Following the initial results from the University of Arkansas trial, numerous studies from around the world have confirmed the efficacy of thalidomide in relapsed, refractory myeloma. In these studies, at least 25-35% of patients with advanced myeloma obtained a significant response to thalidomide therapy. Many of these patients had failed conventional chemotherapy and stem cell transplantation, and had few, if any, options available. In fact, thalidomide is the first drug to show clinically meaningful single agent activity in myeloma in over two decades. Based on this data, thalidomide is now considered an effective treatment for relapsed myeloma. However, the FDA approval for the use of thalidomide in myeloma is pending.
Given the effectiveness of thalidomide as a single agent, there is significant interest in studying thalidomide as initial therapy for myeloma. Preliminary studies from the Mayo Clinic and the M. D. Anderson Cancer Center show that over 70% of patients with newly diagnosed active myeloma respond to the combination of thalidomide and dexamethasone. Since both drugs are administered orally, this combination is more convenient than more aggressive intravenous chemotherapy regimes such as VAD (vincristine, adriamycin, dexamethasone). These are very encouraging results and if confirmed may change the approach to the treatment of newly diagnosed myeloma. However, at present these results should be considered investigational, and need further study.
Additional studies show that thalidomide alone, as a single agent, may be effective in asymptomatic smoldering (indolent, early stage) myeloma. Responses are seen in approximately 40% of patients. The goal of thalidomide therapy early stage myeloma is to prolong the time to progression to active myeloma. The initial results are encouraging, but further studies with long term follow up are needed to determine if thalidomide can delay the time to progression and the need for chemotherapy or stem cell transplantation in myeloma. Until such studies are completed, thalidomide therapy in early stage myeloma must be considered investigational.
Studies have also been initiated to determine if thalidomide can be safely combined with other effective agents for the treatment of relapsed myeloma. Early results show that this approach is feasible. There is now data that some patients who fail thalidomide and dexamethasone separately, may respond to the combination of the two agents. This suggests that the combination of the two drugs may work better than either drug alone.
The initial study of thalidomide in myeloma was initiated because of its ability to inhibit the formation of new blood vessels (angiogenesis). Angiogenesis occurs normally during fetal growth, wound healing and in the uterus during the menstrual cycle, but is also critical for the proliferation and spread of cancers, including myeloma. However, it is still not clear if the effectiveness of thalidomide in myeloma is related to its anti-angiogenic properties. Thalidomide has other effects that may play a role, including a direct effect on cancer cells, changes in the environment in which the myeloma cells grow, and strengthening of the immune system.
Thalidomide is taken orally as a pill, usually at a dose of 200mg/day. Although many physicians attempt to increase the dose of thalidomide to as high as 800mg/day, most patients cannot tolerate doses higher than 400mg/day. The best dosing regimen is still not clear. Excellent, sustained responses have been observed with doses as low as 50mg/day. In most cases, patients will start to show signs of a response within 4-8 weeks.
The main limitation of thalidomide is the risk of teratogenicity and side effects such as drowsiness, fatigue, rash and neuropathy. Although side effects are usually mild, in the elderly population these can be troublesome. To overcome this, analogues of thalidomide (IMiDS; Celgene Corporation) are being developed and tested in clinical trials. These analogues have the promise of improved efficacy with far fewer side effects. One such analogue is CC-5013. In laboratory studies, CC-5013 has significantly more potent effects against human myeloma cells and less side effects than thalidomide. Based on this, a phase I study in patients with advanced myeloma is ongoing at the Dana Farber Cancer Institute. Early results in the first 15 patients treated indicate promising activity. Unlike thalidomide, side effects such as sleepiness, constipation or nerve damage have not been reported so far. A similar trial of CC-5013 is also ongoing at the University of Arkansas for Medical Sciences. A larger multi-institutional study of CC-5013 in relapsed myeloma is expected to open by the end of this year in the United States.
The success of thalidomide in the treatment of myeloma has led to significant interest in the testing of new agents in the disease. At present several novel drugs and strategies are being actively tested in clinical trials. These include anti-angiogenic agents (such as 2 methoxy estradiol and SU-5416), proteasome inhibitors (LDP-341), farnesyl transferase inhibitors, non-myeloablative allogenic transplantation, dendritic cell vaccination and immunotherapy strategies. These developments offer significant momentum for investigators hope for patients and in the war against myeloma.