This was the third conference this spring we attended with Dr Ludwig: The IMF Scientific Advisory Board Meeting, ASCO, and EHA (European Hematology Association) where we conducted this interview. Based on these meetings, Dr Ludwig had some important points to make:
On Stem Cell Transplant, “Transplant is going away definitely. I mean everybody knows that, but people still defend it.”
On the biology of myeloma: “Myeloma is not myeloma. This is a spectrum of diseases.”
On the importance of achieving a Complete Response: “I think there’s a lot of uncertainty about the impact of CR. It depends very much on the quality of CR, namely IF negative or not, or molecular CR and on the type of treatment used for achieving CR.”
We discussed all of that with Dr Ludwig, but we began with his own talk at EHA about kidney disease and multiple myeloma:
Dr. Ludwig: Kidney disease or renal impairment is an emergency for many patients. And it’s most frequently due to nephrotoxic light chains. You have to distinguish this pathomechanism which is most common from the several other causes. But if light chain-induced renal failure is the underlying pathomechanism, you should act as fast as possible and use the best possible treatment.
People have tried to remove the light chains with plasmapheresis or plasma separation from the serum, but that hasn’t proven effective.
There are new dialysis membranes available now, which allow the elimination of larger amounts of light chains, but whether this is clinically more useful has not been proven as yet. What you need is highly effective myeloma therapy, and bortezomib has been used by several groups in a small series, and we also have used it in a previous pilot study.
After these first results we started a phase II trial. 63 patients have been enrolled until this time and 47 of them are eligible for evaluation of treatment outcome so far. The treatment consisted of a combination of bortezomib-doxorubicin and dexamethasone. Bortezomib was selected as main backbone of this regimen because it seems to be an ideal drug for patients with renal insufficiency. There is no need for dose reduction with low creatinine clearance and bortezomib exerts anti-inflammatory activities also. The latter effect may contribute to improvement of renal function because it may ameliorate interstitial inflammation.
Therapy resulted in an overall tumor response rate of 79% with 56% of patients achieving complete or very good partial remission. 62% of the patients experienced any relevant and 32% a major improvement of renal function.
Toxicity was tolerable, and I should mention that eight patients had been started on dialysis and three of them are now off dialysis.
These studies are ongoing. We will close them soon and report the final results.
IMF: If they have already been treated with bortezomib and moved on to something else, can you go back to the bortezomib?
Dr. Ludwig: Yes, you can easily re-treat them that had already been shown in few studies. Presently, a trial is evaluating the efficacy of re-treating patients with a further line of bortezomib therapy who previously had responded to bortezomib. Retreatment should start at least half a year after previous bortezomib therapy had been stopped. But the longer the time between first bortezomib treatment and retreatment with bortezomib, the higher the likelihood of a good response.
IMF: Why bortezomib?
Dr. Ludwig: You can do that with other drugs too, but nobody else took the trouble to show this systematically. You can do this with melphalan-prednisone, but the problem with melphalan-prednisone is that it is not so effective. Reuse of thalidomide is limited by its dose limiting toxicities, particular by neuropathy. Lenalidomide should probably work as well, but there are no data available as yet.
IMF: We’ve just come from ASCO and now we’re here at EHA, what are the key advances in myeloma?
Dr. Ludwig: There are two key advances. One is the introduction of novel drugs. And the other is the increasing understanding of the biology of the disease and the realization that myeloma is not a single disease. Myeloma is not myeloma; it is rather a spectrum of heterogeneous diseases. And in the end we will need to individualize treatment, not only based on patient characteristics – that has always been an important issue, but also based on the tumor biology of the individual patient.
IMF: But we’re not there yet? You can’t examine the tumor and say you go on this drug, and you go on this drug?
Dr. Ludwig: I think it is starting already. Take patients with a translocation 4; 14 or 14; 16, or deletion 17p, then probably it’s futile to use MP; even thalidomide won’t work in those patients. So you have to use something which promises a high response rate and this is either bortezomib or lenalidomide. This is the reality already today.
IMF: Two things came up at a panel in which you participated. One is CR and the notion that gradual treatment may have a longer term result. How do you feel about that?
Dr. Ludwig: I think there’s a lot of uncertainty about the impact of CR. It depends very much on the type of treatment used in order to achieve CR – If you achieve CR with, for example, a dexamethasone based treatment, you have to be careful because dexamethasone may produce a cosmetic effect, since dexamethasone reduces the production of proteins and also of paraproteins, and secondly it enhances the degradation of proteins, so you shouldn’t be too surprised if the response rate is higher with combinations employing dexamethasone, because the reduction in paraprotein does not always correlate with the reduction in tumor cells when you use dex.
When you use transplantation, there are plenty of papers showing CR is associated with better outcome. When you look at conventional treatment the situation is less clear, and there are of course data showing that progression free survival would be much more important in predicting outcome at specific points of time. So probably it’s like many other situations in medicine or in life. It’s not so simple.
We have to consider several facts. What will be shown even more convincinglys that quality of CR is an issue. CR is not CR. Patient who achieve molecular CR will survive much longer. But there is already a difference between conventionally defined true CR and immunofixation-positive CR. Patients with IF-positivity tend to relapse much earlier than those with IF negative CR.
These are all important issues, and these facts have not been looked at in the old studies. Today we have tools for assessing the quality of CR more precisely than in the old days when we did not use free light chains, immunophenotyping or even molecular studies. Therefore, it follows that data which have been produced long before, are not really transferable to present day management.
But in the end, I think nobody would object that aiming for CR is a good thing, because the patient is likely to be without complaints and symptoms, and the tumor is reduced as much as possible to a few grams from one or more kilos: This should also impact on bone health. If you have no or only very few myeloma cells sitting around, bone resorption should not be enhanced too much, this is certainly in contrast to a situation where plenty of tumor cells are around and produce nasty factors which induce bone resorption and thereby creating a major problem.
IMF: You raised the issue of transplant. The other meeting we attended together was the IMF Scientific Advisory Board meeting where there were differences between Europe and the United States. With the novel therapies and the success being reported, is transplant going away?
Dr. Ludwig: Transplant is going away definitely. I assume everybody knows that, but still people defend it and that has many other reasons, not all of them are directly related to medical issues. But again we should not oversimplify the issue, because there seems to be a minority of patients who really do benefit from transplantation
What we know is, if patients present with progressive disease and if you transplant these patients, it doesn’t work. If patients present with stable disease, a transplant may be worthwhile. And if patients present with partial response after induction therapy, transplantation may render a CR. As mentioned before, there seems to be a small segment of patients that will really benefit. But the question is whether novel treatment wouldn’t do the same job or possibly even better, and that is unclear today.
My notion is that a treatment that is very toxic and follows such a simple concept is unlikely to withstand the test of time. You are obliged to use it as long you lack any alternative. But transplantation in its present form cannot be the therapy of the future. It’s like doing a Halstead mastectomy in breast cancer. Today you do just a small segmentectomy and that’s enough.
Very likely in the future we will use just a few specific drugs and this should exceed the results of all previous treatments including such as the old fashioned concept of high dose chemotherapy with autologous stem cell rescue.