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.     

Prognostic significance of stratification systems in multiple myeloma. I. Risk categories (good and poor risk)

A group of 193 patients with multiple myeloma (MM) consisting of cases treated only symptomatically or by nonsystematic therapy with Cyclophosphamide or Melphalan (1959-76), and of patients given systematic polychemotherapy with intensive supportive treatment (1976-84) were subjected to prognostic analysis of the importance of MM stratification into two categories, poor and good risk. The evaluation included only hitherto untreated patients with MM of the IgG, IgA, and Bence-Jones' types. All the three evaluated stratification systems (ALGB, NCI-SECSG and CALGB) were found in the present study to show a good, equally significant relation to the prognosis of the disease. The survival median of poor risk patients in terms of the used classification system for the 1959-76 subgroup was 5-6 months, for the 1976-84 subgroup 20-22 months. In the good risk category it was 24-27 months in the 1959-76 subgroup and 47-50 months in the 1976-84 subgroup. Permanent validity of the initial prognosis and in the poor risk category safe coverage of patients with a high risk of early death was proved. Good agreement of the studied stratification systems with the clinical staging system of Durie and Salmon [14] (most of the Stage III patients consisted of poor risk patients) was recorded, which, however, was not the case with the staging system of Merlini, Waldenstr?m and Jayakar [27]. The CALGB system is considered the most suited to the needs of clinical practice.     

Prognostic significance of stratification systems in multiple myeloma. II. Clinical staging systems

A group of 193 multiple myeloma (MM) patients consisting of cases treated only symptomatically (1959-63) or by nonsystematic monotherapy with Cyclophosphamide or Melphalan (1963-76) and of a subgroup given systematic polychemotherapy and intensive supportive treatment (1976-84) were evaluated for the practical applicability and prognostic relevance of three staging systems. The clinical staging system of Durie and Salmon and the quantitative system of Salmon and Wampler have proved in both subgroups of various periods and with different therapeutic approaches to be well applicable in the clinic allowing the patients to be divided into three prognostically different groups according to the size of the tumor mass. Merlini, Waldenstr?m and Jayakar's staging system has likewise shown relationship to prognosis though the patients could be divided only into two prognostically different groups. It is evident that a deeper knowledge of MM requires nowadays a more comprehensive, complex and prognostically more relevant classification system.     

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.     

Rate of M-component changes and plasma cell labeling index in 25 patients with multiple myeloma treated with peptichemio

Twenty-five consecutive patients with previously untreated multiple myeloma were studied for bone marrow plasma cell labeling index, response to peptichemio induction therapy, and rate of M-component (MC) changes during the course of the disease. They received intermittent melphalan or cyclophosphamide as maintenance therapy and peptichemio associated with vincristine at first relapse. The response rate (76%) was independent of clinical stage, evaluated according to Merlini et al and to Durie and Salmon. Among responsive patients, rapid responders (half-life of MC decrease less than 47 days for IgA and IgG and less than 29 days for light chain myelomas) had a bone marrow plasma cell labeling index significantly higher (P less than 0.01) than that of slow responders. Rapid responders had a median survival of 15 months, while slow responders had a median survival of 42 months (P less than 0.05). The difference in survival between the two groups was accounted for mainly by the difference in duration of first response and the different rates of MC increase following it. Both of these parameters were directly related to the half-life of MC decrease at response in IgA and IgG myelomas. The duration of second response and the half-life of MC increase following it were shorter than the duration of first response and than the half-life of MC increase at first relapse.     

