In an interview with InFo ONCOLOGY & HEMATOLOGY, Prof. Christoph Renner, MD, Onkozentrum Hirslanden, Zurich, discusses the latest therapeutic advances in multiple myeloma. In doing so, he answers questions such as “Who benefits from the new approval of pomalidomide in Switzerland and how tolerable is the substance?” or “What are the developments in first-line and maintenance therapy?”
Prof. Renner, hardly any other malignant disease has made such great progress in recent years as multiple myeloma. In general terms, which outcomes are particularly improved by the “new” agents (thalidomide, lenalidomide, bortezomib, pomalidomide)?
Prof. Renner: If you look at the period of the last 20-25 years, from my point of view, it is especially the quality of life for the patient that has been greatly improved. In the past, there were hardly any drugs available and the disease was treated at a late stage. This can still be seen in the earlier classification systems: There, people relied on the severity of the disease and blood count parameters, which today would actually no longer be accepted because people are already too ill. At the latest in the case of relapses, one then often had no options at all.
With the new substances nowadays, it is usually possible to avoid serious damage and maintain the quality of life at a very good level. Tolerance is generally good. The new substances do not cause the side effects of classic chemotherapy. For example, hair loss and thus a burdensome stigma for the patient can be avoided. And ultimately – as the registry and study data also show – you also live longer with this disease. So, in summary, with the new medications today, you have a better quality of life over a longer period of time. Nevertheless, it should not go unmentioned that at some point these new drugs usually also no longer “work”, i.e. the benefit is no longer given after a certain period of use. Thus, with few exceptions, multiple myeloma remains an incurable disease. However, since it can be controlled for a long time, some also already speak of a “chronic” disease, which must be treated again and again at certain intervals and thus kept in check.
Lenalidomide is being studied in Phase III trials for both newly diagnosed forms of multiple myeloma and in maintenance therapy. What are the most important results of the studies and what is their practical relevance?
To date, lenalidomide has been approved in relapse, or recurrence. But now there was a study (FIRST) presented last year at the American Hematology Congress that compared lenalidmoid in first-line therapy for patients who were not eligible for transplantation with one of the potential first-line chemotherapies. The problem with studies, of course, is that guidelines can change during the time they are being conducted and until they are published. Thus, one criticism of the study was the somewhat outdated comparison arm. However, lenalidomide improved progression-free survival throughout the period, even when it was continued. The advantage would be that this would give you chemotherapy-free first-line therapy. In addition, of course, the costs would also be significantly higher than in the past.
In maintenance therapy, in addition to the positive study by the American study group, there was also a French study that showed that the time to recurrence of the disease could be very significantly delayed under lenalidomide, but the patients nevertheless did not live longer. Indeed, when relapse occurred, patients responded less well to therapy. Thus, in sum, the difference in overall survival is not significant. Therefore, regulatory authorities here are still waiting to add lenalidomide to maintenance therapy.
Pomalidomide is approved in the U.S. and EU (and recently in Switzerland) for relapsed/refractory multiple myeloma. It is indicated in combinations. What is there to say about the research results in this area?
Pomalidomide has been approved in this indication in Switzerland since June 2014 and has been subject to mandatory insurance coverage since August 1. Today there are two newer substances that have a very good response, one is bortezomib and the other is lenalidomide. These work for a certain period of time with good tolerability, but at some point they usually have to be stopped due to new side effects or lack of effect. In younger patients with transplants, this takes significantly longer than in older patients, where a change may be necessary after an average of two and a half to three years. So far, they haven’t had many more options on the third and fourth lines. So there was an urgent need for substances that would help even then. This gap is now filled by pomalidomide, which is indicated in combination with dexamethasone for the treatment of relapsed and refractory multiple myeloma in patients who have received at least two prior therapies (including lenalidomide and bortezomib) and who have shown progression to the last therapy. This doubles the progression-free survival compared to the situation we had before.
How tolerable is the combination of pomalidomide and low-dose dexamethasone?
It is very well tolerated. Fatigue and weakness are sometimes a problem, pre-existing polyneuropathy can worsen, some get constipation or diarrhea, but it is usually a well-tolerated substance.
What concrete practice-relevant progress does the new approval of this combination (pomalidomide/dexamethasone) bring in Switzerland?
It is definitely an important development, because in daily practice you have these patients who need an alternative after bortezomib and lenalidomide. One starts with bortezomib, then may have polyneuropathy or lack of response, and switches to lenalidmoid. Then you have to assume that at some point there will be no response to lenalidomide. So far, these have been the patients where you had to take a close look at what alternatives were left. So one is already happy if one still has a therapy option in this population .
What is the current standard of care for elderly patients?
First, of course, is the question of how to define “older” and “young.” The French have tied this quite strongly to the calendar: old means 65 years or more. This is a simplification that certainly falls short. Today, we still have 70-, sometimes even up to 74-year-olds who are fit and, according to study data, benefit from reduced transplantation. This is still done in order to achieve a so-called consolidation (solidification of the response) after a good response to the new drugs and also sometimes a therapy-free interval. Thus, the effective drugs can be postponed. It was partly thought that the new drugs would make transplantation superfluous, which it does not seem to be so far. So today one rather combines effective substances followed by transplantation.
What other new developments are there in the field of multiple myeloma research?
There are a lot of new drugs coming in the near future. Drugs with entirely new modes of action make the field of myeloma research very exciting. It is gratifying that such intensive research is currently being carried out here. For example, CD-38 antibodies represent attractive future opportunities due to the positive study situation (Phase II-III).
Interview: Andreas Grossmann
InFo Oncology & Hematology 2014; 2(7): 22-24.
