Multiple Myeloma: Stem Cell Transplant and Beyond

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Multiple Myeloma: Stem Cell Transplant and Beyond

Wednesday, April 21, 2021

Presenter: Frits van Rhee MD, PhD, Professor of Medicine and Clinical Director of the UAMS Myeloma Center, University of Arkansas for Medical Sciences

Presentation is 38 minutes long with 21 minutes of Q & A.

Summary: Multiple myeloma is the most common cancer of the bone marrow. This presentation discusses transplant options and drug therapies for treating myeloma. It also reviews options for maintenance therapy and responding to relapses.

Highlights:

• Early aggressive treatment is indicated for multiple myeloma because the second remission is usually shorter than the first one. For transplant eligible patients, autologous transplant remains the frontline therapy.
• Maintenance therapy is better called extended therapy because it is used not only to maintain remission and prevent relapse but also to eradicate residual myeloma cells. However, balancing its benefits versus its toxicity makes for a challenging decision about when to stop maintenance therapy.
• CAR-T cell therapy shows promise for treating multiple myeloma despite significant side-effects. Transplantation remains the standard treatment although with improvement in the efficacy and tolerability CAR-T cell therapy, it may partially replace transplantation in the future.

Key Points:

(03:57) Myeloma involves malignant cells that infiltrate bone marrow and crowd out normal cells. It can cause anemia as well as bone destruction.

(06:53) Physiological age is more important than chronological age in transplant eligibility. Older but fitter patients may be better candidates than younger but sicker individuals.

(08:00) The aggressiveness of the disease also informs decisions about transplantation by dividing patients into high risk or standard risk groups.

(10:39) Transplant involves harvesting the patient’s own cells and returning them after high-dose chemotherapy. Additional cells may be harvested for a second or even third transplant if needed.

(13:11) Survival outcomes are better with transplant than with novel drug therapies alone.

(14:58) Using medications like daratumumab may improve the response rate and overall outcome.

(19:29) There are several options for maintenance therapy. These include Revlimid, proteasome inhibitors, and combinations of various drugs.

(21:35) Relapses can occur sooner or later and slower or faster. Treatment for relapse is highly individualized based on previous toxicity, blood counts, and marrow reserve.

(23:58) Several drugs are available for relapsed myeloma. Their side effects should be closely monitored.

(36:50) Newer therapies are mostly used for relapse, although clinical trials are underway to assess their efficacy for use in earlier treatment and for highly aggressive disease.

Transcript of Presentation:

(00:01) [Sue Stewart]     Introduction. Hello and welcome to the workshop: Multiple Myeloma: Stem Cell Transplant and Beyond. My name is Sue Stewart and I'll be your moderator for today. It's my pleasure to introduce today's speaker, Dr. Frits van Rhee. Dr. van Rhee is a professor of medicine and the clinical director of the Myeloma Center at the University of Arkansas for Medical sciences. He has pioneered many advances that have become standards of care for myeloma patients and have improved survival rates for patients with myeloma. Please join me in welcoming Dr. van Rhee.

(00:43) [Frits van Rhee]     Overview of talk. Thank you. First of all, I'd like to thank all of you for joining this session and I'd like to thank the organizers for giving me the privilege to present about multiple myeloma. I work at the University of Arkansas for Medical Sciences and we've had the myeloma center here for the past 31 years. So we started in 1989 and we've treated the vast number of patients here.

(01:16) I will be talking about myeloma, giving you a brief introduction to myeloma, then turn to stem cell transplantation, particularly discussing the issue who should have a transplant, say a few words about the stem cell transplantation process, then move on to how new drugs are being increasingly incorporated in the transplant treatment algorithm. Then we move on to say a few things about maintenance therapy after stem cell transplantation. And finally, there's the important issue about relapsed myeloma and the advent of novel immunotherapies.

(02:05) Myeloma is the most common cancer of the bone marrow. So, myeloma is a fairly common disorder, about 30,000 cases occur every year. It's the second most common hematological malignancy and it's in fact the most common cancer of the bone marrow.

(02:20) Myeloma is more common in the elderly, males, and African Americans. It's predominantly a disease of the elderly. However, it can also occur in younger patients and we have a whole slew of patients diagnosed in their 30s and 40s and even a few patients who are diagnosed in their 20s.

(02:36) It's more common in males, more common in African Americans. For most patients, we do not know the cause and environmental toxins like Agent Orange and irradiation have been linked to the disease, as well as disorders which chronically stimulate the immune system like autoimmune disorders.

(02:58) Myeloma has several principal features. So what are the principal features of myeloma? Myeloma is characterized by plasma cells whose normal job it is to make antibodies, which become malignant and are in the bone marrow and churn out large amounts of one type of antibody which we call the M-spike or paraprotein. And sometimes they also exclusively make part of the M-spike which are called the free light chains.

(03:31) Another hallmark of myeloma is bone disease and you can see here pictures of lytic lesions in the skull, we've got [inaudible] skull, and here in an arm bone. So these are some of the features of myeloma and the M-spike can be detected on the serum protein electrophoresis.

