Changing clinical presentation of multiple myeloma.

We compared the presentation features of three series of patients with multiple myeloma diagnosed between 1960 and 1971 (Kyle R, Mayo Clin Proc, 1975, 50, 29, n = 869), 1972 and 1986 (Clinica Medica, University of Pavia, n = 345) and 1987 and 1990 (Cooperative Group for Study and Treatment of Multiple Myeloma, n = 341). In the most recently diagnosed patients, the percentage of those who had symptoms related to multiple myeloma (i.e. any of bone pain, systemic symptoms, disturbances related to hypercalcemia, neurological involvement and hyperviscosity) was reduced (90 vs. 86 vs. 66%) (P less than 0.001), while the percentage of asymptomatic patients diagnosed by chance was increased (not reported, and 14 vs. 34%). In the most recent series, a lower percentage of spontaneous bone pain (68 vs. 60 vs. 37%, P less than 0.001) paralleled a lower incidence of advanced bone disease (osteolyses and pathological fractures, 60 vs. 64 vs. 34%), and renal failure (serum creatinine greater than 1.2 mg/dl) was also less common (56 vs. 44 vs. 33%, P less than 0.01), at least partially due to a decreased incidence of both hypercalcemia (30 vs. 20 vs. 18%, P less than 0.001) and of hyperuricemia (serum uric acid greater than 7 mg/dl, 47 vs. 32 vs. 26%, P less than 0.01). Systemic symptoms (weakness, infections, fever or weight loss) were reported more seldom by recently diagnosed patients, due to a decreased frequency of anaemia (haemoglobin less than 12 g/dl), leukopenia and thrombocytopenia, as well as of the systemic effects of bone pain and of renal insufficiency. These data indicate that multiple myeloma is diagnosed earlier now than in the past, and this must be taken into account when comparing survival data in treated series.

Postremission chemotherapy in adult acute non-lymphoblastic leukaemia including intensive or non-intensive consolidation therapy.

From October 1983 to December 1988, 84 consecutive adult patients with acute non-lymphoblastic leukaemia (ANLL; median age = 51 yr) were uniformly treated to induce remission (CR) with intravenous vincristine and cytarabine sequentially followed by daunomycin and infusion cytarabine. From October 1983 to December 1985 consolidation was non-intensive (2 courses with the same drugs used for induction) (protocol ANLL83: 27 patients, median age = 45). From January 1986 to December 1988 consolidation was intensive (4 courses of vincristine and cytarabine sequentially followed by etoposide plus thioguanine or amsacrine) (protocol ANLL86: 57 patients, median age = 57). Excluding early deaths, the CR rate was 71.6%. Median CR, responsive patient survival and overall survival were 11.1, 15.3 and 8.5 mo, respectively. For protocol ANLL83 and ANLL86, median CR was 8.7 and 13.2 mo (P less than 0.05) and median survival was 13.1 and 16.9 mo (P less than 0.05) for responders and 8.0 and 9.2 mo (P not significant) for all patients. Intensive consolidation including drugs not previously used for induction seems to prolong CR duration and responder survival in adult ANLL.

Bone marrow biopsy in monoclonal gammopathies: correlations between pathological findings and clinical data. The Cooperative Group for Study and Treatment of Multiple Myeloma.

Between January 1987 and October 1989, 561 consecutive untreated patients with monoclonal gammopathy of undetermined clinical importance (MGUS) (n = 295) or with multiple myeloma (n = 266) were evaluated in a multicentre trial. Both bone marrow biopsy and aspiration (performed at different anatomical sites) were required at presentation. Bone marrow biopsy data indicated that changes in bone marrow composition from MGUS to early multiple myeloma and to advanced multiple myeloma followed a precise pattern, including an increased percentage of bone marrow plasma cells (BMPC%), a shift from plasmocytic to plasmoblastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual haemopoiesis and an increase in osteoclasts. In multiple myeloma the BMPC% of biopsy specimens and aspirate were closely related, although in 5% of cases the difference between the two values was greater than 20%. Some histological features were remarkably associated with each other. For example, BMPC% was higher in cases with plasmoblastic cytology, heavy fibrosis, or reduced residual haemopoiesis. Anaemia was the clinical characteristic most influenced by bone marrow histology. The BMPC% was the only histological variable which affected the greatest number of clinical and laboratory characteristics, including, besides haemoglobin concentration, erythrocyte sedimentation rate, radiographic skeletal bone disease, and serum concentrations of monoclonal component, calcium, beta 2-microglobulin and thymidine kinase activity. These data indicate that comparative bone marrow histology in monoclonal gammopathies has clinical importance.

