The efficacy and adverse effects of bortezomib combined with methylprednisolone in 33 patients with relapsed, refractory multiple myeloma were retrospectively analyzed. All patients were treated with bortezomib 1.75 mg [(0.9-1.1) mg/m2], administered on days 1, 4, 8, and 11, and also with methylprednisolone 40 mg (4 patients), 80 mg (13 patients), 120 mg (2 patients), 200 mg (9 patients), and 300 mg (5 patients) in combination on days 1, 4, 8, and 11. Outcome phenotype: median follow-up time 10 (3-60) months, number of application sessions 1-8 (mean 4), 24 cases achieved various degrees of remission, with an overall effective rate of 73%;. After completing 2, 4 and 6 courses of treatment, the overall response rate reached 71.9%; (23/32 cases), 93.8%; (15/16 cases), 100%; (7/7 cases), respectively. The major adverse reactions were hematologic toxicity, respiratory tract infection, malaise, gastrointestinal reactions, and peripheral neuropathy. CONCLUSION: The use of bortezomib in combination with methylprednisolone for the treatment of patients with relapsed and refractory MM has a definite efficacy, rapid onset of action, high efficiency, high remission rate and mild toxic side effects and should be given priority.
Multiple myeloma; refractory/relapsed; bortezomib; methylprednisolone
Effects of Bortezomib combination with methylprednisolone in treatment of 33 cases of refractory or relapsed multiple myeloma. Li Xin, Chen Shi-lun Zhong Yu-ping, Hu Ying, Zhang Jia-jia, An Na. Beijing Chaoyang hospital, Capital Medical University, Beijing 100043, China
Corresponding author: Chen Shi-lun, Email: [email protected]
Abstract To elucidate the curative effects and toxicity of Bortezomib combination with methylprednisolone in treatment of refractory or relapsed multiple myeloma (MM). Thirty three MM patients received Bortezomib 1.75mg/m2 on days 1, 4, 8, 11, combined with methylprednisolone 40mg/d (4 cases), 80mg/d (13 cases), and The results showed that the overall response rate was 73%;(24/33). With the median of follow-up time of 10 (3-60)months and 1-8 cycles (4 cycles) therapy,. The overall response rate were 71.9%; (23/32 cases), 93.8%; (15/16 cases), 100%; (7/7 cases) after receiving 2, 4 and 6 cycles therapy, respectively. Main toxicities were haematologic, respiratory tract infections, fatigue, gastrointestinal side effects and peripheral neuropathic. combination with methylprednisolone is an effective and with a higher response rate
Author Affiliation:Department of Hematology, Jingxi Campus, Chaoyang Hospital, Beijing, 10043, China
Corresponding author: Shilun Chen, Email: [email protected]
and safe therapy regimen in treatment of refractory or relapsed multiple myeloma.
Key words Multiple myeloma, refractory or relapse, Bortezomib, methylprednisolone
Multiple myeloma (MM) is an incurable hematologic malignancy, accounting for approximately 10% of hematologic malignancies, and its incidence has been gradually increasing in recent years. Although combination chemotherapy and even autologous hematopoietic stem cell transplantation have improved the remission rate and prolonged the survival of patients with MM, they eventually relapse and become drug-resistant, and the prognosis becomes worse with the increase of chemotherapy. Bortezomib, a novel targeted therapeutic agent, has achieved good efficacy in the treatment of multiple myeloma [1]. We applied this drug in combination with different doses of methylprednisolone to treat 20 patients with relapsed, refractory MM who had failed various treatments, and the results are reported below.
Cases and methods
Case data
From November 2005 to December 2010, 33 patients with relapsed/refractory MM were treated with bortezomib combined with methylprednisolone in our department. There were 23 males and 10 females with a median age of 57 (38-85) years. All patients received at least 2 courses of standard chemotherapy (including melphalan or VAD regimens), with a median of 9 (2-24) courses of chemotherapy; 4 of them had received 2 autologous hematopoietic stem cell transplants and 4 had undergone radiotherapy.
Treatment
All patients were treated with bortezomib 1.75 mg [(0.9-1.1) mg/m2], administered on days 1, 4, 8, and 11, and also with methylprednisolone 40 mg (4 patients), 80 mg (13 patients), 120 mg (2 patients), 200 mg (9 patients), and 300 mg (5 patients) in combination on days 1, 4, 8, and 11. 3 weeks was the duration of treatment, and at least 2 courses of treatment.
Efficacy assessment and observation of adverse effects
The efficacy assessment was mainly based on the Blade efficacy criteria [2], which were classified as complete remission (CR), near complete remission (NCR), partial remission (PR), mild response (MR), stable disease (SD), and disease progression (PD), in order to assess the best efficacy achieved. Adverse effects were judged according to the criteria of the International Organization for the Harmonization of Toxicology Nomenclature (NCI CTCAE 3rd edition).
Results
Case follow-up
All MM patients were evaluated. The median follow-up time was 10 (3-60) months. 1 case received 1 course of treatment, 32 cases received 2 courses of treatment, 4 cases received 3 courses of treatment, 16 cases received 4 courses of treatment, 1 case received 5 courses of treatment, 7 cases received 6 courses of treatment, and 2 cases received 8 courses of treatment. The number of applied treatments ranged from 1 to 8 (mean 4).
