Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

[Clinical Analysis of Combination Chemotherapy Using High Dose Methotrexate, Rituximab, and Vincristine with or without Procarbazine for Elderly Patients with Diffuse Large B-Cell Lymphoma of the Central Nervous System].

We studied the clinical effects of high-dose methotrexate(HD-MTX)combined with rituximab and vincristine in 5 elderly patients, aged 65-83 years, with diffuse large B-cell lymphoma of the central nervous system(DLBCL CNS). Patients aged 65- 71 years were given 3.0 g/m2 of HD-MTX, while patients aged 75-83 years were given 1.5 g/m2 of the drug. All patients showed responses; 1 CR and 1 PR in MTX 3.0 g/m2 group, and 2 CRs and 1 PR in MTX 1.5 g/m2 group.

Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma.

We investigated the treatment and outcome of Japanese patients with primary plasma cell leukemia (pPCL) in the era of novel agents and analyzed the risk factors affecting survival. Among 3,318 patients with symptomatic multiple myeloma (MM), 38 patients were diagnosed with pPCL. The median overall survival (OS) of the pPCL patients was 2.85 years, which was significantly extended compared with that in previous reports. The proportion of patients treated with novel agents was 61%. The OS of the patients treated with novel agents was significantly extended compared with that of patients treated without novel agents according to the generalized Wilcoxon test (2.85 vs. 1.16 years, p = 0.049). This statistical finding suggests that treatment with novel agents could have prevented early death in the patients with pPCL. Age was the only statistically significant prognostic factor associated with an inferior OS (hazard ratio 4.57). Five patients received maintenance therapy with novel agents, and their OS tended to be longer than that of the other patients without maintenance (4.45 vs. 2.85 years). Unlike MM, OS for pPCL has not been improved significantly over the last decade, especially in elderly patients. Therefore, it is important to establish the treatment strategy, particularly after induction treatment.

[Clinical usefulness of serum free light chain measurement in monoclonal gammopathy].

Recently, a highly sensitive assay (FREELITE) capable of measuring serum immunoglobulin-free light chains (FLC) was developed. An abnormal kappa/lambda ratio supports the presence of clonal plasma cell expansion. Using this assay, we measured serum and urine samples of 178 healthy volunteers, 184 patients with polyclonal gamma-globulinemia and 150 patients with monoclonal gamma-globulinemia. The diagnostic sensitivity of the FLC assays for monoclonal gammopathies was 88.0% and the specificity for healthy volunteers and polyclonal gammopathies was 96.1%. The minimal detection sensitivity of this assay for serum FLC was 0.3 mg/l and was greater than 100-fold more sensitive than serum protein electrophoresis (SPE). The combination of FLC with SPE and immunoelectrophoresis identified 99% of patients with monoclonal gammopathies. Effective treatment often leads to a more rapid reduction of the involved FLC level relative to the intact immunoglobulin or total light chain concentration because the half-life of FLC is <6 hours. These observations suggest that FREELITE is useful for diagnosis, disease monitoring and assessment of response to treatment in patients with monoclonal gammopathies such as multiple myeloma and AL amyloidosis.

[Prognositic factors in multiple myeloma].

The article about the prognostic factors in multiple myeloma is reviewed. PS, albumin, sex, LDH, myeloma % in bone marrow, beta2MG, kappa > lambda, IgG>nonIgG, the serum concentration of IgG M protein, Hb, WBC, platelet, creatinine, calcium and CRP were reported as siginificant factors using univariate analysis in Japanese patients with myeloma. According to the result of multivariate analysis, two factors of albumin and beta2 MG have been adopted in the International Staging System in multiple myeloma (ISS). We can use the prognostic factor as a clue to the estimation of the clinical status and the prognosis in each case.

[Evaluation of the clinical relevance of serum measurements of free-light chains in patients with multiple myeloma].

