Effect of pamidronate on skeletal morbidity in myelomatosis. Part 1. The results of the first 12 months of pamidronate therapy.

BACKGROUND: Osteolytic bone destruction caused by increase of osteolytic activity is a major manifestation of multiple myeloma (MM). Pamidronate (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate) inhibits osteoclastic activity and reduces bone resorption. METHODS: Since October 1995 the efficacy of pamidronate is evaluated in MM patients all receiving anti-myeloma chemotherapy acc. to VMCP/VBAP alternating regimen. 46 patients with stage III myeloma and osteolytic lesions were randomized to receive either pamidronate (Aredia; Novartis) 60 mg i.v. in 4-hour infusion monthly (n = 23) or chemotherapy alone (control group n = 23). Estimation of performance status, quality of life, pain score, analgesic consumption, serum calcium concentration and twenty four-hours Calcium excretion, urine Calcium/creatinine ratio is done at least once a month (before pamidronate administration) while X-ray skeletal survey--before treatment and then every six months. RESULTS: In the first months of treatment apparent reduction of bone pain occurred. Hypercalcaemia was revealed in 6 patients at entry into the study. In 5 of these patients pamidronate restored and maintained normocalcaemia for a median 6 months. In 3 patients an aggressive plasma cell proliferation was accompanied by reoccurrence of hypercalcaemia. At skeletal X-ray examination performed after 6 and 12 cycles of pamidronate and by comparing each of consecutive imaging with previous one the progression of osteolysis was respectively found in 67% and 39% of patients. In the control group corresponding figures were: 79% and 70%. The mean number of skeletal events (pathologic fracture, radiation to bone and spinal cord compression) per year was lower in the pamidronate group (1.82) than in control-patients (2.72), p < 0.013. The proportion of patients who developed skeletal event (excluding vertebral fractures) was lower in the pamidronate group -34% v 52%. Adverse events of pamidronate: hypocalcaemia (< 2 mmol/l) observed in 7 patients occurred in particular patients beginning from 2 to 7 days after drug administration. In 2 patients hypocalcaemia that appeared in 24 hours after drug infusion was accompanied by blood pressure decrease; in one case systolic blood pressure dropped up to 60 mmHg, in the other one--to 90 mmHg. Muscular pain and fever up to 39 degrees C (transient and self-limiting "influenza like syndrom") occurred in 5 patients, in two patients after several hours and in three other--after some dozens of hours from drug administration. In one case hypertransaminasaemia was observed. CONCLUSIONS: In the first year of treatment monthly intravenous pamidronate administration as an adjunct to chemotherapy in patients with advanced multiple myeloma with osteolysis is an efficient approach in prevention and treatment of hyperacalcaemia, hypercalciuria and bone pain. It also shows some preventive effect on bone lesion occurrence.

Impaired skin microcirculation and blood rheology in patients with monoclonal gammapathy.

Hemorheological disturbances in patients with monoclonal gammapathies are widely known, but there is little information about microcirculation in these patients. The following study was performed to examine skin microcirculation and its relationship with blood rheology. We analysed both haematological and hemorheological parameters (blood and plasma viscosity, aggregation index and filterability of 1 ml of whole blood) and skin microcirculation in 46 patients with monoclonal gammapathy and 22 healthy controls. Microcirculation on dorsal aspect of the hand was examined with laser Doppler flowmeter. We measured resting flow and biological zero and maximal flow during postischemic hyperaemic reaction after one minute occlusion on the arm. The same parameters were estimated for CMBC (concentration of moving blood cells). Patients with monoclonal gammapathy are characterised by statistically higher whole blood and plasma viscosities and other hemorheological parameters and disturbed skin microcirculation expressed as statistically significant lower resting flux and impaired reaction for temporary occlusion.

Evaluation of the microcolumn technology for pretransfusion testing in multiple myeloma patients.

OBJECTIVE: Microcolumn tests are useful for serological investigations, although because of their high sensitivity, false-positive results might be expected, e.g. in hypergammaglobulinemia. The aim of this study was to evaluate these tests in multiple myeloma. METHODS: Pretransfusion testing was done in 80 patients with multiple myeloma using microcolumn and traditional tube tests. RESULTS: All sera were negative in microcolumn indirect antiglobulin test and enzyme test, positive in 58% of samples in the enzyme tube test. The microcolumn direct antiglobulin test was positive in about 40% of samples but never in the tube direct antiglobulin test. This was not due to the presence of autoantibodies but to nonspecific binding of immunoglobulins related to their concentration in sera. CONCLUSION: Microcolumn tests appeared to be useful for pretransfusion testing in multiple myeloma in spite of positive autocontrols.