Effects of acute smoking on the hemostatic system in humans.

Habitual smoking is one of the best established risk factors for cardiovascular disease. The pathogenesis of smoke-induced damage is not so well clarified, but it probably includes--among some other aspects--an activation of the hemostatic system. Recently it has been shown that smoking a single cigarette can significantly decrease the coronary blood flow in coronary patients as well as in normal subjects. We tested the hypothesis that the acute effects of smoke are mediated by the hemostatic system. Seven healthy male volunteers, aged 20-40 years (mean 32 +/- 6 years), entered the study. All were habitual smokers, but had abstained from smoking in the 12 hours preceding the test. After lying in absolute rest for about 30 minutes, each subject smoked a cigarette containing 1.2 mg of nicotine. Immediately before and after smoking, blood was drawn by clear venipuncture for the evaluation of the following hemostatic variables: collagen-induced platelet aggregation by the method of Born; thromboxane B2 (TxB2) production by platelets stimulated with collagen, radioimmunoassay (RIA); plasma beta thromboglobulin (TG) (RIA); plasma fibrinopeptide A (FPA) (RIA); plasma fibrinolytic activity in the euglobulin fraction (NEF) (fibrin plate method). The following results, respectively before and after smoking, were observed: collagen-induced platelet aggregation 55 +/- 3 vs. 57 +/- 6%; TxB2 100.5 +/- 5.9 vs. 90.3 +/- 9.0 ng/10(8) platelets; plasma beta-TG 20.8 +/- 2.2 vs. 19.2 +/- 2.3 ng/ml; plasma FPA 2.3 +/- 0.3 vs. 2.2 +/- 0.1 ng/ml; NEF, lysis diameter 16.8 +/- 1.6 vs. 16.7 +/- 1.7 mm; NEF + C1 inhibitor lysis diameter 8.8 +/- 0.7 vs. 9.1 +/- 0.7 mm.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum thymidine kinase and beta-2 microglobulin in monoclonal gammopathies.

We evaluated the serum thymidine kinase (TK) and beta-2 microglobulin (beta-2) levels of 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and of 29 patients with multiple myeloma (MM). Both parameters were significantly lower in MGUS than in MM patients and in early (stage I + II) than in advanced (stage III) MM. TK was also lower in MGUS than in stage I MM (p less than 0.025). A seven-fold increase of TK level was documented in one patient who developed a full blown picture of MM 6 years after a diagnosis of MGUS. In 3 patients with stage III MM, a sharp decrease in TK (40-77%) and in beta-2 (29-53%) levels at remission was evident with respect to the levels measured at diagnosis. Patients with high levels of TK or beta-2 had a shorter survival than those with low levels; however, this was statistically significant only for beta-2 levels (p less than 0.02). Serum TK as well as beta-2 levels appear to be of clinical value in monoclonal gammopathies and related to the course of the disease.

Presenting features of monoclonal gammopathies: an analysis of 684 newly diagnosed cases. Cooperative Group for the Study and Treatment of Multiple Myeloma.

OBJECTIVES: The clinical, laboratory and radiologic features at diagnosis of 684 newly diagnosed patients with monoclonal gammopathy were revised in order to underline the differences between monoclonal gammopathies of undetermined significance (MGUS) and stage I multiple myeloma (MM). DESIGN: Patients were screened for inclusion in a prospective controlled protocol for treatment of MM. Those having serum or urine monoclonal component (MC) were diagnosed as MM when they demonstrated osteolysis and/or bone marrow plasma cells (BMPC) > 20%; patients not fulfilling these criteria were considered MGUS. SETTING: Patients were recruited from 24 general or university hospitals from the departments of internal medicine, haematology and medical oncology. SUBJECTS: Seven-hundred-and-fifty were enrolled between January 1986 and March 1990; 684 (343 MGUS and 341 MM) were able to be evaluated for this study and 78 were stage I MM. INTERVENTIONS: Complete clinical, radiologic and laboratory work-up was carried out at the referral centres. MAIN OUTCOME MEASURES: The main outcome expected was the confirmation that BMPC > 20% could reliably differentiate stage I MM from MGUS. RESULTS: At a median follow-up of 36 months (minimum follow-up: 18 months), MGUS had a lower progression rate to overt MM, longer overall survival and different causes of death than stage I MM. Further differences concerned erythrocyte sedimentation rate (28 vs. 47, P < 0.001), per cent reduction of normal immunoglobulin (86 vs. 60%, P < 0.001), serum MC (1.6 vs. 2.2 g dl-1, P < 0.001) and thymidine kinase level (3.3 vs. 4.5 mU ml-1, P < 0.05). CONCLUSIONS: The study suggests that 20% BMPC can be taken as a safe cut-off point at which to differentiate MGUS from early MM and outlines a few simple parameters which can be of diagnostic aid.

