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.     

Clinical Staging in Multiple Myeloma

Analysis of 237 patients with myeloma, retrospectively classified according to the staging system proposed by Durie and Salmon, showed highly significant differences (P less than 0.0001) in the survival of patients with low, intermediate and high tumour cell masses (Stages I, II and III respectively). The median survival for Stage I patients was 64 months, Stage II 32 months, and Stage III 6 months. The median survival of patients presenting with renal impairment was only 2 months, compared to 21 months for those presenting with normal renal function (P less than 0.0001). The use of this clinical staging system, which is based on myeloma protein synthesis rates and the calculation of total body tumour cell mass, should be considered in planning future trials of therapy in this disease.     

Critical Study of Staging in Multiple Myeloma

130 patients with multiple myeloma were revieved for a retrospective study of their classification according to Durie & Salmon. No significant difference was found in survival between patients in stages I, II and III (median survival 24.8, 32.1, and 17.3 months, respectively). Of the classical criteria affecting survival, only the Hb level showed any significant influence (P < 0.04). In accordance with this finding, the survival time was much shorter (P < 0.001) in patients with renal failure than in patients without (median survival 7.4 and 24.8 months, respectively); in addition, thrombopenia, fever, old age, and above all, the % of bone-marrow plasmocytes present, were shown to be decisive factors.     

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.     

Long-term survival and prognostic factors in stage II-III multiple myeloma treated with conventional chemotherapy]

In this retrospective study, survival and prognostic factors were analysed in 65 patients with stage II-III multiple myeloma with osteolytic lesions. Multiple myeloma was diagnosed from 1976 to 1984, and patients were treated with conventional chemotherapy. The response rate to initial chemotherapy was 46%. The median survival time was 31 months. The 10-year survival rate was 10%. Four variables were individually prognostic: response to initial chemotherapy, bone marrow plasma cell percentage, the Durie and Salmon staging system, a biological staging system derived from Durie and Salmon's biological criteria regardless of bone lesions. In the multivariate analysis, only two prognostic variables were retained, namely the response to chemotherapy and the biological staging system. No prognostic value was observed for the extent of osteolytic lesions. This study suggests that, in conventionally treated multiple myeloma, long-term survival has improved compared with the previous decade. It also indicates that the extent of osteolytic lesions has little value for the definition of high-risk myeloma.     

Bone marrow angiogenesis and its correlation with other disease characteristics in multiple myeloma in stage I versus stage II-III

PURPOSE: We studied bone marrow angiogenesis in different stages of multiple myeloma according to the Durie and Salmon classification and its correlations with other disease characteristics. METHODS: Sixty-five immunohistochemical CD34-stained, paraffin-embedded bone marrow biopsies of multiple myeloma patients and 12 controls were studied. The mean number of microvessels per area in each sample was determined as the microvessel density (MVD). In addition, plasma cell infiltration of the bone marrow, serum beta2-microglobulin, immunoglobulin levels, C-reactive protein, and serum calcium concentration were measured in 22 patients with stage I multiple myeloma and in 43 patients in stage II-III. RESULTS: In myeloma patients, the bone marrow MVD was significantly higher than in controls (P<0.001). In 43 patients with stage II-III multiple myeloma, MVD was significantly higher than in 22 patients with stage I (median MVD 46 and 21 vessels/mm(2), respectively, P=0.005). Additionally, in stage II-III the bone marrow MVD correlated positively with the bone marrow plasma cell infiltration (r=0.55, P<0.001) and the serum beta2-microglobulin level (r=0.53, P<0.001), while in stage I patients no correlation could be found. CONCLUSIONS: Angiogenesis is significantly increased in stage II-III myeloma in comparison to stage I. In stages II-III, bone marrow angiogenesis is correlated with plasma cell infiltration and serum beta2-microglobulin levels.     

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.     

Staging and survival in multiple myeloma

The records of 91 patients with multiple myeloma were reviewed and staging was performed according to Durie & Salmon (1). Patients with progressive disease were re-staged. Patients first diagnosed in stage I were younger than patients first diagnosed in stage III and survived longer than patients in stages II or III. The duration of stage I was longer than the duration of stages II and III. When patients in stage I-II progressed into stage III, their age and remaining survival time were similar to the age and survival of patients first diagnosed in stage III. These findings are compatible with the hypothesis that myeloma stage I prededes myeloma stage III and is often diagnosed by chance. It is suggested that patients with myeloma stage I should be omitted from comparisons between different myeloma populations.     

Is the Durie and Salmon diagnostic classification system for plasma cell dyscrasias still the best choice?

Summary There are a number of systems for diagnosing multiple myeloma, myeloma variants and monoclonal gammopathy of undetermined significance. We compared three systems, those according to Durie and Salmon, to Kyle and Greipp, and to the British Columbia Cancer Agency, using material from a populationbased registry of 847 patients with a paraproteinemia or multiple myeloma. Of these, 157 underwent both bone marrow and X-ray examinations and were subsequently included in our analysis. The differences between the systems were small, even though in only 64% of the cases the diagnosis according to all three systems was identical. The system used by the British Columbia Cancer Agency turned out to be the shortest and easiest system reviewed here. We propose a more frequent application of this system instead of the more commonly used Durie and Salmon and Kyle and Greipp criteria.     

