Abstracts of Annual Education Meeting on 25-Nov-2002
Thalidomide and the ImiDs
Steve Schey, Senior Lecturer and Honorary Consultant Haematologist, Guys Hospital, London
The first case of myeloma was reported in the medical literature in 1844. She was admitted to St Thomas' Hospital in London where she was treated with orange peel infusions, rhubarb pills and morphine. However, it took over 100 years before the first effective chemotherapy drug became available and any impact was seen on the outcome of this disease. In the latter half of the last century, better supportive therapy and the availability of haemopoietic stem cell support allowed more intensive chemotherapy treatment with yet better survival.
As we enter the new millennium there has been an unprecedented increase in our knowledge of the basic biology of the disease and this has allowed the development of novel agents to treat myeloma which work through entirely different pathways from chemotherapy agents and therefore offers the opportunity to treat patients with resistant disease or to use these agents in combination to greater effect.
Thalidomide was the first of these novel agents to be found effective in myeloma when it was used in a group of heavily pre-treated patients, many of whom had already undergone 1 or 2 previous stem cell transplants and relapsed with their disease. Approximately a third of the patients responded showing that this agent was significantly better than any other chemotherapy drug given as a single agent.
The UK Myeloma Forum has also used thalidomide in the relapsed setting and found that most patients are able to tolerate a dose of 300 mgs daily by mouth, although some patients responded to as little as 100 mgs on alternate days. 49% of patients achieved a greater than 25% response rate with durable responses. The main side effects seen were pins and needles in the fingers (24%), drowsiness (15%) constipation (7%) and dry skin (6%). All of these side effects were minor and managed with simple medication and taking the drug at night. 11 patients had their medication stopped because of side effects.
A number of other studies have also confirmed the effectiveness of thalidomide in the relapsed setting and a randomised study is due to commence of thalidomide in combination with dexamethasone for patients presenting with previously untreated disease to evaluate its effect in this setting.
In an attempt to improve the effectiveness of thalidomide whilst reducing the side-effects of the drug, the Celgene Corporation examined a large number of modified molecules or analogues of thalidomide. These fell into 2 groups characterised by the activity they demonstrated on chemicals that normally are involved in the immune and inflammatory response and the cells of the immune system that recognise and destroy foreign and tumour cells.
Two compounds have now been used in patients with myeloma, namely Revimid (CC5013) and Actimid (CC4047). We have recently used Actimid in a phase I relapsed/refractory study designed to identify the optimal dose of the drug when given orally on a daily basis. The average age of the patients entered in to the study was 66 years. Patients had received a median of 3 previous courses of chemotherapy (range 1-6) and 21% had relapsed following a stem cell transplant and 29% had failed thalidomide. Five patients reported minimal skin changes (grade 1) and 3 grade I neuropathy, none of which required a change of dose and all of which resolved on continued treatment with Actimid. In addition, 8 patients reported gastro intestinal effects, namely diarrhoea, constipation and nausea, all of which were mild and settled spontaneously or with simple medication and did not necessitate any change in Actimid therapy.
Eight patients with responsive disease (5 = grade 3; 3 = grade 4), five with stable disease, ( 2= grade 3; 3 = grade 4), and one with progressive disease, (grade 3) developed neutropenia. All except 3 patients recovered spontaneously within 4 weeks of stopping drug without the need for cytokine therapy and there were no infectious complications. The 3 patients who failed to recover within 4 weeks were withdrawn from study, the others being allowed to recommence Actimid at a reduced dose. All the neutropenias occurred in the first 3 weeks of entering the study, bar one patient who developed neutropenia whilst taking 1 mg daily at 10 months post entry.
Four patients who developed neutropenia developed thrombocytopenia. One patient with progressive disease taking 5mgs daily of Actimid developed grade 3 thrombocytopenia. One patient on 2 mgs daily with unresponsive disease developed grade 4 neutropenia and grade 3 thrombocytopenia. A further two patients with responding disease, one taking 5 mgs developed grade 3 neutropenia and thrombocytopenia and one taking 10 mgs developed grade 4 neutropenia and grade 2 thrombocytopenia. Both were discontinued because of neutropenia but recommenced Actimid at reduced dose.
Although this study was not designed to evaluate quality of life it is of interest that patients expressed the opinion that they felt subjectively better on treatment ahead of any objective response in the paraprotein, with less systemic complaints than on entry to study. This we would speculate is due to the potent anti-TNF alpha activity of the drug that has been shown in vitro to be a feature of this class of compounds.
The response rates in this study were very encouraging. One patient had a complete response confirmed on bone marrow aspirate and trephine and 2 further patients had a very good response with a >95% reduction in paraprotein levels. 66% of patients had a greater than 25% reduction in paraprotein at a median of 4.5 months of treatment (range 1-14 months).
Dose limiting toxicity therefore occurred in this study at doses greater than 1mg given on a daily basis. Neutropenia was the main dose limiting toxicity occurring at 2-3 weeks but resolved spontaneously without the need for haemopoietic support. Other common side effects associated with thalidomide treatment were seen less frequently and were easily managed without the need to discontinue Actimid. The high response rate in this group of heavily pre-treated patients is very encouraging but further work needs to done to develop better treatment schedules and to elucidate the mechanisms whereby the myelotoxic effects of this agent are produced in the marrow.
Similar results have been reported in phase I/II studies of Revimid and it hoped that a phase III trial of the agent will begin in the United States and Europe during the next 3-6 months. A further phase I/II trial of Actimid is anticipated to develop a schedule for using this drug in the relapsed setting and to further evaluate the neutropenia. A phase III trial of thalidomide and dexamethasone versus dexamethasone and a placebo is planned for the last quarter of this year in de novo disease.
Many obstacles lie ahead of us before this disease can be declared curable but the development of these and other novel agents over the last few years has offered, for the first time in a generation, the opportunity to treat this condition in patients previously thought to be resistant or refractory to conventional treatment and may also provide strategies for improving outcome significantly by combining them with chemotherapy agents or other novel agents to overcome resistance and induce improved outcomes. We live in exciting times and have come along way from orange peel infusion and rhubarb pills but more work needs to be done.