Monoclonal antibody Ki-67 as a marker of proliferative activity in monoclonal gammopathies.

In 16 patients with monoclonal gammopathies of undetermined significance (MGUS) and in 49 with multiple myeloma (MM, 43 untreated and 6 relapsed) we used immunocytochemistry to determine the percentages of bone marrow plasma cells (BMPC) that incorporate bromodeoxyuridine (BUDR-labeling index, BUDR-LI) in vitro and that label with the monoclonal antibody Ki-67 (which recognizes an antigen thought to identify the growth fraction of the population, Ki-67 GF). Both mean and range values were greater for Ki-67 GF than for BUDR-LI. Most patients with high Ki-67 GF also had high BUDR-LI, although a linear correlation was not found between the two parameters. MGUS has lower values than MM, and the difference was much greater for Ki-67 GF than for BUDR-LI (p less than 0.005 vs. p less than 0.05). Differences in Ki-67 GF but not in BUDR-LI were found between MGUS and stage I MM (p less than 0.0005) and between grouped stage I and II MM and stage III MM (p less than 0.025). Both Ki-67 GF and BUDR-LI were significantly (p less than 0.005) greater in relapsed than in untreated MM. Determining Ki-67 GF as a proliferative parameter could be a better way of studying the kinetics of (BMPC) in MGUS and MM than determining the BUDR-LI, since a wider range of values is obtained and this allows patient groups with different clinical characteristics to be separated more easily.

Early plasma cell recruitment in multiple myeloma following chemotherapy.

Therapy-induced modifications of bone marrow plasma cell kinetics were studied in three patients with myelomatosis. The investigation was performed prior to and 15 d after termination of a course of aggressive chemotherapy. An increase in the labelling index (40-212% of pretreatment values) with a corresponding reduction of Ts (5-34%) was observed in all cases. As a consequence of this combined variation, the fractional turnover rate (which represents the percentage of cells produced per unit time) was the parameter with the highest increment (54-276%). These results indicate that plasma cell recruitment occurs soon after chemotherapy and is characterized by a shorter S phase and a higher number of DNA-synthesizing cells.

Ras oncogene expression and DNA content in plasma cell dyscrasias: a flow cytofluorimetric study.

Using bivariate flow cytofluorometry, we have determined the nuclear DNA distribution and the expression of the p21 protein (coded by the Ha-ras oncogene) in the bone marrow (BM) cells of five solid tumour patients having histologically normal BM and in those of 57 patients with plasma cell dyscrasia (28 with monoclonal gammopathies of undertermined significance, MGUS, and 29 with multiple myeloma, MM). All normal and MGUS and 21/29 (72.4%) MM BM had diploid modal DNA content and 8/29 (27.6%) MM BM had both diploid and hyperdiploid cell populations. In normal and MGUS BM, the level of the p21 oncoprotein was low and uniform in all G0/G1, S and G2 cells (median fluorescence values in arbitrary units were 6.1 and 7.5, respectively). The level of p21 was increased both in different aliquots of G0/G1 cells and in the S and G2 cells in diploid MM (median value for G0/G1 cells was 20), and especially in MM with hyperdiploid clones (median value for hyperdiploid cells was 40.5, P less than 0.005 with respect to normal and MGUS BM and less than 0.005 with respect to diploid MM BM). The p21 expression was greater in patients with advanced (stage III) than in earlier MM (stages I + II) (P less than 0.005), and it was directly related to the BMPC infiltration (r = 0.7; P less than 0.005). Since p21 expression is greater in MM than in both normal and MGUS BM, Ha-ras could be involved in the malignant plasma cell transformation that distinguishes MM from MGUS.

Analysis of human myeloma cell population kinetics.

