There are approximately 15,000 new cases of multiple myeloma and approximately 11,000 deaths in the United States each year. The incidence of multiple myeloma in China is 1 in 100,000, and although conventional chemotherapy and salvage therapy with hematopoietic stem cell transplantation can prolong the survival of patients, only a very small percentage of patients can be cured, with a median survival time of 3-4 years. Therefore new therapeutic drugs and protocols are expected to be generated. We conducted a careful and detailed analysis from literature search, subject establishment, case collection, and result analysis, hoping to bring new hope for the treatment of patients with multiple myeloma. Subjects and methods 1. Subjects: A total of 34 patients with newly diagnosed multiple myeloma were selected from May 2006 to March 2008 in four hospitals, namely, Chaoyang Hospital of Beijing, People’s Hospital of Peking University, General Hospital of the Chinese People’s Liberation Army, and Tianjin Hospital of Hematology, Chinese Academy of Medical Sciences. The clinical diagnostic criteria were based on the diagnostic criteria of MM in hematological diagnosis edited by Zhang Zhinan [2], and the Durie-Salmon staging criteria were used. 2. Inclusion criteria: age was not limited; expected survival was greater than six months; subjects were newly diagnosed (stage IB, II, III) multiple myeloma patients according to the International Myeloma Working Group criteria; voluntary informed consent was signed; and appropriate contraception was used throughout the study. 3. METHODS: The drug was administered under the supervision of the investigator or designated co-investigator every 21 d for one course of treatment. Bortezomib 1.3 mg/m2 intravenously (administered at 3-5 seconds) was administered twice weekly for two weeks, on days 1, 4, 8, and 11 of the 21-day treatment period, while patients received thalidomide 100 mg (4 tablets) orally before going to sleep daily from day 1 to day 21. All patients were prepared to receive 8 cycles of treatment. Discontinuation of treatment and/or participation in the study included: concurrent other diseases during the period; unacceptable adverse events; delayed treatment cycle or interruption of bortezomib dosing for more than three weeks or cancellation of three out of four bortezomib doses in a cycle due to toxic reactions; interruption of thalidomide dosing for more than three weeks due to toxic reactions; patient request; violation of study protocol; poor compliance with study protocol; inability to return to study center for follow-up; systemic or specific changes in the patient’s physical condition that, in the opinion of the investigator, precluded continued participation in treatment; and disease progression at any time. The primary evaluation endpoint was the overall remission rate (including complete remission, almost complete remission, partial remission and mild remission) with bortezomib combined with thalidomide treatment. 4, efficacy observation and safety evaluation: the efficacy determination was mainly based on the Bladè [3] criteria to evaluate the efficacy, which were classified as complete remission (CR), near complete remission (near CR), partial remission (PR), mild response (MR), no change (NC) and disease progression (PD). Adverse reactions were judged according to the criteria of the International Organization for the Harmonization of Nomenclature of Toxicological Effects (NCI CTCAE 3rd edition). Bone marrow cytology, routine blood tests, liver and kidney function, electrolyte tests, and immunoglobulin levels were performed before and after drug administration. The primary endpoint studied the remission rate and the safety of the regimen, and the secondary endpoint observed the sustained remission rate (DOR) at 12 months of follow-up and the disease-progression-free rate (TTP). 5. Statistical analysis: Kaplan-Meier analysis was used for time to event analysis, including time to response. Fisher’s exact test or pearson chi-square test was applied to analyze the correlation between qualitative indicators. Cox proportional fractional risk model analysis was also applied to identify independent factors of poor prognosis. p “0.05 was considered statistically significant. RESULTS 1. Basic data: A total of 34 patients were enrolled in this study, including 12 cases in Beijing Chaoyang Hospital, 9 cases in the Institute of Hematology affiliated with China Medical College Union Medical University, 8 cases in Peking University People’s Hospital, and 5 cases in the General Hospital of the Chinese People’s Liberation Army. 2. Efficacy observation: Among the 34 cases enrolled, 4 patients fell off due to serious adverse events and 4 cases withdrew from the clinical study due to poor compliance. The remaining 26 cases