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Erythropoietin activity in serum was measured using 59Fe incorporation into erythrocytes in protein-starved, hypoxic mice. The activity in serum from 20 patients with untreated myelomatosis was not significantly different from that in 31 saline controls. Only three patients had detectable erythropoietin levels in serum: 0.24 IU/ml, 0.27 IU/ml and 0.50 IU/ml (standard B), respectively. The venous haematocrit was correlated positively with the glomerular filtration rate as measured by 51Cr EDTA-clearance. No correlation could be established between venous haematocrit and serum albumin or serum transferrin. The results are in agreement with the assumption of a defective erythropoietin activity due to renal failure in myelomatosis.

The occurrence of malignant lymphomas in 3 siblings is described. The cases include the first report of Hodgkin's disease and non-Hodgkin malignant lymphoma in dizygotic twins. Another remarkable feature was the development of malignant lymphoma, when the siblings were at the same age. Although a transmissible agent or environmental factors cannot be excluded in this family, our observations may suggest a mutual genetic predisposition in Hodgkin's disease and non-Hodgkin malignant lymphoma.

One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1–4 and 17–20) or M + P regimen (melphalan 0.25 mg/kg and prednisolone 100–200 mg/day day 1–4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M + P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR + PR) to NOP versus 64% to M + P (NS). The time to progression was 16 months (95% C.L. 14–51) in the NOP group versus 21 months (95% C.L. 15–27) in the M + P group (NS). The median survival was 14 months (7–21) in the NOP group and 31 months (21–43) in the M + P group (p = 0.02). NOP was significantly more toxic than M + P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M + P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M + P as primary treatment of multiple myeloma.

6 cases of AML with a supernumerary chromosome 8 as the only aberration in practically all bone marrow mitoses and 10 cases with a normal chromosome composition of the marrow cells were investigated in order to evaluate the possible influence of trisomy 8 on some clinical and cytokinetic parameters. No significant differences between the groups were found. In our laboratory a supernumerary chromosome 8 is present in 36% of AML cases with chromosomal aberrations.

Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12 single ), 20 as +12 with additional abnormalities (+12 complex ). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5 + , Slg weak , mainly FMC7 − ) and atypical for CLL in 122 patients (25%) (CD5 − , or Slg strong or FMC7 + ). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) ( P complex , 14q +, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12 single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q +, an abnormal karyotype, +12 complex , more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunopenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12 single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12 complex , 14q +, del 6q and chromosome 17 are found in about 50% of the patients, and in particular chromosome 17 abnormalities suggest a poor prognosis.

Aberrations of chromosome 6 were observed in 11 of 193 cases of chronic lymphocytic leukemia diagnosed January 1, 1984–November 1, 1988 and investigated cytogenetically within 30 days after diagnosis. The 6p was rearranged in 5 cases: 4 balanced and 1 unbalanced translocation. The 6q was involved in 6 cases: 4 deletions and 2 balanced translocations. Three of the del(6q) may be identical: del(6)(q13q27). In two cases there were no additional aberrations. Aberrations of chromosome 6 correlated significantly with an advanced clinical stage, diffuse pattern of bone marrow infiltration, and increased SmlgM-fluorescence intensity. All these factors are associated with poor prognosis. Although the number of cases with 6q aberrations is still too small and the observation period too short to show significant influence on survival, the presence of 6q aberrations at diagnosis may prove useful in delineating a subtype of chronic lymphocytic leukemia with poor prognosis.

Multiple myeloma is characterized by an increased susceptibility to infections and to other malignancies. In a double-blind, placebo-controlled study the potential impact of immunomodulation by ranitidine was studied in 20 patients with multiple myeloma. Three patients were untreated, while 17 after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2.19-2.25 nmol/min) (P less than 0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-alpha-stimulated NK cell activity decreased (P less than 0.03, respectively). As production of oxygen radicals constitutes an important mechanism of monocyte killing activity against microorganisms and probably against malignant cells, it is suggested that ranitidine may be of beneficial impact in the treatment of multiple myeloma.