Aspartylglycosaminuria: An inborn error of glycoprotein catabolism

Aspartylglycosaminuria (AGU, McKusick 20840) is a metabolic disorder affecting the catabolism of glycoproteins. It was first described in 1967, by Jenner and Pollitt, in two mentally retarded English siblings. Subsequently several cases were reported from Finland (Palo and Mattsson, 1970; Autio, 1972; Autio et al., 1973). Today the number of known cases is about 140, most of them Finnish or of Finnish origin (Aula et al., 1980). The incidence of AGU in Finland has been estimated to be approximately 1:26000 and the disease is inherited as an autosomal recessive trait (Autio et al., 1973). Clinical manifestations include progressive mental retardation, coarse gargoyle-like facial features, skeletal abnormalities and recurrent infections. Early development of the patients is usually normal, but by the age of 5-15 years they are already severely retarded (Autio, 1972; Autio et al., 1973). Morphologically AGU is a generalized storage disease (Haltia et al., 1975). Affected tissues show enlarged lysosomes. Vacuolization is a prominent feature of liver and nerve cells (Haltia et al., 1975) and of peripheral lymphocytes (Aula et al., 1975).     

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.     

Prognostic factors in low tumour mass asymptomatic multiple myeloma: A report on 91 patients

Between January 1985 and July 1989 we diagnosed asymptomatic stage I multiple myeloma according to Durie and Salmon [Durie and Salmon: Cancer 36:842, 1975] in 91 patients. All patients were followed without chemotherapy. Disease progression occurred in 41 patients and the median time to progression for all patients was 48 months. In the Cox multivariate regression analysis, hemoglobin levels < 12 g/dl (P < .01), bone marrow plasmacytosis >25% (P < .01), and M-component size ≥30 g/l for lg G or 3 = 25 g/l for lg A (P < .01) were the only significant prognostic factors for progression. The 38 patients without any harmful factor remained free of progression for a median of more than 50 months. The 18 patients with two or three of these characteristics (high-risk group) had the shortest median time to progression of 6 months. Despite different times to progression, the response rate and survival after chemotherapy were similar for all groups of patients. Patients in the high-risk group for progression have to be frequently monitored for disease progression and might benefit from early treatment.     

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).     

A comparative study of pathological staging systems in predicting recurrent hepatocellular carcinoma after liver transplantation

Background/purpose

The applicability of the staging systems of hepatocellular carcinoma (HCC) to liver transplantation (LT) has not been fully evaluated. Therefore, we compared the HCC recurrence after LT as predicted by various staging systems, including the American Joint Committee on Cancer (AJCC) system 5th edition, the AJCC system 6th edition, the American Liver Tumor Study Group (ALTSG) system, and the Liver Cancer Study Group of Japan (LCSGJ) system.

Methods

A total of 108 patients who had HCC were classified according to these systems. We compared cumulative recurrence curves, recurrence-free survival curves, and overall survival curves of the systems estimated by Kaplan–Meier method. We compared cumulative event rates among different stages with the log-rank test for each staging system.

Results

The log-rank test showed that the cumulative recurrence rates were different among different stages with a statistical significance for the staging systems except for the AJCC 5th edition system. Cumulative recurrence curves by the AJCC 6th edition system and the LCSGJ system showed better visual separation than the other two systems. With respect to recurrence-free survival and overall survival, no staging systems showed significant discriminative power.

Conclusions

The current AJCC tumor-node-metastasis staging and the LCSGJ system are superior in predicting HCC recurrence after LT.     

C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system.

Multiple myeloma (MM) staging procedures are still inadequate for detection of the optimal therapeutic procedure for an individual patient. The Durie & Salmon staging system and serum beta 2-microglobulin (beta 2M) are used worldwide because of their easy clinical application. Other prognostic parameters, such as myeloma cell proliferative activity, are of exceeding importance, but are not as simple as standard methods. Recently, interleukin-6 (IL-6) has been shown to be a major growth factor for MM. IL-6 is a pleiotropic cytokine acting on several cell lineages, and, at the hepatocyte level, stimulates the synthesis of acute phase proteins, such as the well known C-Reactive Protein (CRP). Serum CRP concentration actually reflects the IL-6 activity. A survival analysis carried out in 162 MM patients at diagnosis showed that serum CRP level is a highly significant prognostic factor. Moreover, serum CRP was independent of serum beta 2M. This feature allowed stratification of MM patients into 3 groups according to CRP and beta 2M serum levels: (1) low risk group, CRP and beta 2M less than 6 mg/L (50% of patients); (2) intermediate risk group, CRP or beta 2M greater than or equal to 6 mg/L (35% of patients); (3) high risk group, CRP and beta 2M greater than or equal to 6 mg/L (15% of patients). Survival was 54, 27, and 6 months, respectively (P less than .0001). We thus propose a new and powerful myeloma staging system based on simple and reliable laboratory evaluations.     

Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia

PURPOSE: Several prognostic models or staging systems have been published that identify different risk groups in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). The aims of this study were (1) to test, in an independent population, the prognostic reproducibility of these staging systems; and (2) to develop a synthesis staging system that could be easily applied in clinical practice. PATIENTS AND METHODS: A total of 406 patients with newly diagnosed Ph-positive CML were evaluated by the four published staging systems of Tura, Cervantes, Sokal, and our group. The proposed synthesis staging system was developed based on the most consistent prognostic characteristics, and the presence or absence of accelerated disease features at diagnosis. The staging systems were compared according to survival outcome, as well as by looking for differences of survival outcomes within a specific stage of a defined system, when patients in this stage were subclassified by a second staging system. RESULTS: Whereas the staging system of Cervantes et al identified only two prognostic groups (median survivals of 49 versus 40 months; p = 0.01), the remaining three staging systems were able to segregate patients into stage 1, 2, and 3 risk groups with respective median survivals of 56 to 57, 41 to 42, and 28 to 36 months, respectively (p less than 0.001 to p less than 0.002). The new proposed staging system, based on the existence of zero to one (stage 1), two (stage 2), or three or more unfavorable (stage 3) characteristics, or the presence of accelerated disease features (stage 4), categorized patients into four prognostic groups with median survivals of 56, 45, 30, and 30 months, respectively (p less than 0.001), the latter stage (stage 4) being associated with a higher one-year mortality rate (29%). The synthesis staging system was also able to subclassify patients within most of Tura's and Sokal's stages into significantly different prognostic groups by survival outcome. CONCLUSION: The predictive prognostic capacity of three of the four published staging systems was confirmed in this independent or test population. The new proposed staging system was superior to the staging systems of Tura and Sokal in identifying different prognostic subgroups.     

The clinical and prognostic significance of erythrocyte sedimentation rate (ESR), serum interleukin-6 (IL-6) and acute phase protein levels in multiple myeloma

Interleukin-6 (IL-6) and acute phase proteins are commonly increased in patients with multiple myeloma. Several of these acute phase proteins are believed to predict prognosis and influence survival. We measured interleukin-6 (IL-6), C-reactive protein (CRP), alpha-1-antitrypsin (a1AT), acid alpha-1-glycoprotein (a1AG), haptoglobin (HAP), transferrin (TRF), hemoglobin (Hb), beta-2-microglobulin (beta2M) and erythrocyte sedimentation rate (ESR) in 42 newly diagnosed multiple myeloma patients and 25 normal controls. At the time of blood collection, nine patients were at stage I of disease, 14 at stage II, and 19 at stage III according to the Durie and Salmon myeloma staging system. Mean +/- SD values of IL-6, CRP, a1AT, a1AG, HAP, beta2M, and ESR were significantly higher and Hb significantly lower than those found in the controls. Univariate analysis, using the log-rank test, showed that among the acute phase proteins, serum CRP (P < 0.002), a1AT (P < 0.008) and ESR (P < 0.008) were significantly correlated with survival. However, when a multivariate Cox proportional hazard model was performed, ESR, CRP, a1AT, a1AG and beta2M were identified as independent prognostic factors, while the others were not. We conclude that ESR, a simple and easily performed marker, was found to be an independent prognostic factor for survival in patients with multiple myeloma.     