[Use of human anti-Pseudomonas immunoglobulins in treatment of children with burns]. / Zastosowanie ludzkiej immunoglobuliny przeciwko Pseudomonas w leczeniu oparzonych dzieci.

This studies included 15 children with burns involving 10-55% of the whole body surface, treated at the two surgical departments in Poland. All patients have been given 0.5 mL of a 15% solution of anti-Pseudomonas immunoglobulin in a deep i.m. injections for 3 consecutive days. Immunoglobulin has generally been well tolerated, except short fever attacks. Human anti-Pseudomonas immunoglobulin prepared in the institute of Haematology and Transfusion in Warsaw prevented infections with P. aeruginosa in 12 burned children. There have been no cases of bacteremia produced by P. aeruginosa in 15 treated children with burns. The obtained results indicate efficacy of such therapy in burned children.

Effect of recombinant human granulocyte colony stimulating factor on granulocytopenia induced by cytotoxic chemotherapy in patients with multiple myeloma.

15 multiple myeloma patients with severe granulocytopenia after chemotherapy were treated with recombinant human granulocyte colony stimulating factor (Neupogen; Roche). Granulocyte colony stimulating factor (G-CSF) was given s.c. usually in a dose of 5 micrograms/kg for 5-14 (median:8) days. In all cases the increase in ANC was observed; one day after completing therapy the ANC ranged from 2.3 to 19.7 (mean: 10.3) x 10(9)/l. In 3 cases the ANC peak appeared during first (2-4) days of treatment, in one- on 14-th day after 10-day unsuccesful treatment. Generally, ANCs rapidly decreased after discontinuation of treatment to the values observed prior to the last chemotherapy. Both adverse events present in 9 patients and changes in monitored blood biochemistry components were moderate and reversible. In 3 cases symptoms of myeloma progression occurred. The study showed that G-CSF is an efficient and well tolerated drug, but also demonstrated its short-term action.

[Evaluation of the usefulness of measuring the serum and urine levels of light chain immunoglobulins in multiple myeloma and Waldenström's macroglobulinemia]. / Ocena przydatnosci oznaczania stezenia lekkich lancuchów immunoglobulinowych w surowicy krwi i moczu chorych na szpiczaka plazmocytowego i makroglobulinemie Waldenströma.

Quantitative determinations were carried out of light immunoglobulin chains by the method of ring precipitation in the serum and urine of 117 patients with plasmocytic myeloma and 16 with Waldenström's macroglobulinemia. The method was found useful for the identification of the light chain of the monoclonal proteins of IgG, and IgD classes. In the case of the lambda-type light chain disease the method is helpful in the identification of the M-component of the serum. Quantitative determination of light chains of immunoglobulins by ring precipitation is not essentially superior to other immunological and electrophoretic methods of protein analysis in monitoring treatment of cases of this myeloma.

[Therapeutic plasmapheresis in patients with multiple myeloma]. / Plazmafereza lecznicza u chorych na szpiczaka plazmocytowego.

The effectiveness of therapeutic plasmaphereses with antineoplastic chemotherapy was evaluated in 25 cases of plasmocytic myeloma in stage III of progression of the proliferative process. The indication to plasmapheresis was hypergelification of serum with clinical symptoms of central nervous system disturbances, renal failure in various stages of progression, intensification of coronary symptoms, bleeding tendency. Good effects with reduced level of total protein and monoclonal protein in serum by 30-80% with regression of clinical symptoms caused by serum hypergelification were obtained in 11 cases. In the remaining patients clinical improvement of varying degree was noted when the level of total and monoclonal protein in the serum fell by 10-29%.

[Chemotherapy and immunomodulating treatment of patients with multiple myeloma]. / Chemioterapia i leczenie immunomodulacyjne u chorych na szpiczaka plazmocytowego.

Prospective studies were carried out on the effectiveness of various treatment methods in 208 patients with plasmocytic myeloma. In 102 patients induction therapy was based exclusively on melphalan, in 106 cases polychemotherapy was used including vincristine, melphalan, carmustine, cyclophosphamide and prednisone. The differences in the per cent of patients with good response to treatment and in the survival time after treatment beginning were statistically not significant between these groups which suggests that polychemotherapy begun from the diagnosis of the disease is justified in patients with large mass of the neoplasm and poor prognostic factors. In 45 patients chemotherapy was supported by administration of immunomodulatory agents, including calf thymus extract in 25 cases, levamisole in 18 and interferon in 2. It was observed that maintenance of remission with chemotherapy and with immunomodulatory agents calf thymus extract or levamisole prolonged the survival of the patients. In cases of leucopenia the use of calf thymus extract facilitated chemotherapy by stimulation of myelopoiesis.

