was presented in 25.1% (191/750) of patients at the start of bortezomib treatment. After treatment of bortezomib, PNP could be documented in 59.3% (445/750) cases with 16% (71/445) cases of grade 3 and 0.7% (3/445) cases of grade 4 PNP. In subanalysis, groups of patients were compared with relapsed patients who were treated with bortezomib in the second, third or greater-line of therapy. Among these three groups, there were significant differences in the evaluation of ORR (59.8% vs. 53.4% vs. 46.8%, p=0.022), as well as the sCR+CR was dependent on the number of previous treatment lines (15.6% vs 7.3% vs. 1.4%; p<0.001). Median TTP had similar dynamics (14.5 vs. 11.0 vs. 10.0 months; p= < 0.001). Altogether, 55.5% (416/750) of patients were pre-treated with thalidomide, while other patients were pre-treated with only conventional cytotoxic agens. Between these two groups we found differences in the achievement of treatment response: sCR+CR (8% vs. 14.1%; p =0.007), median TTP (11.0 vs. 15.0 months; p = 0.001) and median OS from the start of treatment with bortezomib (28.2 vs. 36.5 months; p = 0.001). Autologous stem cell transplantation after treatment with bortezomib was performed in 13.9% (104/750) of patients with positive effect on survival compared to patients without autologous stem cell transplantation (median OS 42.4 vs. 31.2 months; p = 0.007, median TTP 19.4 vs. 11.4 months; p <0.001).

Conclusion:
Our results show that bortezomib is one of the highly effective drugs for patients with RRMM. In current practice, the benefit (measured TTP) is 10–14 months, according to severity of the disease with a favorable impact on overall survival even in heavily pretreated patients. Implementation of autologous stem cell transplantation in relapsed disease following bortezomib treatment had a beneficial effect on overall survival.

Acknowledgments:
This work was supported by IGA NT 12130–4 and IGA NT 12215–4 grants.

Disclosures:
Maisnar: Janssen Cilag: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer (Schering): Honoraria. Hajek:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria.