New Directions in the Management of Multiple Myeloma: An Interview With William S. Dalton, MD, PhD
Disclosures
[This is another piece from Medscape's reporting from ASH. What I think is interesting is that Trisenox evidently has caught the eye of Dr. Dalton. Now we just need those patents being granted].
Sally Church, PhD
Editor's note: Novel therapeutic options for patients with multiple myeloma continue to improve the overall survival of patients as researchers examine new therapies and explore the use of combination regimens. In an interview with Medscape, Dr. William S. Dalton, from the Moffitt Cancer Center in Tampa, Florida, discussed some of the new data presented at the American Society of Hematology (ASH) on the management of multiple myeloma and offered some insight into how some of these ideas might affect future trials and patient outcomes.
Medscape: Survival in multiple myeloma has gradually been improving over the last few years. What new developments are happening that give you reason to hope for the future?
Dr. Dalton: Yes, I believe you are right that survival is largely improving; probably the most important factor is the use of high-dose therapy in stem-cell rescue. That's been proven over and over again by a number of studies, at least in a subset of patients. Nevertheless, it does remain an incurable disease, and new therapies are needed. Melphalan, introduced in the late 1960s, has remained the major drug, especially in combination with prednisolone, and is still used in high-dose therapy.
It's exciting here at ASH because we are actually at a time now where more drugs are being used for multiple myeloma than ever before. These new therapies being developed are more targeted and include thalidomide, bortezomib, IMiD3 (CC-5013), and arsenic trioxide; we hope that they will improve survival further in the future.
Medscape: Would combining therapies potentially make a difference to improving efficacy and ultimately, survival, in overcoming clinical drug resistance?
Dr. Dalton: Yes, I think it is unlikely that any one particular drug will be a "home run," so to speak. Each of these new drugs that is more target-based clearly is adding benefit, but by themselves, these drugs are unlikely to have an impact on the disease and improve overall survival. What are exciting are the combinations, not only of novel therapies, but also combinations with cytotoxic agents such as melphalan or doxorubicin. There are some interesting papers here by Dr. Berenson's group and others on melphalan, arsenic trioxide, and thalidomide (MAT) or melphalan, arsenic trioxide, and ascorbic acid (MAC) in combination that look promising.[1-3]
Medscape: What new strategies are being considered to overcome clinical drug resistance in multiple myeloma?
Dr. Dalton: I think what we're seeing is a real shift away from using cytotoxics in patients with newly diagnosed multiple myeloma. Again, the classic approach has been to use either melphalan and prednisolone or doxorubicin and dexamethasone, for example, and then to use either combination as induction therapy prior to high-dose therapy in autologous stem-cell rescue. Now, there is a shift to using therapies such as thalidomide plus dexamethasone,[4] which will spare the bone marrow, perhaps improve stem-cell selection, and allow the patient to tolerate the high-dose therapy even better. This might improve the outcomes with high-dose therapy because not using cytotoxics initially may delay the onset of clinical drug resistance. The use of the newer agents earlier in diagnosis might be of value in preventing this. There is also the possibility that targeting the bone marrow microenvironment might also delay the onset of acquired drug resistance.
Medscape: Were there any findings at this meeting that particularly interested you?
Dr. Dalton: The discovery of certain targets appears to have a lot of potential. For example, fibroblast growth factor receptor 3 is very promising, and certainly would be an excellent example of a new target-based therapy approach if agents could be developed for that. The same is true for insulin-like growth factor receptors, so targeting the receptors would be a logical way to go for multiple myeloma in the future.[5-7] There is increasing evidence that there are receptors that are overexpressed or constitutively active in multiple myeloma, which would be a logical approach. We are seeing more evidence that there are receptors that are predominantly signaling in multiple myeloma,[8] so focusing on them and developing methods of predicting who will relapse earlier may be of benefit in designing new target-based therapies for the future.
Disclosures: Dr. Dalton has disclosed that he has received grant support from Millennium Pharmaceuticals for preclinical research.
References
1. Chanan-Khan AA, Miller K, Sirinivasan S, et al. Combination of melphalan (M), ascorbic acid (A) and trisenox (T) (MAT) as salvage therapy for patients (pts) with relapsed/refractory multiple myeloma (MM). Blood. 2003;102:389b. Abstract 5284.
2. Yang HK, Swift R, Sadler K, et al. A phase I/II trial of Velcade(TM) and melphalan combination therapy (Vc+M) for patients with relapsed or refractory multiple myeloma (MM). Blood. 2003;102:235a. Abstract 826.
3. Borad M, Swift RA, Sadler K, Yang H, Berenson JR. Melphalan, arsenic trioxide and ascorbic acid (MAC) is effective in the treatment of refractory and relapsed multiple myeloma (MM). Blood. 2003;102:235a. Abstract 827.
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