Pretreatment plasma cell 3H-thymidine labeling index (LI) was related to chemotherapy response in 37 multiple myeloma patients treated with alkylating agents. Response rate did not significantly differ in patients with high (greater than 3%), intermediate (2-3%) and low (less than 2%) LI values, and survival duration was significantly longer in patients with low LI irrespective of response to chemotherapy. Median response duration was distinctly shorter in patients with high and intermediate values (3 and 11 months, respectively) than in those with low values (30 months; p less than 0.01). LI at relapse was similar to that found at presentation in 5 out of 10 patients studied but was sharply increased in the other 5 who had an aggressive clinical course following initial response. Four of these latters showed a clonal evolution of bone marrow plasma cells, detected by changes in cell ploidy at flow-cytometric analysis.

Expression of p170 protein in multiple myeloma: a clinical study.

The expression of the p170 multidrug resistance protein by bone marrow plasma cells (BMPC) was assessed at clinical presentation in 53 patients with multiple myeloma (MM) using the C219 monoclonal antibody. Twenty-two of the 53 (41 per cent) patients had variable aliquots (1-60 per cent, median = 6 per cent) of p170+ BMPC by immunocytochemistry. Five of 10 patients studied using bivariate flow cytometry had both diploid and hyperdiploid (DNA index ranged from 1.2 to 1.5) BMPC with hyperdiploid clones having significantly greater p170 expression than diploid ones. Of the 37 patients evaluated for a response, 20 (54 per cent) had responded to induction chemotherapy. The presence of p170+ BMPC was a negative indicator for achieving response. The response rate was 75 per cent for p170- and 25 per cent for p170+ cases (p < 0.01), with no difference on the basis of treatment schedule (melphalan and prednisone, 24 patients; peptichemio, vincristine and prednisone, 13 patients). No difference in response and survival duration was found between p170+ and p170- patients. In six of nine patients studied both at diagnosis and following induction chemotherapy the p170+ BMPC% increased irrespective of the type of treatment or outcome.

Proliferation kinetics of plasma cells and of normal haemopoietic cells in multiple myeloma.

DNA synthesis time (Ts) and 3H thymidine (TdR) labelling index (LI) of bone marrow (BM) myelomatous plasma cells (PC) and of the residual haemopoietic cell population (RHCP) were measured by in vitro quantitative 14C-TdR autoradiography in five patients with multiple myeloma (MM) in different phases of disease (three at presentation and two at relapse) and in one patient with solitary extra-osseous myeloma. One other patient with plasma cell leukaemia (PCL) was studied during an initial relapse phase and later during the leukaemic terminal phase. PC Ts was 18.8 +/- 3.7 (from 13.3 to 25.0) hr and PC LI was 2.5 +/- 1.8% (from 1.0 to 6.3%). In the case of PCL, circulating PC had a Ts of 14.4 hr and a LI of 3.1. From these experimental measurements, the fractional turnover rate (FTR-percentage of cells produced per unit time) and the potential doubling time (Td) of BMPC were calculated assuming that all BMPC were in a steady-state at the time of the study. BMPC FTR was 3.53 +/- 2.3% cells per day (from 1.2 to 6.72) and BMPC Td was 46.8 +/- 27.5 days (from 15.0 to 75.4). Comparison with results obtained in BM blasts of children with acute lymphoblastic leukaemia (ALL) indicated that BMPC had a lower proliferative activity (P less than 0.001), although BMPC Ts was not significantly different. In two patients a tumour doubling time of 6 and 13 months was determined by clinical follow up. Comparison of this parameter with Td showed a cell loss factor of more than 90% in both patients. Kinetic data relative to RHCP showed slight variations with respect to those found in normal subjects, with a general tendency towards a prolongation of Ts and a reduction of LI.

Platelet function and thrombin activity in patients with recent cerebral transient ischemic attacks.

Platelet function and thrombin activity were investigated in 12 hospitalized patients (7 men and 5 women, mean age 53 years) who had had transient cerebral ischemic attacks in the previous 2-12 weeks. Each patient was given an extensive clinical and instrumental evaluation, including Doppler sonography of the cervical and lower limb vessels, cerebral angiography, and head computed tomography scan, after which relevant atherosclerotic disease was excluded. The controls consisted of 12 subjects hospitalized for nonvascular neurologic problems and matched for age, sex, and risk factors to the transient ischemic attack patients. Collagen-induced platelet thromboxane B2 production, plasma beta-thromboglobulin, and fibrinopeptide A were significantly higher in the patients than the controls. Platelet aggregability by collagen was the same in the 2 groups. Platelet hyperfunction and enhanced thrombin activity are present in patients some weeks after the acute episode, suggesting that the hemostatic system has a primary pathogenetic role.

