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Summer 1999 Volume 3, Issue 5:
Myeloma Today Profile: James R. Berenson, MD
Myeloma Today: Please tell us about your medical background and how you ultimately became interested in myeloma?,

Dr. Berenson: I went to undergrad at Stanford and medical school at UC San Diego. I trained during my internal medicine residency at the University of Utah with Drs. Wintrobe and Cartwright, who are among the grandfathers of hematology as well as early researchers in the myeloma field. I came to UCLA to do my fellowship. While I was working on immunoglobulin genes, my cousin, a prominent Los Angeles orthopedist, developed myeloma. At the time, he was actually taking care of my wife who had carpel tunnel problems. So, myeloma seemed like a perfect field to get into: not a lot of people were working on myeloma, my cousin was a wonderful physician, and I already had a background in the genes that were producing the bad proteins in these cells. That’s how I got into it., ,

MT: You’ve been the principal investigator on the Aredia trials and, most recently, have been working on the Zoledronate trials. Could you give us an update? ,

Dr. Berenson: We’ve been involved with Zoledronate from its inception, that is from Phase I all the way through the current Phase III trials. In animals and in test tube studies of human cells, Zoledronate is about 100 to 1,000 times more potent than Aredia, which is an FDA-approved product. It has recently entered into randomized studies compared to Aredia in myeloma patients, as well as a number of other cancers which frequently have bone involvement. Whether this drug will prove superior or not, we do not know. We do know that the amount of Zoledronate it takes to have a similar inhibition of bone resorption is a lot less than the amount of Aredia it takes. But we don’t know yet whether larger doses of the newer agent will confer a better clinical effect . It certainly is more convenient – Zoledronate can be given over a minute or two. But I might add that from our recent studies, it looks like Aredia can be safely administered over one hour, not four hours, as was originally approved., ,

MT: What do you think patients have to look forward to as new therapy for bone?,

Dr. Berenson: I’m excited about the possibility that Zoledronate may be better, not only for the bone but also against the myeloma itself. In addition, we are beginning to explore some new modalities in treating the bone disease in myeloma, which similarly may have an anti-tumor effect. There are some drugs in early development from Amgen, a drug called OPG, which they stumbled on in cloning work they were doing. It looks like a very good inhibitor of the osteoclast‘s development from its precursor cells. This is the type of cell that chews up bone and this drug stops it from being developed from its precursor. , ,

MT: What about the suggestion that Aredia causes tumor reduction in myeloma?,

Dr. Berenson: We don’t know yet clinically if that is true. We are investigating this possibility in a current clinical trial. There certainly has been several suggestions from clinical results when Aredia was combined with chemotherapy. One of those comes from our own large myeloma trial in which we showed that in patients who had failed previous chemotherapy, the addition of Aredia to their chemotherapy that they were now receiving for salvage treatment, did lead to survival benefit. In terms of the mechanism by which Aredia may have an anti-tumor effect, it’s most interesting that it directly affects the cancer cells by reducing program cellular death or so called apoptosis. In addition, it also seems to take away the nutrients like IL-6 in the bone marrow micro-environment, so that there is no longer the fertilizer, if you will, to grow the seed. There are a number of potential anti-tumor mechanisms of action beyond Aredia’s ability to inhibit bone resorption., ,

MT: What about dosing? Are there benefits to giving Aredia more frequently and/or increasing the dose?,

Dr. Berenson: That’s a great question. We hope to answer it with a new animal model we have developed. It’s really not known yet whether more frequent dosing is better. In terms of what we do know clinically, 90mg every 3 or 4 weeks works. Does 90mg weekly work better? We don’t know. In the trial which we’ve just completed in which patients got double the dose every other week, we did ask that question in terms of anti-tumor effect, but we haven’t yet finished analyzing the data. These patients received 360mg a month (180mg every other week). We can tell you that it’s safe to give more, but whether it’s more effective, we just don’t know yet. The infusion time for 180mg was three hours. A milligram per minute seems to be a tolerable rate of infusion of these drugs and perhaps even faster, given the recent data showing the safety of 90 milligrams/60 minutes.,

MT: What are your current thoughts on recommending bone marrow transplantation for patients with myeloma?,

Dr. Berenson: I had a lot of hope several years ago that this may indeed be a curative approach and my experience, both clinically as well as in the laboratory is, indeed, it is not. It does reduce tumor burden, but the amount of reduction is probably about 100 fold in tumor cells and that means there is still a lot of tumor left even after a good remission or what appears to be a complete remission. So I think patients should not expect to be cured with the high dose therapy procedure. If you take the overall group of those that do and do not get transplanted, there is some improvement in survival patients who undergo the transplant procedure. This may translate to a median increase in survival of perhaps a year or two – but it’s not 10 or 20 years. Also, there is the risk of toxicity - you can die from the procedure - although that risk has been reduced markedly over the last 10 to 20 years from about 20%, when I started becoming involved, to about 1% these days, or even less. But the bad news is it’s still not curative. Occasionally, we see patients in whom the bone marrow transplant procedure itself seems to accelerate the disease. Why that’s occurring, whether it’s something to do with reinventing the bone marrow, “stirring it all up”, and stimulating the tumor, or whether it’s growth factors or something else that’s being used through the transplant procedure, we really don’t know at this point. So I think you have to be careful how you view transplant. There are patients that I would recommend it to – patients with more aggressive disease who can’t wait around to see if something better comes along would be good candidates. It is a worthwhile procedure, but I think the patients who undergo it need to be well selected., ,

MT: Do you think there will be a benefit to dendritic cell vaccines, especially since these cells may contain HHV-8?,

Dr. Berenson: As your readers may be aware, about two years ago we uncovered a new herpes virus in myeloma bone marrow. Not the tumor cells, but the non-malignant feeder cells, the so-called stromal cells which, surprisingly, turned out to be of a dendritic cell variety. We’ve thought of dendritic cells, as I like to say it, like the waiter who brings food to your table. This is the cell type that brings the antigen to your immune system so it can respond. The hope was that you could arm dendritic cells with specific antigens so that your own immune system could knock off the tumor. Even if these dendritic cells were not infected with the HHV-8, I’m not sure if that’s the right therapeutic approach. I think there may be some potential defect in the virally infected cells. The more important question is: Is the dendritic cell approach going to be one that will lead to curative or therapeutic benefits for the myeloma population? I would have to say the jury is out until we identify better antigens, that is the markers, that are really going to be specific for the cancer cells. I think we are going to have some problems with this form of therapy. The simplistic view has been that the antibody is very unique and, therefore, that’s a great marker, leading to therapeutic benefit. I think we have to expand our horizons to include other markers: perhaps the work that Ken Anderson has suggested recently with MUC – 1, or viral antigens, or other types of markers. It’s not as simple as, "OK, the patient’s making a monoclonal antibody, so let’s go after that as the vaccine target.", ,

MT: What do you think the role of Thalidomide will be for myeloma patients? ,

Dr. Berenson: Very promising data has come out of the group at the University of Arkansas under Dr. Barlogie. We’ve been using this drug now for several months and have observed several impressive responses in patients with advanced myeloma, so I think this drug has activity. But whether this drug will be more effective alone or in combination with chemotherapy is unknown. It does lead us to look into new biological avenues to treat the disease and I think this is very hopeful. My own view is that chemotherapy is too nonspecific and too toxic to have overriding benefit in this disease — what we call the therapeutic ratio of chemotherapy, the good versus the bad that it does. Thalidomide does have toxicity, but I think the new thing about it is that it acts on a biological molecule, a biological effect on angiogenesis, or perhaps even on the tumor cells directly or indirectly. I think that’s exciting. It offers new ways to look at the disease, not simply to think of myeloma as another cancer to use nonspecific chemotherapy, but to begin to think about how the biology can be impacting our therapy or the other way around. I think Aredia has offered us a specific biological approach., ,