Summary. We have re-evaluated mouse rosette formation (MRF) as a marker for B-CLL by estimating the fraction of mouse rosette forming B-lymphocytes (identified by CD20 monoclonal antibodies) in normal donors and malignant CD20 + cell proliferations (ALL, AML, B-NHL, B-HCL and B-CLL). Whereas this ratio was increased in B-CLL, all other CD20 positive malignancies showed mean ratios of less than 0·1. As part of a Danish multi-centre study, we furthermore prospectively analysed 86 patients and found that the mouse/CD20 ratio divided the 78 patients with monoclonal B-cell populations suspected of B-CLL in two distinct groups. In the low ratio group, three patients were categorized as leukaemized B-NHL and one as PLL. The remaining three patients with low ratio were clinically and immunologically (by Smlg density and CD5 expression) B-CLL patients suggesting a frequency of MR-negative B-CLLs of approximately 5%. In the high ratio group two of 70 patients were diagnosed as B-NHLs. Thirdly, MRF was a valuable parameter in patients, where transformation of disease is suspected, since it preceded clinical changes by several months. Thus, MRF is still a useful marker in the age of monoclonal antibodies.

Multiple myeloma (MM) is characterized by an increased susceptibility to infections and to other malignancies. Selected related immune functions were studied. Spontaneous and interleukin-2-stimulated natural killer (NK) cell activities were normal in 19 patients with MM compared with 62 controls. In contrast, interferon-stimulated NK cells had a significantly lower increase in activity in MM than in controls. The normal improvement in lytic NK cell activity after addition of indomethacin to the mononuclear cell cultures (to inhibit prostaglandin-mediated suppression) was not observed in cultures from MM patients. As reported for other lymphoproliferative disorders, the levels of soluble interleukin-2 receptors in serum were significantly higher in MM (600 U/ml median value) compared with controls (317 U/ml median value), P less than 0.0001, and the concentration of interleukin-2 receptors was significantly correlated with the concentration of monoclonal immunoglobulin in serum. Blood monocyte chemotactic responsiveness was significantly lower in MM patients with both zymosan-activated serum and f-Met-Leu-Phe as cytotaxins, suggesting reduced ability to accumulate at inflammatory foci. In contrast, release of reactive oxygen radicals, believed to be associated with the killing ability of monocytes, was normal after in vitro stimulation.

Tetranectin, a recently described human protein widely distributed in the body and with possible importance for cell growth and differentiation, has previously been observed to be decreased in patients with solid malignant tumors. In patients with multiple myeloma, either untreated or previously treated, serum levels were found to be significantly reduced. A negligible interindividual variation was observed. Levels of serum tetranectin were not correlated with serum albumin, hemoglobin, or M-component. Low levels of tetranectin may be related to the growth and spread of malignant cells or reflect a general catabolic state of chronic disease.

The chromosomal findings in 25 cases of multiple myeloma are reported. The chromosomes were directly prepared from bone marrow cells and studied by trypsin-Leishman banding. Abnormal stem lines were found in 16 cases (64%), and were characterized by banding in 12 cases. Twelve cases were hyperdiploid; 11 cases carried marker chromosomes, 50% of which involved chromosome No. 1. Five cases were trisomic for 1q21-1q3. A vulnerable point was located on 3q27 or 28 or 29. The two cases that carried the 14q+ marker chromosome were also the only cases with plasma cells in the peripheral blood. Based on this study and the literature it is suggested that a 14q+ is necessary for the development of plasma cell leukemia. The actuarial survival curves gave no evidence for major prognostic significance of the demonstration of an abnormal cell clone. Trisomy for 1q21-1q3 may be a bad prognostic sign. The results are discussed with special reference to the aberrations in acute nonlymphocytic leukemia as reported earlier in a series of 88 cases from this laboratory.

