Prognostic factors in IgD myeloma: a study of 21 cases

A series of 21 patients with IgD myeloma was studied retrospectively, to assess which parameter present at the time of diagnosis was of prognostic importance for survival and whether the clinical staging system of Durie and Salmon had predictive value for the survival time of these patients. Survival time did not appear to be correlated with haemoglobin concentration, thrombocytopenia, initial level of M-protein, amount of Bence-Jones proteinuria, hypercalcaemia, serum creatinine level, presence of osteolytic lesions or hepatosplenomegaly. Neither did the staging system of Durie and Salmon predict the survival time. It is concluded that clinical staging is of limited value in the management and prediction of the survival time of IgD myeloma patients.     

Long-term survival in multiple myeloma: a Finnish Leukaemia Group study

The long-term survival of 324 multiple myeloma patients treated with conventional chemotherapy (CT) was analysed after at least 10 years follow-up. The unselected group of myeloma patients 70 years, as representative of the population, was derived from three prospective multicentre trials by the Finnish Leukaemia Group.
The median overall survival time (OS) was 49 months. At 10 years, 13% of the patients were alive. The significant single pre-treatment prognostic factors for long-term survival were age, Hb, platelet count, serum-creatinine and proportion of plasma cells in the bone marrow. Staging according to Hb level and plasma cell degree was more useful than that of the Durie and Salmon system in predicting long-term survival. The first-line chemotherapy combination and the level of response were unimportant in this respect. A long plateau phase after first response and response to salvage chemotherapy were important prognostic factors. Not only the salvage regimen but also the whole supportive treatment and adequate control of complications throughout the course of the disease are important.     

Prognostic factors in multiple myeloma in a population-based trial

Prognostic factors have been tested in patients with multiple myeloma treated according to a randomized trial of standard therapy versus 5-drug combination therapy. The following population-based study included 92 patients with a median age of 70 yr. The median survival was 31 months. The Cox regression model was used to search for predictors of survival. The cut-off levels for blood analyses derived in earlier studies tended to select few patients in the high-risk groups, for example only 8% of the patients had hemoglobin (Hb) less than or equal to 7.5 g/dl. Lytic bone lesions in the pelvis or in the long bones, or spontaneous fractures and age greater than 70 yr gave prognostic information in addition to anemia and impaired renal function. The MRC staging system was a better prognostic tool than the Durie & Salmon stages. Palliative treatment regimens which take quality of life into account should be considered carefully in multiple myeloma patients greater than 70 yr.     

Prognostic factors and monitoring of myeloma]

An improved knowledge of the initial prognostic factors of multiple myeloma and regular monitoring of the disease should result in the choice of the most effective treatment. The conventional prognostic factors have been divided into three stages by Durie and Salmon. These stages are based on the proportion and type of the monoclonal component, on haemoglobin, calcium and creatinine blood levels and on the extent of bone lesions. However, this widely used classification has certain disadvantages: the size of the tumoral mass is evaluated mainly from the proportion of monoclonal gammopathy, the bone lesions are difficult to determine and the kinetics of cell proliferation are not taken into account. Parameters with high prognostic value have recently been demonstrated; they include beta 2-microglobulin, LDH, interleukin-6, C-reactive protein, serum albumin and kinetic of cell proliferation. When associated, these data allow to establish prognostic staying that are at least as relevant as those of the Durie-Salmon's classification. Monitoring of patients with multiple myeloma by means of a time-related curve of either the tumoral mass or the amount of monoclonal gammopathy leads to the best possible treatment.     

Prognostic significance of apoptotic index in multiple myeloma patients treated by conventional therapy and novel agents,thalidomide and bortezomib

Objective: To assess the outcome of the measurement of apoptotic index in myeloma patients treated by conventional chemotherapy and novel drugs with biological mechanism of action, thalidomide and bortezomib. Patients and methods: In a cohort of 189 patients with newly diagnosed multiple myeloma from November 1997 through February 2008, we assessed the prognostic significance of plasma cell apoptotic index (PC‐AI) using annexin‐V. The whole group was subsequently divided according to treatment approach (conventional chemotherapy only vs. inclusion of novel drugs, thalidomide and bortezomib), and curves of overall survival were constructed. Results: In the whole group (n = 189), low levels of PC‐AI <4.5% significantly separated patients with unfavorable prognosis (median OS 16 vs. 38 months, P = 0.004). In patients treated with conventional chemotherapy only (n = 139) the results were similar (median OS 10 vs. 25 months, P = 0.02), and the apoptotic index maintained its significance even within the group of 50 patients treated also with novel drugs (median OS 30 vs. 54 months, P = 0.027). PC‐AI was found to be independent on both Durie‐Salmon staging system and the International Prognostic Index. Conclusion: Presented results suggest the use of apoptotic index by flow cytometry measurement as a fast and accessible method for prognostic stratification of myeloma patients in routine practice.     

