[Gene expression of vascular endothelial growth factors and their receptors in different variants of the course of multiple myeloma].

AIM: To determine the significance of the angiogenic activity estimated from the gene expression of the vascular endothelial growth factors (VEGFs) VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFR1, VEGFRls, VEGFR2, and VEGFR3 in the mononuclear cell fraction of bone marrow (BM) aspirates with tumor plasma cells predominating in different variants of the course of multiple myeloma (MM). MATERIALS AND METHODS: The gene expression of VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFRI, VEGFRls, VEGFR2, and VEGFR3 was determined by reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: VEGF-A, VEGF-C, VEGF-D, as well as VEGFR1, VEGFRls, VEGFR2, and VEGFR3 were expressed showing different intensities in the mononuclear cell fraction of BM aspirates with a predominance of tumor plasma cells in the patients with MM, which allowed patient groups to be identified. In the group of high gene expression of VEGFs and their receptors, the number of clusters of plasma cells and vascular endothelium in the BM aspirates and the degree of osteolysis in the skeletal bones of patients with MM were significantly higher than those in the group of low or absent gene expression. The survival in the latter group was significantly higher. CONCLUSION: The investigation could provide an estimate of angiogenic processes in MM and establish their association with clinical manifestations and cytological characteristics.

[Effectiveness of bortezomib and bortezomib-containing programs for the treatment of recurrent and resistant multiple myeloma].

AIM: To evaluate the effectiveness of bortezomib and bortezomib-containing treatment programs in the therapy of resistant and recurrent multiple myeloma (MM) within a large unicenter study in real clinical practice conditions. SUBJECTS AND METHODS: The study enrolled 101 patients (48 men and 53 women aged 34 to 77 years, mean age 54 years) with resistant and recurrent MM. According to the types of paraprotein (PIg), the authors revealed the usual distribution: G, 60.7%; A, 23.8%; BJ, 13%; M, 1.15%; D, 1.15%. The PIg kappa/lambda light chain ratio was 1.7. The complicated course of the disease was noted in 50.4% of the patients. The patients were randomized into 4 treatment groups: V1--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of a 21-day cycle; V2--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 20 mg orally on day 2 of a 28-day cycle; V3--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days of a 42-day cycle; V4--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days, cyclophosphanum, 250 mg/m2 intravenously dropwise on days 1 to 7 of a 60-day cycle. An average of 6.5 induction treatment cycles was performed. RESULTS: Amongst the 27 patients receiving bortezomib therapy (V1), an objective response to therapy was obtained in 70.3%, including a complete response (CR) in 18.5%, a near-complete response (NCR) in 14.8%, and a partial response (PR) in 37%. When a combination of melphalan and bortezomib (VM; V2) was used, 22 patients achieved CR, NCR, and PR, which were equal to 9, 13, and 45.4%, respectively. In the group of 20 patients on the triple combination (VMP; V3), the amount of CR and PR was 90%. The use of the quadruple combination regimen (V4; VMCP) yielded an objective response (CR + NCR + PR) in 63.2% of the 32 patients, which did not virtually differ from other programs other than V3. However, the amount of CR +NCR (43.6%) was more than that in other groups. When all these programs were implemented, clinically significant myelotoxicity and grades 3 and 4 polyneuropathy were not seen. When the bortezomib-containing programs were applied, the median overall survival from the moment of diagnosis was 103 months. CONCLUSION: Bortezomib in the monotherapy and multidrug therapy for resistant and recurrent MM shows immediate and long-term benefits and a low toxicity.

[Characteristics of drug resistance of tumor plasmocytes in vitro in patients with multiple myeloma differently responsive to chemotherapy]. / Kharakteristika lekarstvennoi ustoichivosti opukholevykh plazmotsitov in vitro u bol'nykh mnozhestvennoi mielomoi s razlichnym otvetom na khimioterapiiu.

AIM: To determine sensitivity of tumor plasmocytes in vitro to cytostatic drugs (prednisolone, alkeran belustin, vincristine, rubomycin, doxorubicin, cytarabin, methotrexate, cysplatin, etoposide). MATERIAL AND METHODS: The sensitivity was measured with DISC method in 12 patients with multiple myeloma (MM) in two groups: resistant and responsive to induction polychemotherapy (PCT). RESULTS: The groups appeared significantly different by lowering of pathological paraprotein concentration (PIg): by 7.4 +/- 2.5% and 32.5 +/- 3.7%, respectively (p < 0.05). The resistance to the drugs was higher in the resistant patients than in the responders (0.7 +/- 0.28 versus 0.4 +/- 0.02, p < 0.05). PCT schemes of resistant patients contained 65.0 +/- 2.3% of ineffective drugs. In the responders the percentage was 35.7 +/- 5.3% (p < 0.05). CONCLUSION: The relationship exists between resistance of tumor plasmocytes to drugs in vitro and clinical findings.

[The extratumor mechanisms of osteolysis in multiple myeloma and the means for their correction]. / Vneopukholevye mekhanizmy osteoliza pri mnozhestvennoi mielome i puti ikh korrektsii.

In 70 patients with stage III multiple myeloma (MM) the authors studied spontaneous and lipopolysaccharide-induced production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by blood and bone marrow mononuclear cells, concentration of parathyroid hormone and vitamin D3 in the serum. Bone marrow density was measured at photon absorption (Gambro), in patients treated with osteoprotectors bonefos and oxidevit before and after therapy (3.5-6 month course). It is shown that in MM there is a pathogenetic association between production of osteotropic IL-1, IL-6 and bone demineralization. The cases with reduced concentration of Ca and P ions in the serum (4 and 5.7% of patients, respectively) and increased PTH concentration (7%) suggest the existence of new, extratumor mechanisms of osteolysis. It is found that biphosphonates are optimal osteoprotectors. Bonefos (chlodronat, Lieras, Finland) arrests osteolysis proved by a significant increase of bone marrow density and clinical effect.

[Production of interleukin-1 and interleukin-6 in a culture of mononuclear cells of peripheral blood and bone marrow in multiple myeloma]. / Produktsiia interleikina-1 i interleikina-6 v kul'ture mononuklearnykh kletok perifericheskoi krovi i kostnogo mozga pri mielomnoi bolezni.

Constitutive and lipopolysaccharide (LPS)--induced production of interleukin (IL)-1 and IL-6 have been investigated in peripheral blood (PB) and bone marrow (BM) of patients with multiple myeloma (MM) and PB of health donors. The level of these cytokines has been higher in MM in comparison with norm. Monocytes of PB of patients with MM have been more stimulated by LPS than those of health people. When adherent and nonadherent cells have been cultured apart, there not have not been any differences in constitutive IL-6 production between compared groups. The important role of cell-cell interactions in regulation of IL-6 production is proposed. High level of IL-6 in BM of patients with MM is conditioned by mutual stimulation of adherent and nonadherent cells.