91例初诊多发性骨髓瘤临床及实验室检查分析

目的 总结初诊多发性骨髓瘤（MM）的临床和有关实验室检查的特点。方法 对91例初诊MM患者的临床和实验摩资料作回顾性分析。结果 ①MM起病以骨痛和贫血最多见，IRG和IgA是最常见的免疫分型，占全部MM的83．5％。②本病起病隐匿．临床表现多样化。容易误诊。③大多异常的实验室检查结果无明显特异性。结论临床表现结合实验室相关指标检查，能够提高多发性骨髓瘤诊断的准确性．为临床诊断提供可靠依据。     

Role of thalidomide in previously untreated patients with multiple myeloma

Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.     

Role of thalidomide in previously untreated patients with multiple myeloma

Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.     

Residual serum monoclonal protein predicts progression‐free survival in patients with previously untreated multiple myeloma

BACKGROUND:

Currently used treatment response criteria in multiple myeloma (MM) are based in part on serum monoclonal protein (M‐protein) measurements. A drawback of these criteria is that response is determined solely by the best level of M‐protein reduction, without considering the serial trend. The authors hypothesized that metrics incorporating the serial trend of M‐protein would be better predictors of progression‐free survival (PFS).

METHODS:

Fifty‐five patients with measurable disease at baseline (M‐protein ≥1 g/dL) who received ≥4 cycles of treatment from 2 clinical trials in previously untreated MM were included. Three metrics based on the percentage of M‐protein remaining relative to baseline (residual M‐protein) were considered: metrics based on the number of times residual M‐protein fell within prespecified thresholds, metrics based on area under the residual M‐protein curve, and metrics based on the average residual M‐protein reduction between Cycles 1 and 4. The predictive value of these metrics was assessed in Cox models using landmark analysis.

RESULTS:

The average residual M‐protein reduction was found to be significantly predictive of PFS (P = .02; hazard ratio, 0.37), in which a patient with a 10% lower average residual M‐protein reduction from Cycle 1 to 4 was estimated to be at least 2.7× more likely to develop disease progression or die early. None of the other metrics was predictive of PFS. The concordance index for the average residual M‐protein reduction was 0.63, compared with 0.56 for best response.

CONCLUSIONS:

The average residual M‐protein reduction metric is promising and needs further validation. This exploratory analysis is the first step in the search for treatment‐based trend metrics predictive of outcomes in MM. Cancer 2010. © 2009 American Cancer Society.     

Phase I study of docetaxel and cisplatin for patients with previously untreated metastatic non-small-cell lung cancer: a Japanese cooperative study

Background. Docetaxel is one of the most active agents used in the treatment of advanced non-small-cell lung cancer. This phase I study was performed to determine the toxicities, maximum tolerated dose, and pharmacokinetics of the combination of docetaxel and cisplatin in patients with non-small-cell lung cancer, and to recommend a dose for phase II study. Methods. Patients were required to have previously untreated metastatic non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 2 or less, be aged between 15 and 74 years, to have a measurable lesion, and to have adequate organ function. Treatment consisted of 1-h infusion of docetaxel on day 1, followed by 2-h infusion of cisplatin (3 h after docetaxel) at the following docetaxel/cisplatin (mg/m²) dose levels: 50/50, 60/50, 60/60, 60/70, and 60/80. At least three patients were accrued at each dose level. Treatment was repeated every 3 to 4 weeks for responders. Administration of granulocyte-colony stimulating factor was permitted when leukocytopenia or neutropenia of grade 3 or more occurred. Results. Of the 29 patients entered, all were assessable for toxicity and response, but 2 were excluded from analyses of dose-limiting toxicity and maximum tolerated dose. Neutropenia (grade 4, for 3 days or more; n = 1), hepatic dysfunction (grade 3 or more; n = 2) and renal dysfunction (grade 2 or more; n = 3) were observed as dose-limiting toxicities. However, the maximum tolerated dose was not detected, even at the highest dose examined. Tumor response occurred in 13 of the 29 patients (45%; 95% confidence interval; 26%–64%). The pharmacokinetic profiles of docetaxel and cisplatin (n = 17) were similar to those observed after the administration of each dose as a single agent. Conclusion. Docetaxel/cisplatin doses of 60/80 mg/m² were recommended for phase II study, because grade 4 neutropenia occurred in 50% or more patients at docetaxel/cisplatin dose levels of 60/60 mg/m² and above, and the doses of these drugs were restricted to within the approved dose ranges for single-agent use in Japan. The responses observed in this phase I study suggest a high degree of activity of this combination against previously untreated advanced non-small-cell lung cancer and warrant a phase II study at the recommended dose level. Received: February 29, 2000 / Accepted: June 22, 2000     

Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma

Bisphophonates are the treatment of choice to prevent skeletal events in patients with multiple myeloma. Some preclinical studies suggested that bisphophonates can be useful as antitumor drugs in some malignancies. We conducted a controlled clinical trial to assess if zoledronic acid can have this clinical activity. Ninety four patients with previously untreated multiple myeloma were treated with a conventional chemotherapy program: cyclophosphamide, vincristine, melphalan, and prednisone (CVMP) and were randomized to received either zoledronic acid (4 mg, iv, every 28 d) or not (control group). The end-point of the present study was to assess improvement in outcome, measured by event-free survival (EFS) and overall survival (OS), and the second-end point was to confirm the efficacy in preventing skeletal events. In an intent-to-treat analysis, all patients were available for efficacy and toxicity. Median follow up was 49.6 mo (range: 34-72 mo). Five year actuarial curves showed that EFS was 80% in the zoledronic acid group, which was statistically different from 52% in the control group (p < 0.01). Actuarial 5 yr OS was 80% in the zoledronic acid arm, and 46% in the control group (p < 0.01). Sketeletal events were more frequent in the control group when compared to zoledronic acid. Toxicity was mild. We confirm the efficacy of zoledronic acid to prevent skeletal events, but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group. We began a controlled clinical trial with modern treatment (including transplant procedures) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients.     

A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma

A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.     

Thalidomide alone or with dexamethasone for previously untreated multiple myeloma.

PURPOSE: To evaluate the activity of thalidomide in patients with asymptomatic multiple myeloma and of thalidomide-dexamethasone in patients with previously untreated symptomatic myeloma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated asymptomatic myeloma were treated with thalidomide 100 to 200 mg orally (PO) at bedtime (qhs) with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. Forty consecutive previously untreated patients with symptomatic myeloma were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m(2) for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for at least 3 months. RESULTS: The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with thalidomide-dexamethasone, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (nine patients) and thrombotic/embolic events (seven patients). Five deaths have occurred as a result of multiple myeloma (two patients), infection (one patient), unknown cause (one patient), and a possible thromboembolic event (one patient). CONCLUSION: Thalidomide alone was effective in patients with newly diagnosed myeloma. The combination with dexamethasone induced a high frequency of response, rapid onset of remission, and low incidence of serious irreversible toxicity. These observations support further studies of this promising combination for patients with newly diagnosed multiple myeloma.     

Pomalidomide‐bortezomib‐dexamethasone in relapsed or refractory multiple myeloma: Japanese subset analysis of OPTIMISMM

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression‐free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment‐emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.     

Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Background. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calvert's formula. Dose levels studied were: docetaxel (mg/m²)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m², with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m², with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m², given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified. Received: October 4, 1999 / Accepted: June 28, 2000     

Phase II study of docetaxel in patients with pancreatic cancer previously untreated with cytotoxic chemotherapy

In this study, we estimated the response rate, duration of response, and type, severity and reversibility of toxicities in patients with Stage IV adenocarcinoma of the pancreas treated with docetaxel. Twenty-one patients with locally advanced or metastatic pancreatic cancer, previously untreated or treated with surgery or radiation alone, were treated with 100 mg/m² docetaxel as a 1 hr infusion once every 21 days. All the patients were pretreated with dexamethasone and diphenhydramine. Twenty patients were assessable for both response and toxicity. One patient was assessable for toxicity alone. However, all the patients were assessed for survival. The major side effect of the drug was neutropenia, which required a dose reduction to 75 mg/m² in approximately half of the patients. Nine patients were hospitalized with neutropenic fever. Fluid retention was not a significant problem. One patient had a partial response lasting for 21 weeks and 7 patients had stable disease. The remaining patients had progressive disease. The median survival for all the patients was 5.9 months. Docetaxel as a single agent showed limited activity against adenocarcinoma of the pancreas. Since the completion of this study, molecular predictors of in vitro response to docetaxel have been described. Confirmation of the clinical relevance of such predictors in humans could allow for the identification of a subgroup of patients with a higher rate of response to docetaxel.     