Significance of nucleo-cytoplasmic maturation asynchrony in multiple myeloma

Bone marrow samples of 97 patients with multiple myeloma were examined ultrastructurally over a period of eight years, and the degree of nucleo-cytoplasmic maturation asynchrony (NCA) of myeloma plasmocytes was estimated according to the classification scale of Graham and Bernier. One half of the patients showed first degree, 40 percent second and 10 percent third degree of NCA. Clinical classification of the disease according to the staging system of Durie and Salmon and the quantitative staging system of Salmon and Wampler showed some relation to the degree of NCA. The degree of NCA was found to be related to the density of the bone marrow infiltration with myeloma plasmocytes but not to the response to chemotherapy. Some relation was seen to exist between the degree of NCA in myeloma plasmocytes at diagnosis and the prognosis of the disease. The role of electron microscopical analysis in MM diagnostics and its contribution to management of the disease are discussed.     

Staging systems for multiple myeloma: a comparison

In 152 patients with multiple myeloma who had been treated with cytostatic agents the prognostic value of seven staging systems was evaluated: Carbone et al (1967); Acute Leukemia Group B (ALGB) and Eastern Cooperative Oncology Group (ECOG) (Costa et al, 1973); Southeastern Cancer Study Group (SECSG) (1975); Durie & Salmon (1975); Alexanian et al (1975); Merlini et al (1980); British Medical Research Council (1980). The staging systems of the ALGB (Costa et al, 1973) and SECSG (1975), both dividing patients into 'good risk' and 'poor risk' groups, showed significantly different survival curves. Nevertheless, despite statistical significance the observed differences were rather small. In the systems of Carbone et al (1967), Merlini et al (1980), Alexanian et al (1975) and Durie & Salmon (1975) some of the differences in the survival curves were statistically significant while others were not. Our data best fitted into the British Medical Research Council (1980) staging system, the survival curves of all three stages showing significant differences, with median survival time dropping from 83 months in stage A to 52 months in stage B and 26 months in stage C. Nevertheless, none of those systems was clearly superior to single risk factors, especially creatinine and haemoglobin.     

Subgroup and cost-benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma

Osteolytic lesions and pathological fractures are the major problems in the clinical management of multiple myeloma. We previously reported the main results of a randomized, controlled multicentre trial in 350 Finnish patients with multiple myeloma. All patients received standard melphalan-prednisolone treatment and were randomized to receive either clodronate 2.4 g daily or a placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group as in the clodronate group (24.0%v 12.0%, P= 0.026). The purpose of the present study was to investigate factors associated with the progression of osteolytic lesions and to identify subgroups of patients who would benefit most from clodronate treatment. In univariate logistic regression analysis, including treatment (placebo, clodronate), sex, age, pain index, serum calcium and creatinine, myeloma stage, number of osteolytic lesions at baseline, and number of vertebral fractures at baseline as independent variables and the progression of osteolytic lesions as a dependent variable, only the treatment with a placebo was associated with the progression of osteolytic bone lesions. Separate analyses with respect to the progression of osteolytic bone lesions were carried out in the following subgroups: male v female, ± 64 v > 64 years, stage I v stage II-III myeloma, no osteolytic lesions at baseline versus osteolytic lesions at baseline, no vertebral fractures at baseline versus vertebral fractures at baseline, and a 50% treatment response to cytotoxic drugs versus no treatment response to cytotoxic drugs. The treatment with clodronate delayed the progression of osteolytic lesions similarly in these subgroups, with the exception of a subgroup of patients who did not have a 50% treatment response to cytotoxic drugs. The treatment with clodronate did not significantly increase treatment costs. We conclude that the treatment effect of clodronate seems to be independent of sex and age of the patients, the stage of myeloma, and the severity of bone lesions at diagnosis, but not of treatment response to cytotoxic drugs.     

