On Thursday, March 6th, IMF Scientific Advisory Board Member, and Myeloma Specialist and Cellular Therapist at Memorial Sloan Kettering Cancer Center Saad Z. Usmani, MD, MBA, FACP, FASCO hosted a live Q&A session on Facebook to answer the most pressing questions about multiple myeloma as part of Myeloma Action Month — from the latest treatments to managing side effects.
Dr. Usmani started the Q&A session by introducing himself: “I am a cancer doctor and specialist in hematology and medical oncology. I take care of myeloma patients as well as do clinical research in furthering the mission to cure this disease. I oversee a team of 14 investigators here at Memorial Sloan Kettering Cancer Center in New York, where I serve as the chief of the program. And we are totally committed to the cause and try to do collaborative research with folks around the world.”
Here are some of the top questions and answers we gathered from Dr. Usmani’s informative and insightful Facebook LIVE session (EDITOR’S NOTE: Viewers’ questions and Dr. Usmani’s responses have been edited for conciseness and clarity):
1. How are steroids/dexamethasone used in treating myeloma?
I'm just going to try to provide a general answer here. Dexamethasone is a corticosteroid that is an important part of myeloma treatment. Not does it only have and direct activity against myeloma cells, it can also help the other drugs that we utilize to treat myeloma more tolerable for patients. A little bit of steroids can go a long way in making patients feel better, as they're getting treatment.
However, steroids can also cause other side effects and sleep problems, especially the day that patients take them—you may feel like Superman, or Superwoman, or Wonder Woman. And then, in the next two or three days it's like a steroid crash feeling where you're fatigued and tired. That’s just one of the initial side effects. People may also get heartburn, or some anxiety or personality-related changes. The long-term use of steroids can also cause other issues, including bone loss.
So, in general, our more recent approach has been to try dialing down the dose of dexamethasone after initial therapy.
Whether it's in a newly diagnosed or relapse setting, we utilize dexamethasone as a steroid by starting off at a usual dose that is age appropriate. Then, we try to dial it back down when patients start feeling better or are beginning to respond to the treatment.
After a few months of treatment, if the patients have had a response plateau (where myeloma levels are as low as they can go), we can even consider peeling off dexamethasone or steroids altogether.
2. Are bispecifics safe?
To give a general answer, bispecific antibodies are considered as awesome tools by myeloma doctors. This antibody has two proteins that it can identify—one is on the surface of the myeloma cell, while the other is expressed on the surface of immune cells (called T-cells). An antibody tags the cancer cell and brings the immune cell to the cancer cell. Then, the immune cell gobbles up the myeloma cell which is the intended mechanism of action.
The kind of protein that bispecifics target on the myeloma cell is different (there are different types). The drugs that have been approved by the FDA target two proteins — one is called BCMA, the other GPRC5D. Each protein has its own set of both common and unique side effects.
For BCMA, the things we watch out for are blood count issues and infection risk with long-term use. With GPRC5D, there is an infection risk, but this same protein can also present in skin, nails, and in the salivary glands. GPRC5D can potentially cause appetite issues or dryness of the mouth, changes in taste and sometimes, changes in skin and nails. The extent of symptoms may vary from very mild to possible skin peeling. However, every patient is different, and one can hold the medication, reduce the dose, as well as the schedule of medication. These are some unique issues with both proteins and they are kind of more long-term, as patients continue treatment.
Cytokine release syndrome is a side effect that tends to happen within the first two or three doses of bispecific antibodies. White cells and immune cells get activated and go after myeloma cells; thus, they can secrete certain chemicals which might make you feel as though you have an infection.
Fever, maybe low blood pressure are possible side effects that can happen to a little over half of the patients but are typically very mild and manageable. This is why we watch out for these side effects very carefully when patients get initial or step-up doses and give some steroids or tocilizumab, if needed.
3. Are bispecifics safe for frail patients?
Typically, what we've seen with bispecifics is once the patients are through the step-up dosing, it's pretty safe to give in the outpatient setting.
For frail patients, my practice is, if I need to give them bispecifics as step-up dosing, I will admit them to the hospital to make sure that they're okay during that phase. I would monitor for cytokine release syndrome and treat it right away even when it's low grade.
Once they get into the outpatient setting, we can give the bispecific less frequently. We don't have to give it weekly from the get-go. We can give it every other week, even every fourth week, or once a month because the objective isn't to get a response super-fast, you have to balance the good effects and the side effects at the same time.
We don't mind if we get the best possible response in four months, rather than two months. The idea is to get a recipe that would work for the frail patient.
I saw a patient who is in his mid-eighties recently for step-up dosing. He had a really nice response and tolerated the bispecific combination fine. The patient was then transitioned to the outpatient setting and will be receiving treatment every four weeks. These clinical judgments or decisions can be made after having a discussion with your patient in order to come up with a more personalized plan.