all completed 8 cycles of treatment. A total of 28 cases completed 4 cycles: complete remission (CR) in 6 cases, almost complete remission (nCR) in 8 cases, partial remission (PR) in 12 cases, mild remission (MR) in 1 case, and stable disease (SD) in 1 case, with a total effective rate (CR+nCR+PR+MR) of 96%; (27/28). Among the 26 cases who completed 8 cycles, 8 cases were in complete remission, 6 cases were in almost complete remission, 11 cases were in partial remission, and 1 case was in mild remission, with a total effective rate of 100%; 3. Follow-up results: All patients who completed 8 cycles were followed up for 12 months, and all patients were not treated with any drugs for maintenance. The duration of follow-up ranged from 3 to 12 months, with approximately 62%; (21 patients) had a progression-free time of 12 months, with a sustained remission rate (DOR) of 62% at 12 months; (5 patients were lost to follow-up and one patient did not achieve PR). By the end of follow-up, the overall median survival time of the patients had not been reached. 4. Adverse effects: 4 patients withdrew from the trial due to the development of acute renal insufficiency. Analysis of the reasons for the development of acute renal insufficiency was related to the fact that the patients were very sensitive to the regimen, which caused tumor lysis syndrome [4]. Among the remaining 30 patients, hematological toxicity was the most common (53.3%;), with platelet drop being the most common, but all were mild and could return to normal on their own after discontinuation of the drug, and only three cases had a low platelet drop (NCI grade ≥3) and required platelet transfusion therapy. The NCI grade of leukopenia was 1~2. Gastrointestinal reactions were another common adverse reaction, accounting for about 45%;. Severe diarrhea with dehydration (NCI grade 4) occurred in 2 cases, which was treated with rehydration and symptomatic support and antidiarrheal treatment and resolved after 2 d. Fever was more common, at 32%; and The incidence of peripheral neuropathy was 38%;, of which serious adverse reactions were 10%;, because of peripheral neuropathy lowered bortezomib dosage to 1.0 mg/m2 in 7 patients and bortezomib dosage to 0.7 mg/m2 in 1 patient, numbness and pain in hands and feet (neurotoxicity grade III or higher) occurred in 3 patients, after reducing the thalidomide dosage to 50 mg/d The symptoms did not worsen. All patients were not treated with anticoagulation, and none had symptomatic lower extremity deep vein thrombosis. Discussion Bortezomib is a synthetic dipeptide boronate analogue, which is a reversible proteasome inhibitor. It can be effective in the treatment of multiple myeloma by inhibiting the activation of factor NF-kB, attenuating interleukin-6 (IL-6)-mediated cell growth, and direct apoptotic effects [4]. In our study, bortezomib in combination with thalidomide for newly diagnosed MM was synergistic with each other, with rapid onset of action and high remission rates. Moreover, the complete remission rate increased with increasing course of treatment, and the overall efficiency rate was significantly higher. Twenty-six of the 34 patients in our initial treatment received bortezomib combined with thalidomide for 8 cycles, with an overall efficiency of 100%; and a remission rate of 52%;, which has not been reported in China or abroad [5]. This is difficult to achieve with conventional chemotherapy. Our study is consistent with the results of the international multicenter APEX phase III clinical trial on bortezomib monotherapy, which showed that the efficacy increased with the number of courses, with the best rates of complete remission and near-complete remission achieved at the fourth cycle of dosing. The complete remission rate of our combination regimen is higher in patients with newly diagnosed MM than bortezomib combined with sarcosamine and MP (VMPT) [6-8] and also higher than bortezomib combined with MP (VMP) [9], and a large number of pilot studies have found that a very good remission rate leads to a longer disease-free progression time and overall survival time. In our study, the overall median survival time has not been reached after 12 months of follow-up observation. The regimen of bortezomib combined with thalidomide was well tolerated for adverse effects and most patients recovered with symptomatic treatment only. 4 patients who developed acute renal insufficiency, 2 of whom had normal renal function before treatment and 2 others with elevated blood creatinine on renal function tests, included 2 IgG-κ, 1 IgG-λ, and 1 IgA-K types among the 4 cases. One patient developed infection, vomiting, diarrhea, and weakness during the treatment process, while the patient then entered hemodialysis and eventually died due to pulmonary infection. The cause of the