High-dose therapy for multiple myeloma is effective in increasing median survival, but is severely toxic, limiting its use. In addition, all patients eventually relapse and suffer disease progression. This has led to a market ripe for the entry of low-toxicity therapies that will increase response rates and maintain remission. Datamonitor examines the future entrants to this field and their potential.
In Multiple Myeloma with ASH Highlights,
Datamonitor provides analysis of recent advances and topical issues in the treatment of multiple myeloma and investigates the multiple myeloma drug pipeline in the light of the mass of new clinical data released at the annual meeting of the American Society of Hematology (ASH) in early December, 2002.
Multiple myeloma is the uncontrolled proliferation of a type of white blood cell called "plasma cells." The malignant cells, known as myeloma cells, tend to aggregate in the bone marrow and the hard outer layers of the bone. This aggregation behavior can lead to a number of side effects, including pain, loss of bone mass leading to fracture and the metabolic disorder, hypercalcemia.
The re-organization of the pharmaceutical industry over the last decade has led to greater interest in multiple myeloma. Smaller biotechnology firms have become interested in niche cancers such as multiple myeloma because these indications offer smaller, less-expensive trials, quicker approval schemes and potentially, orphan drug status.
From the approval stage, revenue can be used to test the drug in other more profitable cancer indications. In this way, smaller firms can gain access to highly profitable and competitive markets by taking smaller steps towards approval and marketing.
Multiple myeloma is perhaps one of the most profitable niche tumor indications for new agents because of the high volume usage of drug therapies. Myeloma by its very nature is a disseminated tumor, present in a number of bones and with malignant cells in the blood. This eliminates surgery and radiotherapy as effective treatment options, leaving only drug therapy as a systemic treatment. Myeloma patients can survive for many years if they achieve a stable remission and undergo a number of lines of drug therapy, resulting in a large prevalent population receiving drug therapy as the primary therapeutic intervention.
The need for low-toxicity
As such, new drugs reaching the market are likely to reach high volume usage quickly, especially if they represent an improvement in toxicity, oral administration or a novel mechanism of action, such as Celgene's
The standard drug regimens used in the treatment of multiple myeloma have not changed for twenty years. These regimens are associated with severe toxicities, leaving opportunities in the market for low-toxicity drug regimens.
The need in the multiple myeloma market for a convenient, low-toxicity approach is large. Three molecules currently in phase III development could potentially fill this void. Celgene's Thalomid, Aventis's
Genasense and Millennium Pharmaceuticals'
Velcade represent a new hope for physicians and patients because of their novel mode of action and because they are likely to be used heavily in unresponsive patients, in those relapsed following MP and VAD regimens and in patients unable to withstand the highly toxic traditional regimens.
Thalomid looks favorite to take the lead in this market and is likely to rapidly achieve gold standard status for the treatment of multiple myeloma. However, because all patients relapse after remission, more low-toxicity regimens are needed in patients with Thalomid-resistant disease. Though later to market and used second-line to Thalomid, these additional new agents will see relatively quick uptake because they will benefit from Thalomid having previously broken the mold of standard approaches to multiple myeloma.
Velcade as an option
Genesense, originally developed by Genta, now has the backing of a powerful marketer after a joint development and commercialization agreement was signed with Aventis in mid 2002. However, without efficacy data for multiple myeloma, it is difficult to tell whether this will be one of the indications in which the drug will enjoy success.
Pre-clinical studies of Velcade, Millennium Pharmaceutical's leading pipeline product, in human multiple myeloma cell lines have indicated the drug inhibits replication and induces apoptosis. In a mouse model of multiple myeloma, Velcade was found to significantly reduce tumor size compared to a control group. Survival was also significantly improved in treated mice.
At the December 2002 meeting of the American Society of Hematology Millennium announced the final results from the phase II SUMMIT trial of Velcade in patients with relapsed and refractory multiple myeloma. 194 of the original 202 patients were evaluable. The overall response rate was 35%, with 4% of patients achieving full response with no trace of M-proteins in the blood. A further 24% of patients achieved disease stabilization with Velcade. The median survival of patients was 16.4 months.
The pivotal phase III trial for Velcade in refractory multiple myeloma, now named APEX, will compare high-dose dexamethasone in the control arm to Velcade. The primary endpoint is time-to-disease progression and secondary endpoints include measurements of clinical benefit, quality of life, survival and response rate.
Let battle begin
Velcade is the only proteasome inhibitor to enter trials for the treatment of cancer, and as such represents a novel therapy. Available data suggest the drug has significant activity in refractory patients. On this criterion alone, Velcade is likely to gain approval if it can match the efficacy of high-dose dexamethasone.
The launch of Thalomid, Genasense and Velcade are eagerly anticipated by the prescribing community as they appear to offer options for relapsed and low performance status patients. Both Aventis and Millennium Pharmaceuticals could benefit from physicians looking for alternatives to Thalomid-based regimens providing they aggressively market their drugs as alternatives.
However, a key unmet need within the multiple myeloma market still remains that for a reliable maintenance therapy. It is common within myeloid malignancies to induce remission using an aggressive chemotherapy regimen and then to use a maintenance therapy.
The maintenance therapy is often a low-dose cytotoxic or a cytokine used with the aim of prolonging the duration of remission. At present, no product is commonly used in this role, although investigations using a number of cytokines have produced evidence of activity.
If you found this week's Expert View useful, you may be interested in Datamonitor's reports, all available from http://www.datamonitor.com/healthcare
· Multiple Myeloma: Update with ASH Highlights - Increasing the Therapeutic Option priced $1,500
· Drugs of Tomorrow: Cancer Overview - The Synergistic Advance - Innovatives Complement Traditional Chemotherapies priced $6,100
· Angiogenesis Inhibitors: An Update - Can Iressa and Thalomid Rejuvenate the Angiogenesis Inhibitor Class? priced $1,500
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