R. Luoni

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.

Presenting features of monoclonal gammopathies: an analysis of 684 newly diagnosed cases

Abstract. 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).

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.

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.

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.

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.

Serum thymidine kinase in monoclonal gammopathies : a prospective study

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 < 0.05} and the overall population of those with MM (P < 0.0005). TK levels were increased in advanced stages in comparison with earlier ones (P < 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/μl had shorter survival times than those with lower levels (medians, 23 and 42 months; P < 0.0001). In a multivariate analysis, TK explained most of the variability of survival (P < 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 < 0.01) in those who responded to treatment but increased in those having relapses (P < 0.03) and those with progressive disease (P < 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. Cancer 1992; 69:1368‐1372.

Serum Thymidine Kinase and Beta-2 Microglobulin in Monoclonal Gammopathies

We evaluated the serum thymidine kinase (TK) and β-2 microglobulin (β-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 < 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 β-2 (29–53%) levels at remission was evident with respect to the levels measured at diagnosis. Patients with high levels of TK or [3-2 had a shorter survival than those with low levels; however, this was statistically significant only for β-2 levels (p < 0.02). Serum TK as well as β-2 levels appear to be of clinical value in monoclonal gammopathies and related to the course of the disease.

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.

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

Abstract. 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 < 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.