Once you start the bispecific, it will start working. Many of us in the clinic will also start dialing down the schedule for treatments, beginning with once-a-week dosing. When the patient responds, treatment might be reduced to once every two weeks or once a month. Bispecifics are quite effective even among patients who have had myeloma return 2-3 times. If given to a hundred people, we would expect 60-70 patients to have a very good response. That is quite a high number.
4. When is it appropriate to receive an MMR vaccine after having an autologous stem cell transplant?
Typically, we have to wait a little bit longer to receive live attenuated vaccines after patients have had an autologous stem cell transplant (ASCT). And the practice varies from one transplant center to the other. We would start that series at least 9- 12 months after recovering from ASCT. However, every center is different and there are some minor differences between one versus another center. Just follow the advice of your care team and one protocol. At the end of the day, the objective of each of these protocols is to deliver these vaccines in a sequential fashion to replenish your immune response to each of these vaccines.
5. Has the standard of care for frontline therapy changed recently?
The answer is yes. We have gone from using three drugs as frontline treatment for both transplant eligible and transplant ineligible patients to four-drug combinations or quadruplet induction regiments.
There have been Phase III trials where we've looked at four- versus three-drugs for both transplant eligible patients and patients who are not getting a transplant. In both situations, we discovered in trials that the four-drug combination gives a better depth of response, higher response, depth of response, higher MRT negativity rates, and better progression-free survival compared to the three-drug combination.
Patients go into a deeper response and stay in remission longer than they would, as compared to getting a three-drug combination. This is something that is becoming a standard of care.
The only caveat is for older patients who are not eligible for transplant. For those patients, we still utilize three-drug combinations like DRd. That is an appropriate choice for patients.
However, there is nothing wrong with three-drug combinations. They are still appropriate. It’s just that the standard of care, especially in the last year, year-and-a-half, has started to move towards the four-drug combinations because we are getting all of these clinical trials that are coming down the pike. They are maturing and showing us all this exciting data.
6. Would you suggest clinical trials at each stage of treatment?
That is something that I do encourage and talk to my patients about, if there is a clinical trial that they are eligible for. It's important to have those discussions. The analogy that I give to patients is all the treatments that we've developed in myeloma, it's because of patients who went on those clinical trials to prove that they work.
Just like the example I gave on the four- versus three-drugs clinical trials, there were patients who actually went on those studies to prove that four drugs may give better depth of response and survival outcomes. That is why it has become a standard of care. It’s a way of paying things forward.
There were patients who went on studies to enable you to get the treatments that you are getting now. It might be a bit altruistic from that standpoint. Who will be the first patients who can get cured from myeloma? They'll be those who go on trials first. It'll be probably a trial where patients get a new treatment approach that may cure them. I mean that's what we are looking for right now. It could be a little bit self-serving too. If you go on the clinical trial and get a treatment approach that could potentially be a future cure.
There are many different reasons, but it is a nuanced discussion. You have to weigh the pros and cons. The decision is always yours. And one thing that I have to also share: when patients go on a clinical trial, just because they signed up does not mean they cannot withdraw consent. If, for any reason, you feel that you can no longer participate in a clinical trial, it's okay to have that discussion.
7. Is myeloma curable and what is your definition of cure? What is your prediction for the prospect of more patients being cured?
We know that there is a subset of myeloma patients who were treated and have been cured or can be cured. We have known this over the past two decades, but the proportion of patients was very low. It's like single digits. What is our aspirational goal? We want the majority of our patients to be cured, where we treat patients, they're off treatment, and the stuff never comes back.
The way that we are thinking about this now, we have all these wonderful treatments four-drug induction treatments, immunotherapies, bispecific antibodies, CAR T-cell therapies, and we are working on the right sequence of these treatments in clinical trials. We want our patients to go into a deep response, which is called MRD negativity.
We want our patients to stay MRD-negative for an extended period of time. After being MRD-negative for maybe two or three years, we are comfortable that “Hey, this is real, this is happening. There is nothing on PET scans, there is nothing that we can detect in the blood, the bone marrow biopsy and MRD negativity testing looks fine. Let's take patients off treatment and then continue to do the MRD testing for a few years.”
Many of us feel that once patients have achieved MRD negativity in that fashion and we discontinue treatment and patients stay in remission, with very deep response for at least five years (if not more) then we'd be comfortable to say that myeloma is likely cured in this situation.
We are just beginning to delve into these definitions for myeloma because myeloma generally happens later in life, although we have young myeloma patients as well. But to define curability in myeloma, we are going to have to draw a line somewhere. And that's what we are thinking about at the moment.
In case you missed it, you can still watch a replay of Dr. Usmani’s Facebook Live Q&A in its entirety.