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Every which way

Multiple myeloma is a malignant B-cell cancer that is characterised by diffuse osteolytic bone lesions, found usually in the pelvis, spine, ribs, and skull. New therapies attack the condition from several different angles.

Test laboratoryMultiple myeloma is a malignant B-cell cancer that is characterised by diffuse osteolytic bone lesions, found usually in the pelvis, spine, ribs, and skull, and is the second most common haematological cancer after non-Hodgkin's lymphoma.

Approximately four to five new cases of multiple myeloma are expected to be diagnosed per 100,000 persons per year, which translates into approximately 15,000 new cases in the US in 2004. Primarily, treatment comprises glucocorticoids such as prednisone, and alkylating agents such as melphalan, yet although these treatments improve patient survival (five-year survival rate is 29 per cent), the disease remains incurable.

Research into the biology of multiple myeloma has revealed several molecular mechanisms that hold promise as therapeutic targets. Intracellular regulatory proteins and the interactions between diseased cells and the bone marrow microenvironment play an important role in the growth, survival, drug resistance and malignant progression of multiple myeloma cells.

It is these targets that form the foci of new treatment strategies for multiple myeloma. Clinical trials with new drugs have been promising and suggest that the way forward should be to target MM cells and the microenvironment that sustains them.

Thalidomide & analogues
The antiangiogenic mechanisms of thalidomide and the relationship between bone marrow angiogenesis and the development of the disease were the rationale for developing the drug for MM. However, there is also evidence to suggest that thalidomide operates in MM by other modes of action, such as inducing growth arrest and apoptosis in MM cells. Clinical trials of thalidomide monotherapy have shown the agent to be capable of achieving disease stabilisation and reducing tumour burden in substantial numbers of patients.

However, the best results have been seen where the agent was used in combination with dexamethasone, where it acts synergistically. Among 46 patients with refractory multiple myeloma, thalidomide + dexamethasone produced a response rate of 40 per cent and 31 per cent for patients with primary refractory disease and refractory relapse, respectively. This contrasted with a response rate of 32 per cent and 18 per cent for thalidomide alone.

Thalidomide is currently awaiting approval in the US, and its sponsor Celgene is hoping that the results of the completed E1A100 trial (in early myeloma patients) could provide sufficient support for accelerated approval.

Celgene is also developing lenalidomide (REVLIMID) an immunomodulatory drug (IMiD) and a structural analogue of thalidomide, which is in phase III trials in patients for refractory multiple myeloma.

A phase II trial of lenalidomide in relapsed or refractory multiple myeloma patients has revealed that among the 46 evaluable patients with progressive disease, some 39 (85 per cent) experienced a reduction or stabilisation in their paraprotein levels (a measure of tumour burden).

Importantly, five of seven patients who experienced progressive disease on lenalidomide monotherapy subsequently experienced a reduction or stabilisation of paraprotein levels after lenalidomide + dexamethasone combination therapy.

Thus, some 44 of 46 evaluable patients (96 per cent) experienced a reduction or stabilisation of paraprotein levels after either lenalidomide monotherapy or lenalidomide + dexamethasone combination therapy. If results of these pivotal trials prove positive, lenalidomide could gain US approval sometime during 2005.

Bortezomib
Millennium Pharmaceutical's bortezomib (VELCADE) was the prototype of the proteasome inhibitors and was the first proteasome inhibitor to enter clinical trials for cancer. The drug comes from the boronate class of inhibitors, and its molecular target is thought to be the 26S proteosome; a protein complex that regulates turnover of a vast number of intracellular proteins.

Bortezomib blocks the degradation of the inhibitory protein IkB which, when complexed to NF-kB, stops the latter protein from moving to the nucleus and activating antiapoptotic genes that are upregulated in MM.

Results of the phase II SUMMIT trial in 193 evaluable patients showed that 4 per cent of patients experienced complete remissions on bortezomib treatment, with an additional 6 per cent experiencing a 100 per cent reduction in M-protein. The overall response rate was 35 per cent, with 59 per cent of patients experiencing a response, or achieving stable disease.

Bortezomib has been launched by Millennium in the UK and the US and is registered throughout the EU for patients who have experienced disease progression after receiving at least two prior therapies.

Other agents
Arsenic trioxide has apoptotic activity in MM cells and appears to operate by two distinct mechanisms, depending on the P53 status in the MM cell. Preliminary results of phase II studies revealed that a combination regimen known as MAC (melphalan, arsenic trioxide + vitamin C) had a response rate of 54 per cent in 7/13 patients then enrolled in a European trial.

Another target for a class of inhibitory compounds being developed for MM is farnesyl transferase; a catalyst for the transfer of a farnesyl group to the cysteine terminal amino acid of substrate proteins, thereby activating them. By inhibiting the post translational farnesylation of the RAS protein (mutated in 30 to 40 per cent of patients with MM) it is envisaged that downstream signalling pathways favouring survival will be inactivated.

Jansen Pharmaceutica's tipifarnib, which is in phase II trials in the US, achieved disease stabilisation in 64 per cent of patients with relapsed MM.

Other agents with potential in MM include histone deacetylase inhibitors (Anton Pharma has suberanilohydroxamic acid in a phase I trial in the US) and the bisphosphonates, which are widely recognised for their antiosteoclastic activity and are known to reduce skeletal events by 50 per cent in advanced MM.

The Authors
Glenn Whiteside and Anita Brummer, Adis

3rd October 1969

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