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.     

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.     

Comparison of whole-body MR imaging and conventional X-ray examination in patients with multiple myeloma and implications for therapy

Skeletal X-ray survey is the established method of diagnosis in patients with multiple myeloma; however, whole-body magnetic resonance imaging (wb-MRI) has become an important additional tool. The aim of this study was to compare the different patterns of infiltration on conventional X-ray examinations (X-ray survey) with findings from wb-MRI to subsequently determine the influence of wb-MRI on therapy changes. In 60 patients with a mean age of 65.1 ± 11.7 years, wb-MRI examinations were correlated with a recent X-ray survey. The results were independently assessed by two radiologists and the patterns of infiltration were described in both modalities. Subsequently, the disease was staged according to Salmon and Durie and Salmon and Durie PLUS. Additionally, the influence of MRI on potential changes in therapy was assessed using a three-range Likert-type scale. In all, 480 skeletal regions were compared. In 183 skeletal regions, an increased degree of infiltration was identified on wb-MRI. Significant differences (p < 0.05) between the modalities could be found in the thorax, spine, pelvis, and both lower extremities. Based on wb-MRI, tumor stage was upgraded in 19 of the 60 patients using the Durie and Salmon PLUS classification. In ten out of these 19 patients (42%), the wb-MRI result was essential for making the decision to initiate further therapy due to the degree of infiltration, extramedullary tumor extension, and/or further risk of fracture. Whole-body MRI provides a more detailed assessment of the pattern of bone marrow infiltration and strongly influences therapeutic strategies.     

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.     

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.     

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.     

Skeletal survey in advanced multiple myeloma: radiographic versus MR imaging survey

In an attempt to compare the sensitivity of bone radiographs and bone marrow magnetic resonance (MR) imaging for bone lesion detection in patients with stage III multiple myeloma (MM) and to evaluate the possible consequences of the replacement of the conventional radiographic skeletal survey (RSS) by an MR survey of the spinal and pelvic bone marrow in these patients, we obtained MR studies of the thoracic and lumbar spine, pelvis and proximal femurs in addition to the conventional RSS (including radiographs of the skull, entire spine, pelvis, ribs, humerus and femurs) in 80 consecutive patients with newly diagnosed stage III MM according to the Durie and Salmon staging system (based on blood tests and on the RSS). The performance of MR and radiographic studies to detect bone lesions in given anatomic areas and in given patients were compared. The consequences on MM staging following the substitution of the RSS by the MR survey were assessed. MR imaging was superior to radiographs for lesion detection in the spine (76% v 42% of patients) and pelvis (75% v 46% of patients). The RSS was superior to the limited MR imaging survey for the detection of bone involvement in the patient population (87.5% v 79% of patients). If the RSS had been replaced by the MR imaging survey for patient staging, 7/80 patients would have been categorized as stage I and one as stage II MM on the basis of normal MR findings and biological findings consistent with these stages. Substitution of the RSS by a limited spinal and pelvic marrow MR survey would lead to 'understaging' of 10% of patients with otherwise stage III MM on the basis of blood tests and the conventional RSS.     

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.     

Prediction of prognosis by electron microscopic analysis of myeloma cells

 Myeloma cells were ultrastructurally analyzed in relation to survival in 54 patients with myeloma who were treated with melphalan-prednisolone or cyclophosphamide-prednisolone. Since previous studies by electron microscope had demonstrated that the degree of nuclear-cytoplasmic asynchrony of myeloma cells was associated with poor prognosis, this study focused on three kinds of nuclear abnormalities and eight kinds of cytoplasmic abnormalities. The patients were classified into three groups according to the presence of these abnormalities. The median survival times of the first group with five or fewer of 11 different kinds of abnormalities, the second group with 6–8 abnormalities, and the third group with nine or more abnormalities were 2353, 531, and 115 days, respectively. Furthermore, this classification by ultrastructural abnormalities corresponded to those by the initial hemoglobin concentrations, platelet counts, and percentages of myeloma cells and plasmablasts in the bone marrow. These findings suggest that ultrastructural analysis of nuclear and cytoplasmic abnormalities, in addition to nuclear maturity, of myeloma cells may provide important information for predicting the prognosis in myeloma patients. Received: 18 March 1996 / Accepted: 14 June 1996     

Comparison of plasma cell infiltration in bone marrow biopsies and aspirates in patients with multiple myeloma

In 54 patients with multiple myeloma plasma cell infiltration was compared in bone marrow biopsies and aspirates. In 48% of cases plasma cell infiltration was comparable, in 48% infiltration in the aspirate was lower than in the biopsy. In only two cases more plasma cells were found in the aspirate. Eleven patients (20%) had less than 20% plasma cells in the aspirate and more than 50% in the biopsy. Underestimation of plasma cell load especially seems to occur in patients with a focal growth pattern of multiple myeloma or when strong fibrosis is present. 69% of patients with stage III, according to Durie & Salmon (1975), and 76% of patients with a high beta 2-microglobulin had more than 50% plasma cells in the biopsy, indicating that these parameters, which are based on tumour load, are influenced by other factors as well. The bone marrow biopsy is of superior value for direct estimation of the tumour load in multiple myeloma compared to bone marrow aspirates. A prospective study is needed to determine its prognostic significance.     

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.