Measurement of serum free-light chains (FLCs) was performed using a recently developed immunoassay in 180 healthy individuals, 16 patients with multiple myeloma, and each 1 patient with Waldenström's macroglobulinemia, primary amyloidosis, or MGUS (monoclonal gammopathy of undetermined significance) to evaluate the clinical relevance of FLCs in the diagnosis and disease monitoring. Serum FLC levels of each patient were elevated compared with the levels of healthy individuals. The changes in FLC levels after treatment and at the time of relapse occurred earlier than those in serum immunoglobulin levels due to the short half-life of FLCs. Serum FLC levels were elevated in patients with Bence Jones type myeloma in spite of negative urinary immunoelectrophoresis. The serum FLC assay is a sensitive and useful tool for the diagnosis and monitoring of multiple myeloma and other B-cell proliferative disorders.

Management of patients with multiple myeloma in Japan: data of 1,383 patients from 16 hospitals and 1 treatment group.

The available information regarding relevant treatment approaches and outcome in Japanese myeloma patients has been fragmentary and clarification of the position is required. The Japan Myeloma Study Group collected data on 1,383 patients who had been diagnosed and treated during the 11 year period between 1990 and 2000 from 16 participating hospitals and 1 treatment group to investigate the status of the management of multiple myeloma across Japan. There were 724 (53%) male and 643 (47%) female patients with median age being 66-years-old. More than 60% of the patients were classified as having stage III disease. As initial therapy, 1,162 (84.4%) patients were treated with chemotherapy and the median survival was 3.1 years. High-dose therapy followed by stem cell transplantation (SCT) as part of first-line therapy was given in 113 (7.4%) patients with median survival being 4.4 years.

Superior efficacy of MMCP regimen compared with VMCP and MMPP regimens in the treatment of multiple myeloma.

OBJECTIVE: A newly designed combination chemotherapy for multiple myeloma, MMCP [ranimustine (MCNU), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL)], was analyzed and compared with the results of our previous randomized trial of VMCP [vincristine, MPH, CPM and PSL] and MMPP [MCNU, MPH, procarbazine and PSL]. METHODS: MCNU (33.3 mg/m2, div) on day 1 and MPH (4 mg/m2, po), CPM (66.7 mg/m2, po) and PSL (30 mg/m2, po) from day 1 to 4, were administered. Each cycle was repeated every 3 weeks. PATIENTS OR MATERIALS: From January 1991 until August 1995, 104 patients with multiple myeloma diagnosed at 10 hospitals of Nagoya Cooperative Study Group were enrolled. RESULTS: Of the 87 evaluable patients, partial response rate for MMCP was 65.5% and was significantly higher than that of VMCP (13/47=27.7%, p<0.0001) and that of MMPP (21/47=44.7%, p=0.0196). A plateau attainment was observed in 49.4%. The percentage of the patients who attained plateau was significantly increased in the MMCP arm than in the VMCP arm (19.1 %, p=0.0017) but was not in comparison with that of MMPP arm (42.6%, p=0.6790). Patients treated with MMCP survived significantly longer than those treated with VMCP or MMPP (p=0.0009 by generalized Wilcoxon test, p=0.0023 by log-rank test) with median survival for MMCP being 31.6 months, for VMCP 22.5 months, and for MMPP 22.9 months. No significant differences were observed with respect to adverse effects among the three regimens. CONCLUSION: The newly designed MMCP is a candidate as an induction chemotherapy for multiple myeloma.

[DAD, new intensive chemotherapy for patients with myeloma: a preliminary report].

A new intensive chemotherapy regimen, DAD, composed of doxorubicin, melphalan and dexamethasone, was given to 17 patients with multiple myeloma. The end point of this regimen was to obtain a deep posttreatment nadir in the M-protein levels so as to increase the chance of plateau attainment which would be associated with prolonged survival in each patient. It was noteworthy that all the 17 evaluable patients achieved a partial response. Nine of the 17 (52.9%) attained a plateau. Ten of the 17 patients (58.8%) obtained a deep posttreatment nadir in their M-protein levels (IgG < 2,000 mg/dl, IgA < 1,000 mg/dl, BJP = 0 g/dl/day), and six of them reached a plateau phase, which was not significantly more frequent than those who did not obtain a deep posttreatment nadir in their M-protein levels (three of seven reached plateau phase). The median survival of the 17 patients (37.6 months) was significantly prolonged compared with that of patients treated with our previous chemotherapy regimens, VMCP (22.5 months) and MMPP (23.5 months), and was comparable to that of MMCP (29.5 months).