Therapeutic effect
Twenty-four of the 33 refractory or relapsed patients achieved various degrees of remission, with an overall effective rate of 73%;. One patient refused to continue after 1 course of treatment due to elevated transaminases, but this patient achieved partial remission of the disease after 1 course. 32 patients were evaluated for efficacy after 2 courses of treatment, including 8 CR, 2 NCR, 13 PR, 3 SD, and 6 PD; 4 patients received 3 courses of treatment, including 2 PR, 1 SD, and The other 28 patients only completed 4 courses of treatment in 16 patients and 12 patients were switched to other regimens. 16 patients continued with 10 CR, 1 NCR, 4 PR, and 1 SD. 7 patients who achieved efficacy went on to complete 6 courses of treatment, 5 CR, 1 NCR, and 1 PR. 2 patients who achieved efficacy reached CR and NCR after 8 courses of treatment, respectively. The nine patients with extramedullary plasmacytoma had significantly smaller extramedullary plasmacytomas, and two patients had complete disappearance.
Overall survival
The median survival time of the 33 patients with relapsed refractory MM was 41.5 (2-120) months, with an overall survival rate (OS) of 80% at 2 years; and 59.1% at 3 years; and 21.1% at 5 years;.
Discussion
The use of conventional chemotherapy and autologous hematopoietic stem cell transplantation cannot cure MM, and the treatment of refractory and recurrent MM has been a problem for clinicians, so it is extremely important to find new treatment methods and strategies. large phase II/III clinical trials such as SUMMIT, CREST, and APEX have confirmed the effectiveness of bortezomib in treating relapsed and refractory MM. The overall efficiency of bortezomib monotherapy for relapsed, refractory MM was 35%; to 43%;, CR rate 6%; to 13%;, median disease-free progression period 7 months, and median overall survival about 17 months.Jagannath [3] et al. reported 55 patients with relapsed, refractory MM randomized into bortezomib 1.0 mg/m2 and 1.3 mg/m2 groups, with overall response rates were 33%; and 50%; respectively, which increased to 44%; and 62%; with the combination of dexamethasone. Several clinical trials of bortezomib in combination with other drugs for relapsed/refractory MM have been reported in recent years [4-6]. The combinations include glucocorticoids such as dexamethasone, anthracyclines such as adriamycin, alkylating agents such as mafran, and thalidomide and arsenic agents. The experimental results showed that most of the efficiency rates were up to 6O%; to 8%;, all of which were higher than the efficiency of bortezomib monotherapy.
The purpose of our study was to investigate the efficacy and safety of bortezomib combined with methylprednisolone in the treatment of relapsed, refractory MM. Methylprednisolone is a synthetic medium-acting glucocorticoid with stronger affinity for glucocorticoid receptors than dexamethasone; it is highly lipophilic and can rapidly penetrate cell membranes, resulting in a rapid increase in intracellular activated steroid receptors within a short period of time and a 30-fold higher blood concentration than dexamethasone. The overall response rate in this study was 73%; (24/33), and the overall response rate after completing 2 courses of treatment was 71.9%; (24/32), of which the CR rate reached 25%; (8/24), compared with that of dexamethasone. The efficacy was significantly better than that of bortezomib alone and bortezomib combined with other chemotherapy regimens compared with the above-mentioned literature. And after completing 4 courses of treatment, the overall response rate reached 93.8%;, the efficacy was significantly improved, and the efficiency rate further improved with the increase of the number of courses, and the proportion of CR and NCR increased. We suggest that a minimum of 2 courses of bortezomib combined with methylprednisolone is required for the treatment of relapsed, refractory MM, and preferably more than 4 courses should be applied in order to achieve optimal therapeutic results.
In this study, the most common hematologic adverse effect was thrombocytopenia, which was transient and recovered quickly with drug discontinuation. Other major adverse reactions, such as malaise, gastrointestinal reactions, and elevated transaminases, were recovered after symptomatic treatment and discontinuation of the drug, similar to those reported by Bao Li et al [7]. However, the incidence of infections was high in this study, with upper respiratory tract infections being the most common, with five of the patients having a combination of pneumonia during treatment and three others having a complication of herpes zoster. Only one of the patients had chronic bronchitis, which was interrupted during the treatment not only with pneumonia but also with pulmonary encephalopathy, while the other patients improved after active anti-inflammatory treatment. The reason for the higher incidence of infection in this group of patients was related to the application of larger doses of hormones. Another major adverse effect was peripheral neuropathy, which often occurred in patients who completed more than 4 courses of treatment, but it was mostly grade 1-2 neurotoxicity, which was tolerated by most patients, and the symptoms could be gradually relieved after 1-3 months, but the symptoms disappeared completely in fewer cases. Grade 4 neurotoxicity occurred in one of the patients, who had been previously treated with more drugs affecting peripheral nerves.
Our results show that bortezomib combined with methylprednisolone is effective in the treatment of relapsed and refractory MM patients, with rapid onset of action, high efficiency, high remission rate, mild toxic side effects, and many adverse effects, but they are tolerable. Of course, the dose of methylprednisolone should be reduced in elderly patients with previous chronic cardiopulmonary disease.
Reference literature
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