Ronald E. Merrill

The Vth International Workshop on Multiple Myeloma was held in La Baule, France, in September. Attendance was over 400, and a number of patients were present, of whom I was one. What follows is an overview of the workshop from one patient's perspective. Since this was a scientific meeting, the account is unavoidably somewhat technical.

Advances in Treatment

This topic of course is of prime interest to patients. In general there is no magic bullet on the horizon. However, improvements in chemotherapy are being made and there are some promising agents in the pipeline. Also interesting are biological agents, which are discussed later.

Among conventional drugs, idarubacin (Zavedos; currently approved in Europe) is drawing interest. It is similar to adriamycin, but can be taken orally, and there are claims that it is less toxic. Etoposide (VP-16) shows good activity in some patients. For "third-line" therapy after failure or relapse from other treatments, topotecan was found effective in 25% of patients. On the other hand, nucleoside analogs such as fludarabine and 2-CDA seem to be inactive against multiple myeloma, though the latter has proved valuable against Waldenstrom's macroglobulinemia.

The popular (among physicians, that is!) VAD regime generally causes development of multi-drug resistance (MDR). To reverse MDR, agents such as verapamil and cyclosporin have been used, but they are rather toxic. Currently less toxic variations are in trial. Dexverapamil seems to be proving somewhat disappointing in tests against MDR. The new Sandoz drug, PSC 833, is also being tested for this use.

Speaking of VAD, Daniel Bergsagel has pointed out that vincristine (the "V" in VAD, VBAP, etc.) has never been shown to have any significant activity against myeloma. In view of the extreme toxicity of this drug, its use, he says, is "surprising." I got the impression that this argument is gaining ground, and several groups apparently are looking for alternative regimens to replace VAD, including idarubacin-dexamethasone and etoposide-dexamethasone.

Interest in bone marrow transplants (BMTs), including stem-cell variations, remains strong. However, the enthusiasm so evident a couple of years ago is now tempered with more caution, and even advocates hesitate to say it can be curative. I found it widely (though not always publicly) acknowledged that BMT is not more effective than conventional therapies over the entire patient group. It merely looks better in the statistics because only patients in relatively good condition are allowed to undergo the procedure. However, BMT is still considered a useful option to offer certain patients, and much work is being done to improve procedures. There were many reports on methods to "purge" or purify stem cells to prevent re-infusion of the disease.

The bisphosphonate agents, such as pamidronate, clodronate, and the newer alendronate (Fosfamax), can stop or even reverse bone loss, and relieve the pain associated with it. However, I was told that a major study of clodronate showed no improvement in survival.

There was an extensive debate over the merits of alpha-interferon. In general this agent has proved disappointing in front-line therapy, either alone or in combination with other drugs. However, the big question is the value of interferon as "maintenance" therapy for patients in plateau phase. Does this prolong survival? Most studies seem to show that the plateau phase is prolonged, but not survival. It may be that interferon delays relapse, but makes it more severe when it comes. Or possibly interferon somehow postpones the symptoms of relapse so that it is not detected so soon. During the question period, the comment was made that if interferon does not prolong survival but merely lengthens the plateau phase, it is worthless. I think, though, that many patients will disagree with this evaluation.

New Drug Candidates

What's in the pipeline? Sidney Salmon's group at Arizona remains very interested in imexon. There is also some promising work on agents that, like dexamethasone (Decadron) or prednisone, cause myeloma cells to undergo apoptosis (programmed cell death). One candidate is HMBA (hexamethylenebisacetamide), currently in development at Sloan-Kettering. Unfortunately, a Phase II trial, though approved, has been stalled by budget reductions at the National Cancer Institute. A somewhat similar approach is being tried with phenylbutyrate, but this compound is at an even earlier stage of research.

The biotech revolution continues to produce new and exotic approaches to treatment, and a number of biological agents were discussed at the workshop. IL-4 is in clinical trials at Arkansas. The word--unofficial--is that results are proving very disappointing. The theoretical basis for IL-4 treatment is that it could assist the patient's immune system in attacking the myeloma cells. Unfortunately, trials on radically new agents such as IL-4 are usually conducted on patients who have failed other therapies, and whose immune systems have been badly damaged by cytotoxic drugs. Perhaps as a front-line therapy IL-4 would produce better results.

Other biologicals include OKT-3 (studied by Massaia and coworkers in Italy); anti-IL-6 and anti-IL-6R (Kishimoto's group at Osaka is a leader here); and soluble CD-16 (under study in Arkansas). All of these agents are showing promising results; however, they are so difficult and expensive to prepare that they will probably not be available for practical clinical use in the foreseeable future.

Research and the Future

A cure for multiple myeloma can come only from basic research into the nature of the disease. At the workshop, several groups reported progress in elucidating the complex biochemical pathways by which the malignancy develops in multiple myeloma. Important areas of research range from studies of chromosome damage and how it may result in genetic effects that turn cells malignant, to the strange and mystical transmigrations of IL-6, which plays a key role in myeloma.

Other exciting possibilities are suggested by the conjecture that the immune system, though it cannot defeat multiple myeloma, somehow "regulates" it. Research along these lines is still at a very early stage.

At the workshop, a major controversy raged over the nature of the malignancy in multiple myeloma. The traditional view is that all of the myeloma cells in the bone marrow are (at least potentially) malignant. More recently, it has been suggested that there is a "malignant compartment." In this view, most myeloma cells are non-malignant, incapable of further division; there is just a small fraction that can still grow and maintain the tumor. Linda Pilarski of the University of Alberta, who takes the strongest position on this issue, believes that the actual malignancy consists of cells circulating in the blood. This question is very important, because if we could clearly identify the nature of the malignancy, we would have a much better chance of designing treatment to deal with it.

I came back from France encouraged to see that, after a long drought, new ideas are being developed in research on myeloma. Progress is still slow, but there is progress. And the much greater interest that this disease is drawing, as evidenced by the high turn-out at this workshop, is a very hopeful sign for the future.

Ronald E. Merrill, an MIT graduate, holds a PhD in chemistry. Formerly he worked in the pharmaceutical industry as a research manager; currently he does consulting and database development work. He was diagnosed with multiple myeloma in January 1993.