Phase II study with etoposide in previously untreated advanced breast cancer

Summary A phase II study was carried out to evaluate the efficacy and safety of etoposide used as first-line chemotherapy for patients with advanced breast carcinoma. A total of 20 patients received 230 mg/m² i.v. etoposide per day for 3 days (total, 690 mg/m² per course) every 4 weeks. A total of 95 courses were given. Observed responses included 3 partial remissions (PR) and 14 cases of stable disease (NC). The median duration of response was 6 (PR) and 5.6 months (NC). Contrary to the severe hematological toxicity in heavily pretreated patients described in previous studies, no substantial problems were observed in this trial. No dose reduction was necessary, and only once did leukopenia lead to a 1-week delay in therapy. An increase in platelets up to a maximum of 685,000/mm³ was seen in all patients, particularly in those with bone metastases. No relation to the quality of remission or pretreatment was seen. Nausea, vomiting, and fatique were mild and transient, but alopecia occurred in all cases. One patient developed nonfatal anaphylactic shock after etoposide treatment.     

Thalidomide for previously untreated indolent or smoldering multiple myeloma.

We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.     

Phase II trial of menogaril in patients with previously treated multiple myeloma or chronic lymphocytic leukemia

Menogaril is a semisynthetic anthracycline with relative lack of cardiotoxicity. Ten patients with multiple myeloma (MM), seven patients with chronic lymphocytic leukemia (CLL), and one patient with diffuse well-differentiated lymphocytic lymphoma (DWDL) were treated with menogaril, 160 mg/m2 (for MM) or 200 mg/m2 (for CLL/DWDL), given as a 2-hour intravenous infusion, repeated every 28 days. All patients except one with CLL had been previously treated with one chemotherapy regimen and had either not responded or had relapsed after a response to prior treatment. There were no objective responses to treatment. Among the six evaluable patients with MM, two had stable disease with subjective improvement in symptoms for five to 25 cycles, and among the eight patients with CLL/DWDL, five patients remained stable for two to eight cycles on treatment. The remainder of the patients had progressive disease after one to two cycles of chemotherapy. Five grade 4 hematologic toxicities were observed. There was one fatal neutropenic sepsis. Menogaril, as administered in this study, does not appear to have significant activity in patients with previously treated MM or CLL.     

Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose-escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty-four patients were enrolled. A dose-limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest-dose cohort in phase I and led to the selection of 1.3 mg/m² as the recommended dose. Adverse events ≥ grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16–49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration–time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules. ( Cancer Sci 2008; 99: 140–144)     

Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T‐cell lymphoma

Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T‐cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we undertook a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7‐week cycle. All patients received concurrent vitamin B₁₂ and folic acid. In phase I, three patients received pralatrexate 30 mg/m² and none experienced a dose‐limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1–9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut‐off, median progression‐free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia (20%), and mucositis (20%). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results indicate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T‐cell lymphoma. This trial was registered with ClinicalTrials.gov (NCT02013362).     

Mitochondrial modulation decreases the bortezomib‐resistance in multiple myeloma cells

Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib‐induced cell death in two different MM cell lines (bortezomib‐resistant KMS20 cells and bortezomib‐sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine‐5′‐triphosphate and mitochondrial Ca²⁺ concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2‐methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision‐making.     

Phase I/II and pharmacokinetic study of S-1 and oxaliplatin in previously untreated advanced gastric cancer

Background

We aimed to determine the maximum-tolerated dose (MTD) of S-1 when given with oxaliplatin, to evaluate S-1 pharmacokinetics, and to determine the efficacy and safety of this regimen as a first-line treatment for advanced gastric cancer (AGC).

Methods

Oxaliplatin was fixed at a dose of 130 mg/m² on day 1 (D1). S-1 was administered from D1 to D14 of a 3-week cycle, and escalated by 10 mg/m² per day from 70 mg/m² per day up to 100 mg/m² per day. Pharmacokinetic analyses were performed following a single dose of S-1 on D-5 and D1 of the first cycle.

Results

In phase I (n = 18), MTD was not defined. In phase II (n = 47) with the planned maximum dose, partial response was achieved in 26 patients (55.3%) and stable disease in 14 patients (29.8%). The median time to progression was 6.6 months (95% CI 4.0–9.2 months) and the median overall survival was 12.5 months (95% CI 9.2–15.9 months). Frequent grade 3/4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), and leukopenia (13%). There was one grade 5 febrile neutropenia during the first cycle.

Conclusions

The pharmacokinetics of S-1 was not influenced by oxaliplatin. S-1/Oxaliplatin combination therapy is highly active against AGC and has a favorable toxicity profile.