The chromosomal findings in 88 consecutive cases of acute nonlymphocytic leukemia (ANLL) which have been cytogenetically evaluated are reported. The chromosomes were directly prepared from bone marrow cells and studied by trypsin-Giemsa banding. Abnormal stem lines were found in 42% of the cases. Supernumerary chromosomes Nos. 6, 8 and 21, missing chromosomes 7 and Y, and structural rearrangements t(8;21) and 5q—occurred so often that nonrandom events are presumably underlying. It is shown that nonidentical marker chromosomes often have break points in common. Several vulnerable points which particularly often appear to break in structural rearrangements are located. It is pointed out and discussed that the large series of ANLL analysed with banding which have been published so far disagree concerning the frequencies of nonrandom aberrations.

Chromosome studies with the banding technique have been performed in a considerable number of cases of myeloproliferative diseases, but technical difficulties have so far prevented detailed studies of chromosomal abnormalities in multiple myeloma. The karyotypes of bone marrow cells from two patients with multiple myeloma have been analyzed by a trypsin-Giemsa banding technique. Evidence is given for clonal evolution which in one patient has probably occurred by cell fusion and subsequent chromosome loss. Eight different marker chromosomes are characterized. Nonrandom chromosomal participation in the translocations and the existence of specific vulnerable points on chromosomes 1, 3, and 16 are suggested.

Summary. Immunocytomas are defined as disorders in the B-lymphocyte series, characterized by production of an M-component. After a basic description of the immunoglobulin molecule and the development of the cellular immune system by which it is built up, the production of M-components is discussed in relation to possible aetiology and pathogenesis. The turn-over of M-components is mentioned, especially on the basis of the studies of Salmon and colleagues (Salmon, 1973) with reference to the different types of M-components and to cellular aspects. The production of interferon and osteoclast activating factor is touched on, and a brief review is given of the most common clinical features of malignant immunocytomas. Finally, the interrelationship of the different manifestations of immunocytomas is described on the basis of the hypothesis put forward by Salmon & Seligmann (1974).

Forty-two consecutive patients with untreated myelomatosis (MM) formed the basis of settling the validity of measuring the renal plasma clearance (RPC), either indirectly using the serum creatinine or directly using the glomerular filtration rate (GFR) when studying anaemia, calcium metabolism, proteins in serum and urine, and prognosis. Patients without light chain excretion in the urine had a higher GFR (P less than 0.01) than patients with light chain excretion. The haemoglobin concentration (Hb) was strongly correlated (P less than 0.001) to both, serum creatinine and GFR. Patients with normal serum concentrations of the physiological immunoglobulins had higher Hb (P less than 0.01) than patients with reduced serum immunoglobulins. Patients with serum calcium greater than 3.00 mmol/1 had additional reduced GFR compared with the other myeloma patients. The serum parathyroid hormone was decreased (P less than 0.01) and inversely correlated to the GFR. Patients with increased serum creatinine, reduced GFR or with osteolytic bone lesions had a decreased survival rate. The study shows that the major factor in prediction of Hb and prognosis in patients with MM is the RPC expressed either as the serum creatinine or the GFR. In addition, the significant correlations between the GFR and the other variables in MM assessed the RPC to be a useful and valuable marker in studies of anaemia, protein and calcium metabolism and prognosis in MM.

Chromosome studies were done on 73 patients with multiple myeloma and three patients with plasma cell leukemia. Eighteen of 76 patients (24%) had chromosomally abnormal clones, including all three patients with PCL. The most common anomalous chromosomes were #1, #14, and #12. In addition, i(17q) was found in two patients with plasma cell leukemia. Among newly diagnosed patients there was no difference in survival for those with abnormal karyotypes and those with normal karyotypes. Among previously diagnosed patients receiving treatment, however, individuals with an abnormal clone had a significantly higher mortality during the first 2 years compared to those with a normal clone. Patients with no growth of metaphases in their bone marrow aspirate had a significantly lower mortality than other patients (p less than 0.05).