Prognostic value of the staging system proposed by Merlini, Waldenstr?m and Jayakar for multiple myeloma

We have reviewed a series of 90 consecutive patients with multiple myeloma (MM) diagnosed in the period 1.1.1971-31.12.1980 and subsequently treated with an intermittent administration of melphalan and prednisone (62 IgG MM, 20 IgA MM and 8 Bence-Jones (BJ) MM). Unfavorable prognostic factors were: presence of micromolecular M component (K or lambda), serum creatinine greater than or equal to 2 mg/dl, serum calcium greater than or equal to 12 mg/dl, presence of BJ proteinuria, Hb less than 10 g/dl, diffuse osteolytic lesions, bone marrow plasma cell percentage greater than or equal to 30%. In particular, according to the recent staging system proposed by Merlini et al. [Blood 55: 1011, 1980], the most important prognostic parameters for IgG and BJ MM were: serum creatinine, BMPC % and serum calcium; for IgA MM the most important were: serum hemoglobin, calcium and M component levels. We have compared the survival curve of 45 patients who died, with the predicted survival curve according to the multivariate regression analysis of Merlini and co-workers; the prediction was equally precise for all the three types of MM considered, thus showing the high sensibility of this new staging system.     

Quantification of bone lytic lesions and prognosis in myelomatosis

Degree and extent of lytic bone lesions were quantified at diagnosis in 69 patients with myelomatosis (MM). longest survival was found in patients with minimal lytic lesions and shortest survival was found in those either without bone lesions or with severe and extensive lesions. Among the 12 patients without bone lesions only 6 were Durie & Salmon stage I and only 1 later developed a single lesion. Based on these data, bone involvement in MM does not seem to be a reliable predictive factor of survival in all cases. This suggests the existence of 2 distinct types of MM: 1 with tumour and 1 without. Lytic lesions could have a prognostic value only in the 1st type.     

A new prognostic system for multiple myeloma based on easily available parameters

The prognostic significance of different presenting features in 180 patients with multiple myeloma (MM) from a single institution was analysed. Out of eight variables isolated from the univariate analysis only two (blood urea and serum albumin), were significant in the multivariate model. Derived from these two simple variables, the relative risk of each patient was calculated, and subsequently two subpopulations of patients could be recognized. The first group included patients with a very active myeloma and a high risk of death soon after diagnosis, their median survival being of only 11.6 months, and the second one comprised patients with low risk of death during the first year and a median survival of 28 months. A hazard function derived from two-thirds of the patient population (training group) was successfully validated in the remaining subset of patients (test group). Finally, the three major available myeloma staging systems (Durie & Salmon's, Merlini et al's, and the one proposed by the British Medical Research Council) were tested in the present series, and only the latter one showed prognostic validity.     

International prognostic index (IPI)--a critical comparison with five multiple myeloma staging systems in the group of 270 patients treated by conventional chemotherapy

In the group of 270 patients with multiple myeloma (MM) treated during 1991-2004 by conventional chemotherapy, the prognostic value and practical utility of IPI (International Prognostic Index) was assessed and compared with five other actual staging systems. Prognostic significance was assessed using the curves of overall survival (OS) according to Kaplan-Meier and log rank test (p<0.05). Good practical utility and prognostic significance of Durie-Salmon (D-S) system was confirmed (p<0.001). Good overall prognostic significance was observed in simple staging systems based on the measurement of beta2-microglobulin and albumin serum levels according to Bataille (p<0.001), SWOG (South West Oncology Group, p<0.001) and IPI (p<0.001). Regardless of a short 5-year duration of the study, the scoring system according to San Miguel enclosing apart from other parameters also propidium iodide proliferation index (PC-PI) of myeloma plasmocytes seems to be promising with very different characteristics of curves of overall survival (p<0.001). Very good prognostic value and easy practical utility were examined in Olomouc staging system (OSS) based on the measurement of beta2-microglobulin and thymidinekinase serum levels (p<0.001). With regard to detection of patients of stage 1, i. e. "low risk", not requiring an immediate initiation of conventional chemotherapy ("wait and see" approach), the most suitable was the system according to D-S, SWOG and IPI (median OS 77, 76 and 77 months). To select a cohort of "high risk" patients, i.e. stage 3, with very unfavourable disease prognosis, the most advantageous was the system OSS and San Miguel (median OS was 5 and 6 months) and/or SWOG system selecting patients of stage 4, i.e. "worst prognosis", with median OS 8 months. It was found that IPI did not meet expectations for effective identification of "high risk" patients (median OS of stage 3 was 20 months) nor for the distinction of different prognosis of patients during initial 25 months of MM course at stage 2 vs. 3. The study indicates that under conditions of common clinical practice and conventional chemotherapy, the staging system according to D-S is still useful, while practical application of SWOG and IPI as simpler alternative to the assessment of clinical stage should be verified by further comparative studies. In harmony with the progress in cytogenetics and molecular biology as well as a prospective requirement of individual target therapy, a future suitable stratification system should be based on parameters of internal biological properties of myeloma tissue and microenvironment of bone marrow, allowing in addition a continuous evaluation of the disease course and the effect of therapy.     

