In recent years, a number of promising therapeutic approaches have been developed for multiple myeloma (MM). What challenges do they pose for medical specialists and research companies? Oncologist Prof. Dr. Heinz Ludwig (HL), head of the Wilhelminian Cancer Research Institute, Vienna, in conversation with Dr. Thomas Schnelle (TS), Partner at Metaplan.
TS: Over the past 15 years, proteasome inhibitors and IMiDs have brought about significant progress in the therapy of MM. What do you expect from the CD38 antibody daratumumab?
HL: With previous therapies we have already been able to extend the median survival of younger patients to between 7 and 10 years. 20 to 30 % of patients under 50 are still alive 20 years after transplantation. In the future, this percentage should increase significantly. Daratumumab promises dramatic progress. Like lymphoma, multiple myeloma can now be treated with combined chemo-immunotherapy. That will get things going. For poor-risk patients, the result has unfortunately not changed significantly so far. OS remains unchanged at 2 to 3 years. Sadly, this will not improve fundamentally through the use of CD38 antibodies.
TS: CAR T-cell therapies also seem to be revolutionizing the treatment of multiple myeloma. As it looks so far, many patients might only need a single course of therapy.
HL: The initial results really are excellent — we have observed response rates of 60 % to 100 % in heavily pretreated patients. There are admittedly several limitations to this therapy. One is the need to limit the administration of CAR T-cells to a few centers. This will considerably reduce the acceptance of hematologists. They have to send their patients to centers and don’t know whether they will return because it’s still unclear which follow-up treatment will be necessary, let alone who can do it.
TS: This means that only providers who manage to develop interesting cooperation models for both sides will be successful. Without such cooperation models, they face a fate similar to Zevalin in NHL: the labeled antibody against CD20 is more effective than the ‘naked’ antibody but is hardly used because hematologists don’t prescribe it, lacking effective cooperation between hematologists and nuclear medicine physicians.
HL: Exactly. This means other therapies without such limitations and with sufficiently equivalent results will have an advantage over CAR T-cell therapies. In addition, CAR T-cell therapies can only be used on a relatively small number of patients for the time being — and the few specialized centers are not able to treat so many patients. Another limitation is the narrow selection criteria of the studies. Furthermore, the cell production process before therapy will take up to 4, later perhaps 3 weeks. Patients must be able to hold out for that long. It therefore won’t be possible to give this therapy to patients who are in need for immediate therapy. Also, clinical questions still remain unanswered: How long will remissions actually last? How many relapses will there be? Whether additional treatments after CAR T-cell therapy are necessary and helpful can only be clarified with follow-up observation and further studies.
TS: What else needs to be considered?
HL: Toxicity is currently at a significant level. We’ll have to learn how to handle that. Trying to insert a suicide gene is an interesting idea. In this way, in a cytokine storm the T-cells could be inactivated and later continue the treatment The cost of $ 450,000 per patient today will also be off-putting. However, a EU program is currently underway with the aim of allowing research centers to produce their own CAR T-cells locally. This would reduce costs to an estimated $ 60–70,000.
TS: What alternatives are still under development?
HL: For one, there are bispecific antibodies such as BCMA antibody drug conjugates. The toxin is coupled directly to the antibody, as is currently the case with trastuzumab emtansine in Her2-positive mBC. In principle, such a therapy can be done by any hematologist. It’s likely that the therapy will have to be repeated in intervals, which requires closer cooperation between the patient and the hematologist in charge. A second way involves bispecific antibodies that bind to both BCMA and CD3. With one binding domain they dock to BCMA on B and plasma cells and to CD3 on T-cells on the other side. T-cells are placed in the immediate vicinity of plasma cells and kill them. The advantage of these inhibitors is that they don’t require very high receptor density on myeloma cells.
TS: However, the Bcl2 inhibitor venetoclax is the most advanced in its clinical development.
HL: Yes. It shows response rates of about 60 % in patients with t(11;14) translocation and high BCL2/MCL expression. Venetoclax is also being tested in combination with bortezomib in patients without t(11;14) translocation. Initial tests have also shown considerable efficacy.
TS: Could tumor lysis at the start of therapy hinder acceptance, as with CLL?
HL: I don’t think so. There have been reports about isolated cases of tumor lysis in MM patients. However, I think a real tumor lysis syndrome in myeloma is unlikely to occur. I suspect that other complications — such as severe sepsis — have led to renal dysfunction in these patients.
TS: Will checkpoint inhibitors still manage to get a place in the MM therapy algorithm?
HL: I have doubts about that. Some of the studies that were put on hold by the FDA can now be continued. But the manufacturers themselves are very cautious. It is questionable whether this treatment approach is actually suitable for MM. For this therapy, the patient needs a healthy immune system, and that is severely suppressed with MM. Selinexor, a so-called Selective Inhibitor of Nuclear Export (SINE), looks more promising. In combination with dexamethasone, this molecule is about to be approved by the FDA. A phase III study that looks at combining it with bortezomib is ongoing. Selinexor is likely to become a high flyer: It is taken orally. Side effects such as fatigue and loss of appetite can be kept under control and also automatically improve when the patient responds. Nonetheless, we’re still waiting for more study results.
TS: What about MEK and BET inhibitors?
HL: MEK inhibitors like trametinib and cobimetinib are of particular interest for patients with RAS mutations. But I’m a little skeptical: MEK is an important switching point in the cascade of intracellular signaling pathways. However, it works more like a node in a network: if you switch off only one node, others can compensate for it. BET inhibitors are of interest for various tumors. They impede the transcription of cMYC. And this is an important driver of malignancy, a central protein that stimulates progression in MM. It already works in test tubes. Now we’re waiting for the clinical development.
TS: Can’t wait to see what happens. Clearly developments in MM will demand changes from everyone involved: manufacturers as well as clinicians. If they succeed, there’ll be much cause for optimism.
PROF. DR. HEINZ LUDWIG
is Head of the Wilhelminian Cancer Research Institute and former Director of the I. Medical Department, Center for Oncology, Hematology and Palliative Medicine at the Wilhelminenspital, Vienna.
DR. THOMAS SCHNELLE
is Partner at Metaplan and an expert in research and development planning and product launch.
This interview has been published in Metaplan’s new international Life Science magazine ‚connect‘.
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