deterioration of renal function in this patient was considered to be related to infection, insufficient blood volume due to diarrhea, and poor renal perfusion, rather than caused by bortezomib itself. In the remaining three cases, renal function gradually recovered after discontinuation of the drug, dialysis and adequate hydration, alkalinization of urine, and renal preservation, and the M protein on subsequent reexamination was substantially lower than before treatment. The specific mechanism of acute renal failure in patients with multiple myeloma treated with Vanco is not well understood. We believe that the following factors may be involved: (1) Systemic inflammatory response syndrome (SIRS): SIRS is the result of an inflammatory overreaction triggered by infectious or non-infectious factors that stimulate the host’s immune system and release humoral and cytokines that affect vascular tone and permeability, leading to microcirculatory disorders, shock, or organ failure, i.e. multi-organ dysfunction syndrome (MODS). Among these, the kidney is an important target organ in systemic inflammatory response syndrome, often associated with acute renal failure (ARF), and the mechanisms of renal injury are complex, involving bacterial products and host reactivity. (ii) Because bortezomib is a cytotoxic agent, it rapidly kills tumor cells and causes tumor lysis syndrome (ATLS). Tumor lysis syndrome is a metabolic disorder in which tumor cells are destroyed by lysis and intracellular metabolites are rapidly released into the extracellular fluid, resulting in hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute renal failure. The fact that ATLS occurs less frequently in multiple myeloma may be related to the slower proliferation cycle of myeloma cells. The application of bortezomib combined with thalidomide can cause tumor lysis syndrome related to the rapid onset of this regimen and the sensitivity of myeloma cells to it. In the remaining three cases, MM was controlled by aggressive hydration and alkalinization of the urine, treatment with blood purification and concomitant application of a regimen containing dexamethasone, and the patients’ renal function largely returned to normal after one month. The deterioration of renal function was considered to be related to tumor cell lysis, since the patients all had a substantial decrease in the values of abnormal globulin detected at the time of discontinuation of the regimen [10]. In our group of cases, other patients with renal insufficiency had stable or improved renal function after application of this regimen, and in general, this regimen did not have a direct effect on renal function, but during application, especially when the patient had a high tumor load, adequate hydration and alkalinization of the urine was beneficial to avoid damage to renal function from tumor cell necrotic material. Since both bortezomib and thalidomide can cause peripheral neuropathy as a side effect, the incidence of severe peripheral neuropathy in the combination regimen was of great concern to us, and it is reassuring that the incidence of severe peripheral neuropathy in our group of cases was only 10%; which was much lower than expected. This is probably due to the fact that we systematically evaluated the neurotoxicity during the treatment, closely observed the patient’s performance, and reduced the dose of bortezomib in case of peripheral neuropathy such as mild numbness. On the other hand, our patients are newly diagnosed, previously treated patients, unlike the APEX trial, which was used in patients with relapsed refractory multiple myeloma. Bortezomib offers a new approach to the treatment of MM. It is efficacious, has a rapid onset of action, and is tolerable, although it has many toxic side effects. Although it is currently recommended for refractory relapsed multiple myeloma that is resistant to chemotherapy, it is more effective as first-line treatment for primary MM . The combination of bortezomib and thalidomide significantly increased the efficacy without an increase in toxic effects. (We have published more than 100 relevant papers in core journals during the study which lasted nearly three years, and the research results achieved the intended purpose and were praised and recognized by the majority of colleagues. The relevant scientific research results were exchanged at the 49th American Hematology Annual Meeting in 2007 and received unanimous praise. And the research results have been gradually applied in clinical practice, finding a new and effective way for the treatment of multiple myeloma. The results of the study have achieved the intended purpose.) References; [1]. Barlogie B, Shaughnessy J, Tricot G, et al. Treatment of multiple myeloma. Blood , 2004;103:20-32. 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