Bacterial infections were registered in 39 patients with myelomatosis during 18 months in a prospective study. The infection incidence was 0.80 infections per patient year. 81 % of a total of 32 isolates were gram-negative. Urinary tract infections due to Escherichia coli were the most frequent infections. Pneumonia due to Streptococcus pneumoniae were infrequently seen compared to previous studies. Hence, the etiologic spectrum has clearly shifted from gram-positive to gram-negative bacteria in these patients. 53 % of all infections were hospital-acquired, and most of these were preceded by instrumentation of the urinary tract or indwelling venous catheters. The infections were nosocomial in 7/9 cases of septicemia registered. All 4 patients who died of infection, suffered from hospital-acquired infections. Patients who attracted infections had significantly higher serum creatinine levels and higher mortality compared to the rest of the patients.

Plasma volume (PV), venous haematocrit (PCV) and total blood volume (BV) were measured in 24 patients with untreated myelomatosis using Evans Blue dye technique and PCV corrected for ‘trapped’ plasma and body/venous haematocrit ratio. The state of renal insufficiency was expressed as a serum creatinine and a glomerular filtration rate using 51CrEDTA clearance. The total BV was normal in all but 3 patients, whereas the PCV was subnormal with an average value of 0.267. Consequently, the PV was expanded with an average value of 25 % compared to normal values. The PV was positively corrected to the concentration of gammaglobulin in serum. The 3 patients with increased BV caused by an increased PV had subnormal red blood cell mass and thus a partial haemo-dilution anaemia only. A highly significant correlation was found between renal clearance and PCV and between renal clearance and the indirectly measured red blood cell mass, respectively (P < 0.001). The data demonstrate that renal failure in myelomatosis is associated by an increase in PV and a decrease in PCV without any change in total BV. No correlation was found between the degree of renal insufficiency and body/venous haematocrit ratio. Thus, the major determining factor in prediction of PCV and red blood cell mass was the glomerular filtration rate. The results are in agreement with the assumption of a nephrogenic pathogenesis in anaemia of myelomatosis.

T-cell and B-cell functions were studied in 35 patients with untreated multiple myeloma (MM) and in 16 patients with MM treated with prednisolone, melphalan and vincristine. The numbers of CD4+ T cells were normal in untreated MM patients, but markedly decreased in treated patients, whereas CD8+ cell numbers were normal in untreated and treated patients. Mitogen-induced as well as antigen-induced lymphocyte proliferative responses were reduced, but not further affected by treatment. The antigen-induced proliferative responses by lymphocytes of treated, but not of untreated patients, correlated positively to the proportions of CD4+ cells among MNC. Taken together, the findings suggest selective loss of CD4+ subpopulations during cytotoxic treatment. Pokeweed mitogen (PWM)-induced Ig production was generally low, but significantly reduced Ig production was only seen in experiments employing MM B cells and monocytes co-cultured with irradiated T-enriched cells. Irradiated MM T cells displayed normal helper function when co-cultured with normal B cells stimulated with PWM. MM B cells and monocytes cultured with irradiated normal T cells produced little Ig; however, MM monocytes were not suppressive. In 2 of 3 patients with either IgG-kappa or IgA-kappa myeloma, the numbers of PWM-stimulated B cells that produced kappa chains were somewhat higher than those found among normal MNC. The impaired ability of antibody production by B cells from untreated MM patients seems to relate to intrinsic B cell defect(s) rather than to abnormal regulation by T cells or monocytes. However, disturbances in the functions of CD4+ cells may be observed in treated MM.

17 patients with myelomatosis were vaccinated with a 14-valent pneumococcal capsular polysaccharide vaccine. In comparison to 12 healthy controls, they had statistically significant lower combined geometric mean antibody concentrations (the geometric means of all 14 antigens), both before and 4 weeks after the immunization. Mean antibody increases, however, were remarkably similar in the 2 groups. After 18 months the geometric mean antibody concentrations of the patient group had returned to preimmunization levels or lower for 7 out of 14 antigens. 1 case of pneumococcal bacteraemia occurred in the patient group 8 1/2 months after vaccination in spite of a significant initial antibody response against the infecting serotype 23 F. Pneumococcal vaccination in patients with myelomatosis appears to yield subnormal antibody responses and therefore probably insufficient protection against pneumococcal infection.

