An interview with Mohamad Hussein, M.D., Director of the Myeloma Research Program at the Cleveland Clinic Taussig Cancer Center in Cleveland, Ohio.
DOXIL® (pegylated liposomal doxorubicin) is an advanced form of doxorubicin. Unlike conventional doxorubicin therapy, Doxil is a liposomal formulation that is encapsulated in a thin fatty layer. The liposome is pegylated, which helps protect the drug from the immune system, resulting in the product circulating in the blood for a longer period of time. Although Doxil is commercially available, it is not currently specifically approved for myeloma. There are several ongoing trials to further delineate the use of Doxil in myeloma. More widespread use of Doxil will depend upon the trial results.
Myeloma Today: Are there new studies that highlight the use of Doxil in the management of multiple myeloma?
Dr. Hussein: Yes, there are several trials. There is, for example, the national multi-center trial, involving over 200 patients, comparing Doxil, Vincristine, and decadron (DVd) versus Vincristine, Adriamycin, and Dexamethasone (VAD). This study has completed accrual and towards the end of this year, or early next year, we should have the results available. At this stage, it looks promising.
MT: What advantages do you see, or hope to see, in DVd versus the standard VAD?
Dr. Hussein: Ease of use and reduced toxicity. The aspect that I am most interested to see is if the response and the durability are any different from VAD. The first DVd cycle is usually three hours. After that, it can be given over one and a half to two hours. And the steroids are only for 4 days, not 12 days as in the VAD protocol. If we can have a less toxic regimen that is easier to give on an outpatient basis, and patients' overall performance status can stay maintained, that would be a big deal.
MT: Do you see DVd replacing VAD as an induction for stem cell transplantation?
Dr. Hussein: I do. I think the reason for that is that it doesn't impact the normal cells of the bone marrow negatively, it's a quick outpatient regimen, and it does not have the steroid toxicity that occurs with VAD. Infection is therefore less of an issue. I think those are the things that make this regimen relatively easy. And if [doctors] are interested in preparing their patients for transplant, this is a regimen that can get them there without a whole lot of toxicity. That's my impression. I'm hoping that this multi-center trial confirms this information.
MT: How long does it take a myeloma patient on DVd to get into remission?
Dr. Hussein: On average, a response occurs by the second cycle. Patients tend to reach maximum response after 5 cycles. If they don't respond by cycle 2 or 3, they usually don't respond. But 5 cycles seems to be the magic number for maximum response.
MT: What place do you see for DVd in frontline therapy?
Dr. Hussein: I think it's going to be in combination with thalidomide or with Revimid. We recently completed a trial with DVd and thalidomide (DVd-T). We presented preliminary data in ASH, ASCO, and Salamanca. Hopefully, in the upcoming ASH meeting, we will present a more complete therapy data of over 100 patients. And I think this is where the combination (DVd) will be positioned – in combination with an immunomodulator.
MT: So, in myeloma, you see DVd fitting in with novel therapies?
Dr. Hussein: Absolutely. Unlike VAD, our preliminary results show that DVd does get rid of the abnormal blood vessels in the bone marrow. However, the duration of the responses were not positively impacted probably because we were not able to maintain the clearance of blood vessels. Novel therapies like Revimid and thalidomide don't get rid of the abnormal blood vessels but they maintain the status. So, if Doxil gets rid of the abnormal blood vessels and those other drugs maintain the status of it being gone, then I think you could make an impact on the disease overall. This is what I am hoping to be able to show with DVd-T. And we've started a DVd-Revimid trial.
MT: Does DVd have a place for relapse?
Dr. Hussein: Not by itself – the response has been disappointing, about 20% to 25%. But when you combine it with thalidomide, the response rate is a really impressive 75%, with 45% of those patients either CR (complete remission) or near CR. So, I would say that DVd-T definitely does have a place. Some people would say that because you can get responses with decadron- thalidomide only, why add Doxil and vincristine? Because I think that the quantity of the responses is better and the quality of the responses is definitely better. With decadron-thalidomide in relapse/refractory, you may get only 5% CR and few near CRs.
MT: What is the dosing in the DVd-T combination?
Dr. Hussein: We use doxorubicin (40 mg/m2), vincristine (2.0 mg IV), and oral or intravenous dexamethasone (40 mg/day x 4 days) every 4 weeks. We start thalidomide at 50 mg/day, increasing by 50 mg/day every week to the maximum tolerated dose not to exceed 400 mg/day. We also add amoxicillin (which we are now thinking is probably not necessary) and acyclovir to reduce infection; low-dose aspirin in an effort to reduce blood clotting problems and so far this has worked very well for us.
MT: How does a Doxil side effect such as the palmar-plantar erythrodysesthesia (PPE) syndrome – swelling and pain of the extremities – impact quality of life?
Dr. Hussein: The PPE is more of an education issue. When we first started using the regimen, 4 out of our first 9 patients had severe PPE. What we learned was that without patient education, patients were not careful in the first few days with touching, repetitive movement, and pressure areas. With education, our incidence of PPE is down to about 7%, and we've treated about 300 patients with the regimen without any particular prophylaxis other than the education.
MT: What about other side effects, such as anemia and neutropenia?
Dr. Hussein: That has not really been an issue for us. In over 200 patients, we have not had a patient admitted because of neutropenic fever. We have not seen any issues with thrombocytopenia requiring transfusion. We have not had to resort to any drastic measures that we tend to do with regular chemotherapy like VAD, for instance.
MT: What are the most frequently occurring side effects with DVd?
Dr. Hussein: With DVd regimen by itself, it's the drop in the white counts. I would say leukopenia, not neutropenia. The count drops but the patients are not necessarily neutropenic. That's pretty much it. PPE is about 7%, hair loss is less than 5%, nausea and vomiting is less than 5%, transfusions related to platelets is zero, and infections requiring IV antibiotics has not been an issue. With this being said, we aggressively follow patients and teach them to avoid infectious problems. For instance, if patients qualify, we use intravenous immunoglobulins, and early in URI we use oral antibiotics. When you combine Doxil with thalidomide, the toxicity can be significant but we've modified the regimen, adding some supportive care drugs, like Neulasta and Procrit, and we've done really well with that. So what started as a problematic regimen with the thalidomide addition, now is a very straightforward regimen to use.
MT: What about the impact on a patient's quality of life?
Dr. Hussein: I would say that the quality of life is definitely better. But you are talking to someone who is biased – we developed the regimen.
MT: Any closing comments?
Dr. Hussein: I think that the regimen is moving forward in combination with other drugs, like thalidomide and Revimid. At ASH 2003, we should have a major update on DVd in combination with thalidomide. And in combination with Revimid, I would expect some results by ASCO 2004.
Note: For additional information about Doxil-based regimens in the management of multiple myeloma, please see Dr. Hussein's report in the IMF Salamanca Guide. This guide can be obtained by calling the IMF at (800) 452-CURE (2873).