Improved survival times in multiple myeloma treated with melphalan, prednisone, cyclophosphamide, vincristine and BCNU: M-2 protocol

Seventy-three patients in whom multiple myeloma could be evaluated were treated with a combination drug protocol (M-2), consisting of melphalan, prednisone, cyclophosphamide, vincristine and BCNU (1,3-bis(2-chloroethyl 1)-1-nitrosourea). All patients were classified according to the clinical staging system of Salmon and Durie; 75 per cent of them were in stage III. Total tumor cell number was calculated according to the method of Salmon. A significant objective remission was obtained in 40 of 46 (87 per cent) previously untreated patients. The median duration of response for this group is presently 20+ months. Twenty-seven of these 40 responders are still in remission. Thirteen of 26 (50 per cent) previously treated patients responded. With eight of these still in remission, the median duration of response for the group is 22+ months. The median times between the first dose and an established response were two and three months for the previously untreated and treated groups, respectively. The duration of remission in the more rapid responders does not appear to be shorter. The response rate does not appear to correlate with the type of immunoglobulin or light chain secreted. One patient, without immunoglobulin secretion, has been in remission for 45+ months, and three with primary amyloid have failed to respond. At this point, it appears that survival time in patients treated with M-2 will be significantly longer than in the earlier group treated at this center with melphalan and prednisone alone.     

Staging multiple myeloma patients with active disease using serum levels of beta2m-free HLA class I heavy chain together with IgM or platelet count

Purpose: In multiple myeloma (MM), serum beta-2-microglobulin (β2m)-free heavy chains (FHC) of HLA class I has been shown to reflect disease activity. We investigated the possibility of stratifying patients with active disease according to FHC and other clinical parameters.Experimental design: We studied 146 patients with MM, including 100 at diagnosis, 31 in relapse and 15 unresponsive to therapy. Univariate and multivariate analyses were used to assess the prognostic significance of FHC together with continuous variables (age, albumin, creatinine, hemoglobin, erythrocyte sedimentation rate, β2m, calcium, IgM, platelet count) and categorical variables (Durie–Salmon disease stage, gender, bone lesion burden, heavy and light chain isotypes of M-component, clinical status). Survival tree analysis on significant variables was used to develop an MM staging system.Results: FHC, IgM, platelet count and hemoglobin were independent predictors of prognosis. Survival tree analysis of these variables defined 2 three-risk-group staging systems involving FHC and either IgM or platelet count. Median survival for FHC/IgM stages II and III was 41.5 and 27.8 months, whereas it was not reached for stage I patients (p < 0.0001). In the FHC/platelets system, median survival was 93.2 (stage I), 44.1 (stage II) or 27.8 (stage III) months (p < 0.0001). Similar results were obtained for the 117 MM patients without renal insufficiency (FHC/IgM p < 0.0001; FHC/platelets p = 0.001). For the 100 patients at diagnosis, FHC/IgM (p = 0.001) was more effective than FHC/platelets (p = 0.04).Conclusions: The independent prognostic markers FHC, IgM and platelets provide two staging systems unaffected by renal insufficiency. Both are effective in evaluating MM patients with active disease.     

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.     

Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group

The National Cancer Institute (NCI)-sponsored Chronic Lymphocytic Leukemia (CLL) Working Group was convened to develop a set of standardized eligibility, response, and toxicity criteria for clinical trials. We recognized the previous efforts in 1967 (published again in 1973 as the report of the Chronic Leukemia-Myeloma Task Force [1] and 1978 of Cancer and Leukemia Group B (CALGB) [2]). We have used these reports for guidance during the current effort. Several noteworthy developments in the past few years have made it necessary to modify the previous guidelines. First, the diagnostic criteria for CLL and its clinical staging have been developed and well defined. Second, although staging systems facilitated entry of comparable and relatively homogeneous groups of patients in clinical trials, the definitions of response (CR) and partial response (PR) were not uniformly adopted from the previous guidelines in the clinical trials (Tables IA, IB); therefore, comparisons of results obtained in different studies became difficult. Third, there has been an improvement in our understanding of the immunology and biology of CLL. Finally, we are witnessing the emergence of several chemotherapy agents that promise impressive activity in CLL (e.g., 2'-deoxycoformycin [3], fludarabine monophosphate [4, 5]), and thereby offer the potential for improving survival time in this disease. To best identify regimens worthy of continued pursuit in large comparative trials, standardized guidelines for evaluation are essential. A number of laboratory investigations are also presented for which scientific interest is high yet relevance remains to be determined; thus, they are presented as companion studies to the clinical trials. This mechanism allows for flexibility in the testing of these questions and for additional ideas in the future without requiring modification of an entire treatment protocol. The following guidelines were developed to be used as a form of standardization for clinical trials, incorporating current technologies, yet remaining relevant to the general hematology/oncology community. Based on the membership of the Working Group, it is expected that these guidelines will serve as the criteria for most clinical trials in the near future.     

Modified Japan Integrated Staging is currently the best available staging system for hepatocellular carcinoma patients who have undergone hepatectomy

Background We previously reported the effectiveness of the modified Cancer of the Liver Italian Program (CLIP) score in hepatocellular carcinoma (HCC) staging. To determine the best predictive staging system for HCC patients, we conducted a comparative analysis of prognosis using multivariate analysis in 230 Japanese HCC patients following hepatic resection. Methods We compared overall survival as predicted by different staging systems: the tumor node metastasis (TNM) system by the Liver Cancer Study Group of Japan, the Japan Integrated Staging (JIS) score (Japanese TNM and Child-Pugh classification), the modified JIS score using liver damage grade, the CLIP score, and our modified CLIP score using protein induced by vitamin K absence or the antagonist II (PIVKA-II). Results By a univariate analysis the PIVKA-II level (cut-off level, 400 mAU/ml) was significantly associated with patient survival (P = 0.031); however, alpha-fetoprotein level was not related to survival. Liver damage grade was significantly associated with patient survival (P = 0.039), although Child-Pugh classification was not related to survival. Univariate analysis showed that prediction of survival, according to disease stage, was better with the modified JIS score than with the TNM system, CLIP, modified CLIP, or JIS score. Multivariate analysis showed the modified JIS score showed the best ability to predict overall survival according to disease stage (Hazard ratio, 1.77; P = 0.002), and its Akaike information criteria statistic was the lowest (634.3). Conclusions The modified JIS score, a staging system that combines tumor factors and hepatic function, is a better predictor of prognosis than other systems in HCC patients who have undergone hepatic resection.     

Prognostic factors in chronic lymphocytic leukemia

The Rai staging system is widely used and is easy to apply in clinical practice. The system introduced by Binet et al offers an advantage that it consists only of three stages and, therefore, is more practical for initiation of controlled therapeutic trials than the five-stage Rai system. However, when we take into consideration the survival curves, it is important to note that the Rai system has three groups (and not five), low risk (stage O), intermediate risk (stages I and II), and high risk (stages III and IV). These groups are roughly equivalent to Binet's A, B, and C stages, respectively. Although the IWCLL has recommended a unified, integrated method of combining Binet and Rai systems, in practice, however, such a combination is cumbersome and unusable. Both systems, however, suffer from an important limitation--they cannot predict for the large majority of patients in the low and intermediate risk groups (Binet's stages A and B and Rai's O, I, and II) who will have an indolent course and good prognosis in contrast to those in the same stages whose disease will progress rapidly. It is necessary, therefore, to combine the bone marrow histology findings, the lymphocyte doubling time and the threshold values of blood lymphocyte count with the clinical staging systems to distinguish between indolent disease course and aggressive disease on a prospective basis within a given clinical stage.