Novel Therapies Under Investigation in Multiple Myeloma
Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Rafael Fonseca, MD: Working in the field of myeloma, one can see the progress that we have made over the last 20 years—the concerted effort of many across the board. And as I mentioned previously, I do think there’s a fraction of myeloma patients that are curable, and we just need to get smart about how we’re going to expand that fraction.
Ideally, we would have a future where there’s a therapy that lasts 5 days, just like we have for hairy cell leukemia, and then all patients can be cured. But we’re not there yet. But we can extend the lives substantially. And I think even with some of the results, for instance, from the MAIA study, there are a lot of patients who are not transplant candidates, who are elderly, who will have a close-to-normal life expectancy once they receive some of these better therapies. I’d like to see a future where stem cell transplant goes away. Despite my affiliation and my affection for it right now as an effective tool, I’d like that to go away. I’d like to see a future where we don’t deal with long-term toxicities, and a future with peripheral neuropathy absent from the lives of myeloma patients. Patients are going to live many years, and have to deal now with the effects of that peripheral neuropathy. And I’d like to see a future where we can use a dexamethasone equivalent without the toxicity of dexamethasone.
We’re getting closer. It’s going to take time, unfortunately, but we’re getting closer and I think that our ability to treat myeloma will only continue to improve. Maybe it will include CAR [chimeric antigen receptor] T cells in frontline therapy for patients after a quick induction, and will allow us to get patients back to their normal lives instead of spending so much time in the clinics.
Kenneth C. Anderson, MD: The progress in the past has been palpable. Progression-free survival is 3 to 4 times longer than it used to be, and many patients have myeloma as a chronic illness. But there is much work to be done. If you look at age-matched controls who don’t have myeloma, those patients live much longer than patients who have myeloma, at least in the data that exist in the CR [complete response] database.
Suffice it to say we have more work to do, and the 2 areas of most promise include targeted therapies—the therapies that are based on targeting the abnormality in the genomic profile that’s present in a given patient with multiple myeloma. I’ll mention a clinical trial called MyDRUG, which is about to begin, where patients are profiled for their genetic abnormality. There are multiple arms in this clinical trial and novel agents that are going to be tested that are directed at those abnormalities. So, for example, if patients had a (11;14) translocation, they would have venetoclax. If they have another abnormality, there’s a specific drug for that target, etcetera.
In this particular trial, it’s in relapsed myeloma. And so, how can you do a novel agent like this in relapsed myeloma when we have so many accepted regimens? What is simply being done is patients are profiled. They get a standard, acceptable level of treatment for their relapsed myeloma—in this case, ixazomib and pomalidomide. And then they get the addition of the novel agent that’s directed at their particular abnormality. We examine whether the abnormal clone of cells is reduced when you add in the targeted therapy. This is called MyDRUG, and the point is that it will give us leads for what might be targeted therapies we could use in myeloma, and then we’ll have to do tests later to prove that. So targeted therapies on the one hand, and venetoclax in the (11;14) translocation myeloma patients is already the first targeted therapy that likely will get FDA approved.
The other category, besides targeted therapy, is the immune therapies. And I’ll just mention that there are many immune therapies, but there are new monoclonal antibodies such as elotuzumab. There are new immunotoxins where you have antibodies bound to toxins—so BCMA, B-cell maturation antigen as a target antigen bound to an immunotoxin such as an RO [rosuvastatin] statin. That medicine is already in clinical trials and is showing promising results.
Perhaps the other 2 immune therapies I’ll just quickly mention are the bispecific T-cell engagers, or BiTEs. We know that in leukemia and lymphoma the BiTEs are active and are even now, in some cases, FDA approved. But in myeloma, we have the BCMA antibody binding to myeloma cells and an antibody attracting the CD3-positive T cells to the microenvironment of the tumor, hoping to get more activity and fewer adverse effects. So monoclonal antibodies, or immunotoxins, and the BiTEs are bispecific antibodies.
And the last is the CAR T-cells. There is much excitement about CAR T-cells, where you harvest the patient’s T-cells, infect them with a vector that has them target, in most cases, BCMA, activates their T-cell receptor, and in fact allows for their expansion ex vivo into large numbers and subsequent transfusion back to patients, as I like to call it, as their own immune army. And this concept of CAR T-cells has really been very exciting in myeloma.
The most exciting news is the depth of response, even in patients who have had 6, 7, 8, 9, 10 prior lines of therapy. We can get MRD [minimal residual disease]-negativity of fewer than 1 myeloma in a million normal cells.
We have work left to do, however, because we need to make this procedure safer. And we need to make it also so that the benefit is more sustained. We’re at the earliest level of the CAR T-cells, so there’s much excitement and there should be. But I think we also need to recognize that there’s much work to be done to improve the efficacy, on the one hand, and safety, on the other.
Noopur S. Raje, MD: The future of a multiple myeloma is even more exciting. We have lots of interesting and exciting approaches. I think what we’ve seen in the last year or so is a really good and relevant target in multiple myeloma—that being BCMA, the B-cell maturation antigen. We’ve seen remarkable responses with the conjugated antibody. We’ve seen incredible responses with the BiTE, which is off the shelf, and we are seeing incredible results with cellular therapy now for the first time in myeloma. With CAR T-cells in multiple myeloma, we’ve seen really nice results with durability of responses in patients who’ve achieved MRD-negative disease state.
So these are all very exciting, and I think we will have to figure out, obviously when things like this work very late in disease, all of these are going to be brought earlier on in disease. And at least with the bb2121 product, we’re already bringing it up front, not quite up front, but up front in the high-risk patient population or at the time of first relapse, and in relapsed myeloma after 1 to 3 lines of treatment as well. Those are ongoing trials that are actually asking the question on durability of responses with a cellular product such as bb2121.
There are a whole bunch of other interesting targets as well, and I think to me what’s most interesting in the small molecule in a better space specifically is MCL1 inhibition. You saw a lot of nice data with venetoclax, which is a BCL2 inhibitor, and the BCL2 inhibitor in combination with bortezomib or with carfilzomib has shown remarkable results.
Now most of us know that in multiple myeloma MCL1 is actually a predominant pathway. And if you can block that pathway, you’re going to see incredible results with an MCL1 inhibitor as well. So we have early data in phase I trials with an MCL1 inhibitor, and we have to see. As long as it’s not a very toxic drug, that’s a drug that I would be looking forward to seeing the data on.
Other drugs being studied and that may get approval for the treatment of myeloma are drugs with a very different mechanism of action like selinexor. It’s a nuclear transport-export inhibitor, and this one, in combination with dexamethasone, has in fact shown nice responses in a penta refractory population. Now we’re talking about penta refractory patients. So penta refractory include patients who are refractory to pomalidomide, lenalidomide, bortezomib, carfilzomib, and daratumumab. So if you can have an oral drug that can give you a durable response rate, that would be incredible as well. We’ll have to see what the data with selinexor look like, and whether the combination of selinexor with either bortezomib or carfilzomib is here to stay. But these are all interesting compounds that are going to continue to change or keep moving our goal post for myeloma, and hopefully we will see a significant subset of patients for whom we’re able to control this disease for a long time, which in effect would be curing this disease.