Bone resorption parameters [carboxy-terminal telopeptide of type-I collagen (ICTP), amino-terminal collagen type-I telopeptide (NTx), and deoxypyridinoline (Dpd)] in MGUS and multiple myeloma

Skeletal morbidity is a major problem in multiple myeloma. Histomorphometric studies have demonstrated that increased bone resorption can be present even in the absence of radiographic abnormalities. To overcome diagnostic problems in estimating the activity of bone resorption, new laboratory parameters that reflect bone metabolism accurately are urgently needed. We analyzed three parameters of osteoclastic bone destruction, i.e. deoxypyridinoline (Dpd) and amino-terminal collagen type-I telopeptide (NTx) in urine and carboxy-terminal telopeptide of type-I collagen (ICTP) in serum, of 75 patients with multiple myeloma (n = 57) or monoclonal gammopathy of undetermined significance (MGUS, n = 18) by ELISA/RIA techniques. Serum ICTP and urinary Dpd levels increased parallel to the stage of the disease and differed significantly (P < 0.001 for ICTP and P = 0.03 for Dpd) between MGUS, myeloma stage I, and myeloma in stages II and III according to Salmon and Durie. ICTP and Dpd were significantly elevated in patients with multiple myeloma in stage I compared to individuals with MGUS, while no significant difference was found for NTx. In this first study comparing the prognostic relevance of ICTP, NTx, and Dpd in multiple myeloma patients, ICTP was found to be a prognostic factor for overall survival in the Kaplan-Meier analysis (log-rank test: P < 0.03). Urinary NTx showed borderline significance (P = 0.05), and Dpd had no prognostic value in the survival analysis. Our data show that serum ICTP and urinary Dpd levels increase in parallel to advanced disease stages, and gives the first report on a significant difference in the bone resorption parameters ICTP and Dpd between individuals with MGUS and patients with myeloma in stage I. Among the bone resorption parameters studied serum ICTP was found to be the best prognostic factor for survival in multiple myeloma.     

不同年龄组多发性骨髓瘤患者的骨损表现

目的：观察不同年龄组多发性骨髓瘤患者的骨损临床表现以及预后.方法：将本院70例多发性骨髓瘤患者按年龄分成＜65岁和≥65岁2组，观察骨损表现形式（溶骨性损害、广泛的骨质疏松）、发生部位（颅骨、颈椎、胸肋骨、腰骶椎、骨盆、四肢长骨）、高钙血症和骨损的关系以及相关预后、骨损和血β2-微球蛋白（β2-MG）的关系.结果：≥65岁组溶骨性损害发生率要高于＜65岁组.前者溶骨性损害常见部位是颅骨和胸肋骨;后者常见部位是腰椎和胸肋骨.并发高钙血症的老年患者预后可能较差.＜65岁组β2-MG异常患者中，非骨痛起病者预后好于骨痛起病者.结论：骨损表现及其相关预后指标在不同年龄组多发性骨髓瘤患者中意义不同。     

Prognostic relevance of a histologic classification system applied in bone marrow biopsies from patients with multiple myeloma: A histopathological evaluation of biopsies from 153 untreated patients*

Abstract: A total of 153 diagnostic bone marrow biopsies from patients with advanced stages of multiple myeloma corresponding to stages II and III according to the Durie/Salmon classification were evaluated prior to any treatment in a prospective therapy trial of the German Myeloma Treatment Group. Histologic sections were analyzed according to a pre-defined system of criteria microscopically by 2 observers, determining three criteria: 1) grading by histopathology, regarding the cytologic differentiation of neoplastic cells and quantifying the percentage of plasmacytic, pleomorphic, and plasmablastic myeloma cells distributed within the sections; 2) the volume of infiltration; and 3) the pattern of neoplastic growth. Furthermore, four other criteria, namely hematopoiesis, fiber increase, osteomalacia, and micro-osteo-lesions, were evaluated. A cluster analysis using the three histological criteria revealed three groups of patients with significantly different survival times based on histological criteria only; the three criteria were mentioned above. It is concluded from these results that bone marrow biopsies, when evaluated histologically by grading and staging according to the three criteria, provide most valuable prognostic parameters in myeloma patients.     