MT: Are there other anti-angiogenesis drugs that also look promising?,

Dr. Berenson: Having just come from a lecture at UCLA on new anti-angiogenesis agents in cancer, I can tell you that there are several being evaluated. One from Sugen and one from Genetech, both of which are in early clinical trials at our institution. These are not being evaluated in myeloma at this point. However, we are beginning pre-clinical studies with a compound from Novartis, the maker of both Aredia and Zoledronate, and we hope that this drug will also prove useful in myeloma. We are eager to try it with our myeloma patients once we obtain pre-clinical data in our animals that are injected with myeloma cells, showing that there is some activity against the myeloma. In addition, the safety data on this Novartis product appears excellent., ,

MT: The role of HHV-8 has been somewhat controversial. Could you explain this?,

Dr. Berenson: We’ve just published in Blood regarding that, in fact the title was: "Contro-versies in Hematology". We’ve argued that there is virus there and another group has argued that they couldn’t find it. Dr. Ken Anderson has recently confirmed all of our data, showing the presence of the virus in the same type of bone marrow dendritic cell as we did in our myeloma patients. I think the problem has been the lack of specificity of the cells that have been analyzed for the virus. Many groups have studied "dendritic cells" but these were a different type of dendritic cell. In addition, the use of different antibody tests may be fraught with problems. First of all, myeloma patients are immuno-deficient. Secondarily, if the myeloma version of the virus is different, this certainly comes into play. We’ve now completed blinded studies with a number of investigators confirming our results, so I don’t have any doubt about the presence of a virus. Can it be a trigger factor for myeloma? We’re pursuing that in the lab, going after specific viral genes that are expressed in the myeloma patients’ bone marrow, hoping to begin to unravel how these may come into play in driving the tumor., ,

MT: What do you see as the most promising area of research for myeloma? ,

Dr. Berenson: The most promising area of research in myeloma is to begin to think about how we can translate the biology into new therapeutics and also use the therapeutics to better understand the biology. That’s what our laboratory has tried to accomplish. The interesting areas now are to begin to figure out whether the specific molecules that drive the clone can actually be exploited to inhibit the clone. Exploring whether it’s viral proteins or, for example, cytokines like IL-6 which are the most critical, and exploring angiogenesis and whether it is truly angiogenesis or some other related factor. I think this is how we need to view the disease: promising areas are being specific. My wife is an actress and she is always specific with her work. And I apply that credo to myeloma and cancer therapy. Immuno-therapy may hold promise, but the jury is still out. I’m very excited about the IMF research grant program. I think it’s very important. Hopefully, we will get more investigators into the field and finally cure, or at least control, this disease. , ,

MT: You’ve been involved with the IMF since its inception. What are your thoughts on what the IMF has been able to achieve and our direction in the future?,

Dr. Berenson: I remember one of the first meetings that Brian Durie, Brian Novis, and myself had. Who would’ve dreamt that the IMF would become this big? With the help of Susie, it’s been a great resource for my patients and patients from around the world whom I’ve spoken with. The IMF is a great network, disseminating information to the patients and getting myeloma experts together. I’m really excited about the opportunity to particpate in the IMF Clinical Conference and the Los Angeles Patient Seminar., ,

MT: In the short term, how do you see the quality of life improving for patients?,

Dr. Berenson: It’s been improving with the help of supportive care drugs, such as erythropoetin. Many of these types of studies were led by a myeloma doctor, Dr. Heinz Ludwig of Vienna, and have since been used in all sorts of cancer patients with bone disease. Not only the quantity of life, but the quality of life is improving as a result of these drugs. We thought they were just supportive care drugs but are learning that maybe they have effects on the cancer that are good for the patient as well. I think the patients should look at the glass as half full, not half empty. We’re certainly making progress both in the laboratory and in the clinic. There is opportunity for novel therapies out there which, I think, will be available to patients over the next several years. The patients should be excited about this. I have been less inclined to give a lot of chemotherapy to patients with more indolent, less aggressive myeloma, because I really think there are going to be new treatments available, maybe even in the year 2000, as we enter the new millenium.

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