[Clinical and laboratory analysis of the cases of multiple myeloma with over 5-year survival time from the beginning of the antineoplastic treatment]. / Analiza kliniczna i laboratoryjna przypadków szpiczaka plazmocytowego z czasem przezycia powyzej 5 lat od rozpoczecia leczenia przeciwnowotworowego.

Out of 436 studied patients with plasmocytic myeloma 67 (15.0%) survived over 5 years from the beginning of antineoplastic treatment, and 18 survived over 10 years from the first symptom of the proliferative process. The patients with long survival were younger at the time of diagnosis than the whole studied group and had normal creatinine and calcium levels in the serum. Nearly half these patients had I or II stage of clinical progression and IgG monoclonal protein. Treatment with melphalan only was given to 17 patients, 33 were treated with melphalan, followed by vincristine, cyclophosphamide, BCNU, prednisone and doxorubicin. Polychemotherapy was given from the time of the diagnosis to 13 patients, and 4 received radiotherapy or 60Co irradiation besides chemotherapy. In 81% of the analysed cases a good response was obtained. Thirteen patients are alive. In 5 cases myeloid leukaemia, in 1 case bronchogenic carcinoma and in 1 case liver carcinoma were the causes of death.

[IgM monoclonal gammopathy in plasmacytic neoplasms]. / Gammapatia monoklonalna IgM w nowotworach plazmocytowych.

In 331 patients with the diagnosis of multiple myeloma in 4 cases proliferation of plasma cells was associated with synthesis of a monoclonal IgM. In 3 of these cases coexistence was noted of features typical of multiple myeloma and Waldenström's macroglobulinaemia. In the clinical picture in two of these cases sings of blood hyperviscosity prevailed. These patients showed impairment of plasma clotting factors. The count of T and B cells in blood and the adherence and phagocytic activity of monocytes were not abnormal. The ultrastructural pattern of plasma cells in bone marrow was similar to that observed in classical cases of IgG or IgA multiple myeloma. In one case of lymphoplasmocytic proliferation with leucocytosis over 100 x 10(9)/l immunoelectroscopic examination of bone marrow cells demonstrated a formidable accumulation of the heavy chain of mu immunoglobulin in the cytoplasm of lymphoplasmacytes. In the serum and urine no monoclonal protein was found. In this case compression of vertebral bodies Th7 and L2 occurred.

[Clinical usefulness of serum beta2-microglobulin determination in patients with multiple myeloma]. / Ocena przydatnosci klinicznej oznaczania stezenia beta 2-mikroglobuliny w surowicy krwi chorych na szpiczaka plazmacytowego.

Serum concentrations of beta 2-microglobulin (beta 2M) were determined in 73 patients with various forms of multiple myeloma and in various phases of the proliferative process. These determinations showed that beta 2M may be a useful indicator of changes in tumour mass and proliferation activity, and also an important prognostic factor. In patients with active proliferation the serum beta 2M concentration was significantly higher than in the group with stable proliferative process, and particularly in remission. A correlation was found between the serum concentration of monoclonal protein and beta 2M concentration. In the group with the secretory form of myeloma significant differences were showed in the length of survival which depended on beta 2M concentration in serum. The median survival of patients with beta 2M concentration in serum below 5.0 mg/l was 52 months and that in those with this concentration above 8.0 mg/l was 24 months.

HIV antibody status and immunological abnormalities in Polish haemophiliacs.

Sera of 520 multitransfused haemophiliacs were examined for antibody to HIV; 447 patients had haemophilia A and 73 had haemophilia B. In 382 patients with haemophilia A and in 62 with haemophilia B solely Polish-made blood products were used for replacement therapy. The remaining haemophiliacs had also received imported clotting factor concentrates prior to the investigation. Only 8 patients (haemophilia A - 7, haemophilia B - 1) developed anti-HIV and all of them had been exposed to commercial concentrates. The analysis of T-cell subsets demonstrated an inverted T4/T8 ratio (less than 1.0) in 7 (30%) of the 23 haemophiliacs treated solely with domestic cryoprecipitate and in 3 (37%) of the 8 seropositive recipients of commercial concentrates. The most frequent alteration in both subgroups was a reduced ratio with either normal absolute numbers or an increase in T8 cells. Increased serum IgG levels were found in 82% of the users of cryoprecipitate and in 75% of the seropositive patients. Serum beta-2-microglobulin level was elevated in 69 and 62% of each subgroup, respectively. The observed immunological abnormalities, at least in the cryoprecipitate treated subgroup, may be causally related to factors other than HIV infection.