Evaluation of five staging systems in 470 patients with multiple myeloma

We evaluated the prognostic significance of five staging systems in 470 consecutive, previously untreated patients with multiple myeloma diagnosed between 1989 and 2006. The five staging systems were those proposed by Durie and Salmon, Bataille et al., the South West Oncology Group, Weber et al. and the International Staging System. This last proved to be superior to the others.     

Serum beta2-microglobulin: a real improvement in the management of multiple myeloma?

Beta 2-microglobulin (B2-m) determinations in serum have recently been introduced as a method of stratifying patients suffering from multiple myeloma. Conflicting results from several studies prompted us to study retrospectively the correlation of B2-m with presenting features and disease stage, as well as the prognostic value of B2-m, in 87 myeloma patients. Significant correlations were found between B2-m and presenting features such as haemoglobin level, serum calcium level and total body myeloma cell mass. The strongest correlation existed between B2-m and serum creatinine (r = 0.68). B2-m did not discriminate between the different disease stages as defined by Durie and Salmon, nor between myeloma Stage IA and monoclonal gammopathy of undetermined significance (MGUS). Considered alone, B2-m was found to have prognostic value in terms of survival. This correlation disappeared after correction for serum creatinine level and tumour load (multivariate analysis). Furthermore, changes in tumour load during therapy were not reflected in changes in B2-m levels, thereby rendering B2-m levels invalid as tumour marker. Our findings indicate no value for B2-m determinations in the staging and follow-up of myeloma patients.     

Prognostic variables and clinical staging in multiple myeloma

To evaluate the most important factors in the prognosis and staging of multiple myeloma (MM), the presenting clinical features of 163 previously untreated patients with MM were correlated with survival duration using univariate and multivariate regression analyses. The univariate proportional hazard analysis ranked the parameters in the following order of importance: platelet count, hemoglobin level (Hb), tumor cell mass stage, lytic bone lesions, creatinine, and age. When the individual contribution of each variable was assessed by multivariate regression analysis, platelet count was confirmed to be the dominant feature for prognosis and clinical stage provided additional information. The introduction of platelet count could then be used to improve the reliability of the Durie and Salmon staging, by allowing to separate the high-risk group (stages II and III) into a smaller subgroup (22%) of thrombocytopenic patients (less than 150 x 10(9) platelets/L) whose risk of death was actually very high (median survival, 9 months) and a larger subgroup (46%) of patients with normal platelet count and intermediate or standard risk (median survival, 48 months). This simple change in the prognostic system gave rise to markedly different survival curves also after the exclusion of patients with renal failure and applied successfully to both old and young patients (greater than and less than 50 years, respectively). Finally, platelet count, Hb, and lytic bone lesions could be combined simply to stratify patients with normal renal function into three risk groups: (1) low (39% of cases; median survival, 79 months), (2) intermediate (53% of cases; median survival, 48 months), and (3) high (8% of cases; median survival, 19 months).     

Bone marrow histology in myeloma: its importance in diagnosis, prognosis, classification and staging

A study has been made of 420 bone marrow biopsies from patients with multiple myeloma (220), idiopathic monoclonal gammapathy (50), reactive plasmacytosis (42) and solitary plasmacytoma (22). Histology and immunohistological parameters were more reliable than cytology in distinguishing a reactive from a neoplastic plasmacytosis. Histological variables were correlated with the clinical features of the patients to determine the factors which were of value in predicting prognosis. Plasma cell maturity and the extent of infiltration in the biopsy by myeloma cells proved to be highly significant in predicting the duration of survival. On the basis of these criteria multiple myeloma was classified into two types: plasmacytic of low-grade malignancy and plasmablastic of high-grade malignancy; and into three stages which accurately reflected the progression of the disease. We conclude that a bone biopsy provides useful information for the diagnosis, classification and staging of patients with multiple myeloma.     

Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Nordic Myeloma Study Group (NMSG)

The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty-nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high-dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970-83, 101 during the period 1984-89 and 141 during the period 1990-92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan-prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high-dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.