P-glycoprotein expression in multiple myeloma.

P-glycoprotein expression was investigated in ten drug resistant patients suffering from multiple myeloma. The immunoperoxidase method on bone marrow plasma cells and immunoblotting were performed by using the monoclonal antibody C219. Five patients resistant to protocols including vincristine, melphalan and doxorubicin were found to express P-glycoprotein. The immunoperoxidase method appeared to be sensitive and suitable for P-glycoprotein detection in bone marrow samples.

Serum thymidine kinase in monoclonal gammopathies. A prospective study. The Cooperative Group for Study and Treatment of Multiple Myeloma.

Between January 1986 and March 1990, the serum levels of thymidine kinase (TK) were evaluated at diagnosis in 97 patients with monoclonal gammopathy of undetermined significance (MGUS) and 149 patients with multiple myeloma (MM) enrolled in a prospective protocol for treatment of MM. At presentation, patients with MGUS had lower TK levels than those with Stage I MM (P less than 0.05) and the overall population of those with MM (P less than 0.0005). TK levels were increased in advanced stages in comparison with earlier ones (P less than 0.01). The TK level was related to survival. With a median follow-up of 29 months, patients with TK levels greater than 7.0 U/microliters had shorter survival times than those with lower levels (medians, 23 and 42 months; P less than 0.0001). In a multivariate analysis, TK explained most of the variability of survival (P less than 0.0001), the remaining being accounted for by serum creatinine and beta-2 microglobulin. No changes in TK levels occurred during follow-up of patients with stable MGUS, whereas TK levels increased in two patients at time of progression to overt MM. In patients with MM, TK levels decreased (P less than 0.01) in those who responded to treatment but increased in those having relapses (P less than 0.03) and those with progressive disease (P less than 0.03). These results indicate that TK has clinical and prognostic relevance in monoclonal gammopathies, and additional investigations are warranted to determine whether it is a useful tool for the clinical evaluation, staging, and follow-up of patients with MM.

Treatment of multiple myeloma according to the extension of the disease: a prospective, randomised study comparing a less with a more aggressive cystostatic policy. Cooperative Group of Study and Treatment of Multiple Myeloma.

The purpose of the study was to ascertain whether the prognostic significance of staging in multiple myeloma (MM) is influenced by the aggressiveness of effective induction treatment and/or by continuing or discontinuing maintenance chemotherapy. Patients with untreated stage I MM (defined according to Durie and Salmon) were randomised between being followed without cytostatics until the disease progressed and receiving six courses of melphalan and prednisone (MP-P) just after diagnosis; stage II patients were uniformly treated with MPH-P and stage III patients were randomised between MPH-P and four courses of combination chemotherapy with Peptichemio, vincristine and prednisone (PTC-VCR-P). Within each stage, responsive patients were randomised between receiving additional therapy only until maximal tumour reduction was reached (plateau phase) and continuing induction therapy indefinitely until relapse. With resistant, progressive or relapsing disease, patients originally treated with MPH-P for induction received combination chemotherapy and vice versa. The overall first response rate was 43.8% (42.2% in 206 stage I, II and III patients treated with MPH-P and 48.0% in 75 stage III patients treated with combination chemotherapy, P = NS). Combination chemotherapy was more myelotoxic than MPH-P and, in particular, caused more non-haematological side-effects. Both the less and the more aggressive induction policies gave the same disease control. Progression of disease was statistically similar in stage I patients who were initially left untreated and in t hose who received MPH-P just after diagnosis; median duration of first response was similar in stage III patients receiving MPH-P and in those on combination chemotherapy. In all stages, discontinuing or continuing maintenance did not alter the median duration of first response. The overall second response rate was 28.5% (34.0% to MPH-P and 25.3% to combination chemotherapy, P = NS). Median survival was greater than 78 months in stage I, was 46.3 months in stage II and was 24.3 months in stage III patients, still independent of both induction and post-induction policies. In MM, the significance of staging for survival is independent of both the aggressiveness of induction and of continuing or discontinuing maintenance chemotherapy after the maximal tumor reduction has been achieved. Both MPH-P and and the association of PTC, VCR and P are effective in inducing first response and also second response in patients failing on the alternative regimen, but PTC-VCR-P causes more side effects. Thus, the overwhelming majority of patients with MM can safely be given MPH-P as first therapy, and this treatment may be delayed in early diseases.