On the basis of the literature, so-called secondary acute nonlymphocytic leukaemia (S-ANLL) in myelomatosis is reviewed. Using the banding technique, cytogenetic changes including hypodiploidy and partially or totally missing chromosomes # 5 and # 7 are recorded. The findings are in accordance with the cytogenetic changes seen in S-ANLL in other malignancies which have been treated with cytostatics, especially alkylating agents. So, S-ANLL in myelomatosis seems to be a result of treatment with cytostatics, though a causal relationship has to be documented.

In 38 patients with myelomatosis the serum cobalamin varied from 34 pmol/1 to 404 pmol/1, median 181.5 pmol/1, which is significantly lower than the levels in 22 control persons with range 173-535 pmol/1, median 265 pmol/1. In spite of low serum cobalamin no symptoms of vitamin B12 deficiency could be demonstrated in any of the patients, except for the one patient who had a serum cobalamin of 34 pmol/1. Mean values for Hb, MCV, PCV, serum lactate-dehydrogenase, adjested red cell folate and nucleated neutrophil count were similar in a group of patients with a serum cobalamin below 160 pmol/1 and a group of patients with higher serum cobalamin values. The decrease in serum cobalamin is due in part to a reduction in the major cobalamin binder (TC-I) in serum. Measuring serum cobalamin in relationship to gastric acis secretion, we found a significantly higher frequency of hypo- and achlorhydria in patients with serum cobalamin below 160 pmol/1 although the intestinal absorption of vitamin B12 was normal by a Schilling test. Although our finding of low saturation of TC-I in serum seems to demonstrate decreased vitamin B12 content in the body in myelomatosis, the lack of evidence for a functional vitamin B12 deficiency speaks against giving a supplement to patients with myelomatosis.

Cobalamin and folate metabolism was investigated in 43 patients with myelomatosis, in 8 control subjects of similar age and 22 younger controls. Plasma total cobalamin was lower in myeloma patients than in either of the control groups and methylcobalamin (Me-Cbl) was disproportionately reduced. Erythrocyte levels of total cobalamin were very similar in patients and elderly controls but were half the levels in younger controls. Erythrocyte levels of Me-Cbl were slightly higher in patients than in the dlderly controls. FIGLU excretion after L-histidine was elevated in 53% of the patients but values did not correlate with serum or erythrocyte folate or with plasma total cobalamin. FIGLU excretion decreased after DL-methionine or Me-Cbl only in patients whose FIGLU excretion was initially high. The results are discussed in the light of the 'methylfolate trap hypothesis' and suggest that some patients with myelomatosis have insufficient activity of methionine synthetase to meet the additional metabolic demand for one carbon compounds.

A prospective randomized trial in 96 patients with previously untreated myelomatosis was performed comparing 3 regimens of chemotherapy: (i) Intermittent vincristine, BCNU, cyclophosphamide, melphalan, and prednisone (VBCMP) to (ii) intermittent vincristine, melphalan and prednisone (VMP) to (iii) intermittent melphalan and prednisone (MP). Induction response rates and survival were similar in all 3 regimens. An improvement in relapse-free survival was observed by adding vincristine to MP, but this did not achieve statistical difference (p = 0.10). Patients given VBCMP fared slightly worse than those given VMP. The haematologic toxicity was similar in all 3 regimens, but the tolerability of VBCMP was lower. Although showing no statistical differences between the 3 treatment regimens, the results support the view that a combination of MP ‘standard’ induction therapy in MM with frequently administered vincristine has a trend towards postponing treatment failure due to development of resistance to melphalan.