Multiple myeloma progression

A. T., and Pazdur, R. Velcade U.S. FDA approval forthe treatment of multiple myeloma progressing on prior therapy. Oncologist 2003, 8, 508-13. 

Newly diagnosed, asymptomatic patients may be observed without treatment. This asymptomatic period may last for months to a couple years. All patients with multiple myeloma will become symptomatic, and once this occurs, treatment is required. First-line treatment may be one of several therapies, including VAD, thalidomide plus steroids, and autologous transplant. Nearly all patients will progress at some point, and second-line therapy usually will include bortezomib. All patients who have bone lesions should receive monthly bis-phosphonates, with the hope of reducing pain and fractures. 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

MA, U.S.A.). The recent approval of Velcade has been based on Phase II data in which Velcade or Velcade and desamethasone gave a response rate in patients with multiple myeloma who had received at least two prior therapies (progressing on the most recent one). The response rate was 22.7% (95% Cl = 21 to 35%). A follow-up study for full approval is ongoing and appears promising. ... 

Enrolment is ongoing for PXDIOI, for which another Phase I study in hematological mahgnancies is in progress, exploring the possibiUty for oral dosing. A Phase 11 study in multiple myeloma is also currently ongoing. 

Unless M protein concentrations exceed 60 g/L, patients with multiple myeloma do not develop hyperviscosity syndrome. Despite the presence of plasma cells in bone marrow exceeding 10% and the presence of M protein exceeding 25 g/L, nearly 15% of patients with multiple myeloma are asymptomatic. However, asymptomatic patients presenting with IgA myeloma protein and M protein concentrations exceeding 30 g/L and Bence Jones-protein excretion in excess of 50 mg/day in presence of a lytic bone lesion can progress to multiple myeloma earlier than other, asymptomatic patients (Wl). 

K35. Kyle, R. A., Monoclonal gammopathy of undetermined significance and solitary plasmacytoma. Implications for progression to overt multiple myeloma. Hematol. Oncol. Clin. North Am. 11,... 

Boyd, K., Morgan, G., Davies, F., Wu, P., Gregory, W., Bell, S.E., Szubert, A., Navarro-Coy, N., Drayson, M., Owen, R.G., Feyler, S., Ashcroft, J., et al. (2011). Does zoledronic acid (ZOL) reduce skeletal-related events (SREs) and improve progression-free survival (PFS) in patients (Pts) with multiple myeloma (MM) with or without bone disease MRC myeloma IX study results J Clin Oncol 29(Suppl.) abstr 8010, 506pp. 

Recombinant human erythropoietin (epoetin and darbepoetin) provides effective therapy with a very favorable risk-benefit ratio in hemodialysis patients with end-stage chronic renal insufficiency, and in patients with progressive renal insufficiency who are not yet being dialysed (1). It improves cognitive function and the quality of life of patients with chronic uremia (2-5) and is very effective in children with chronic renal graft rejection and anemia (6). It also offers new opportunities for treating anemia in non-uremic patients. In patients with chemotherapy-induced anemia, epoetin increases hemoglobin concentration, reduces transfusion requirements, and improves quality of life (7,8). The response rate to epoetin in patients with multiple myeloma and anemia, which is 55-85% (9), increases when GM-CSF or G-CSF is... 

The safety of growth factors in patients with myeloma is also of concern, as they can stimulate the proliferation of myeloma cells through IL-6 expression. Only isolated case reports, including accounts of the mobilization of clonal myeloma cells into the peripheral circulation, rapid progression of a multiple myeloma, or the new onset of a monoclonal gammopathy, directly or indirectly support the view that caution should be exercised in patients with multiple myeloma (SED-13,1118) (92). 

Of 50 patients with multiple myeloma, 14 developed a deep venous thrombosis after taking thalidomide 400 mg/day, compared with two of 50 patients who did not take it (24) All the episodes occurred during the first 3 cycles of therapy. One patient taking thalidomide had a pulmonary embolus. Most of the patients continued to take thalidomide with the addition of low molecular weight heparin followed by warfarin and there was no progression of deep venous thrombosis. 

Of 44 patients who took thalidomide for refractory multiple myeloma, 10 developed grade 3 or 4 neutropenia, usually in the first or second week of treatment (70). There was concomitant progression of thrombocytopenia in five cases and bone marrow hypoplasia without a significant increase in myeloma cell numbers in five. Neutropenia was more common in patients with low neutrophil and platelet counts, anemia, or a high percentage of plasma cells in the bone marrow before thalidomide treatment. 

Abildgaard N, Brixen K, Kristensen JE, Eriksen EF, Nielsen JL, Heickendorff L. Comparison of five bio-chemical markers of bone resorption in multiple myeloma elevated pre-treatment levels of S-ICTP and U-Ntx are predictive of early progression of the bone disease during standard chemotherapy. Br J Hematoi 2003 120 235-42. 

Stewart AK, Vescio R, Schiller G, et al. Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma results of a multicenter randomized controlled trial. J Clin Oncol 2001 19 3771-3779. 

In a study intravenous zoledronic acid 4 mg every 4 weeks with alternate day prednisolone was given with or without thalidomide 200 mg daily for up to 1 year. The zoledronic acid pharmacokinetics were not affected by thalidomide and based on renal function no clinically adverse interaction occurred during concurrent use. The subjects in this study were patients with multiple myeloma with no disease progression 6 weeks after autologous stem-cell transplantation and conditioning with melphalan. ... 

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