(03:57) Myeloma involves malignant cells that infiltrate bone marrow and crowd out normal cells. So myeloma infiltrates to bone marrow can crowd out the normal cells and cause anemia. Myeloma also can cause bone destruction, particularly in the vertebrae and in the long bones and could give rise to fractures and elevate the blood calcium. The elevated blood calcium, as well as the light change, can affect kidneys and cause kidney impairment or even complete kidney failure.

(04:29) Very high quantities of the myeloma protein can cause what we call hyperviscosity syndrome which is sluggishness of the blood and can give rise to circulation problems and then seizure.

(04:45) The myeloma protein can deposit in the tissues as light chains or as clusters, clusters of light chains which we call amyloidosis, which can affect organs like the heart and kidney.

(05:01) And lastly, there's a deficiency in production of normal antibodies and patients are more prone to get infections.

(05:16) There are two basic treatment strategies: with or without transplant. So what is the current treatment strategy for myeloma? If you're transplant-eligible, you get induction chemotherapy, at least one transplant, often some form of consolidation after the transplant, and then maintenance.

(05:33) If you're not eligible for transplant, there is induction chemotherapy and then often after eight to 12 cycles of treatment, the intensity of treatment is reduced and patients remain on one or two drugs and these are continued until progression. So this is the overall treatment algorithm for myeloma.

(05:57) Early aggressive treatment is the best course. It is also true to say that you need to get your best therapy upfront because usually the second remission is shorter than the first one. So in general terms, most of us subscribe to the idea that you really should go to war with your best army upfront and don't keep drugs in reserve. So you don't keep your crack troops on standby, so to speak.

(06:33) Transplant is part of frontline therapy. An important question also is whether to transplant or not. And I think in 2021, many of us myeloma physicians would still consider transplantation part of frontline therapy.

(06:53) Physiological age is more important than chronological age in transplant eligibility. In Europe, patients are divided into transplant-eligible or not eligible based on age and the cut-off is 65 years. In the States, we tend to more look at what we call physiological age or, in effect, how fit the patients are. Whilst it's true that elderly patients may be transplant-ineligible, there are also fit elderly patients who are, for instance, 70 years old, are in good physical condition, who have a lifespan of 10 years or longer and well, might still be considered for stem cell transplantation.

(07:32) Obviously, you need to look at the fact of whether there are other diseases present which makes a patient less fit, particularly lung disease, heart disease, sometimes liver disease. Kidney disease can be an issue. Older patients with kidney impairment and even those on dialysis can still be considered for transplantation.

(08:00) The aggressiveness of the disease also informs decisions about transplantation by dividing patients into high risk or standard risk groups. The other thing that we sometimes look at is the aggressiveness of the disease and this can be measured by a number of tests and I will talk about this later and these include MRI, PET scanning, blood markers for disease burden such as β 2 microglobulin, albumin, LDH which is also measured in the blood or marrow examination. We do that to divide patients into two groups, high-risk or standard-risk disease. First of all, this has an impact on prognosis, whether you know whether patient is high-risk or standard-risk. Secondly, we often do tailor our therapy with regards to whether a patient is high or standard-risk disease.

(09:00) One of the tests we do is called metaphase cytogenetics, which means we take the patient's myeloma cells and grow them in the test tubes and look at them when they divide. The advantage of this test is that you can see all the human chromosomes under a microscope, so you can sort of see all the genetic material. There are patients who have extra copies of the long arm of Chromosome 1, which are from Chromosome 13 and 15 in the red arrows. The advantage of this test again is that you can see all the material. The disadvantage, that only in 30% of patients, the myeloma cells will grow outside the bone marrow environment in the test tube. So it's only informative in 30% of patients.

(09:51) The other test is called fluorescent in situ hybridization or called FISH. And we use very specific probes to detect specific abnormalities, such as translocation (4;14) which means Chromosome 4 and 14 has swapped material. And if you label two copies of Chromosome 4 and 14 with different color probes, you can see here on the right-hand side, when these overlap, that you've got a yellow-ish signal. So the FISH test can be done on resting cells and it's, in principle, informative in all patients. However, you will only find what you look for, so it depends on what probe you look.

(10:39) Transplant involves harvesting the patient’s own cells and returning them after high-dose chemotherapy. Turning over to the stem cell transplantation process. Typically, we mobilize stem cells into the bloodstream using growth factors like G-CSF also called Neupogen or Granix. And sometimes we use a drug called Mozobil. Some of us like to give chemotherapy beforehand which we think enhances the ease and the yield of the stem cells.

(11:11) The stem cells are then frozen and returned to the patients after high-dose chemotherapy. The stem cells are infused into the bloodstream and take about 10 days to start to grow in the bone marrow. And usually the blood counts, particularly neutrophil count starts to come back around day ninth and tenth, and the platelets start to recover around day 14. The whole process can be done as an outpatient. We did our first outpatient stem cell transplant in 1991. We in fact, prefer to do our transplants as an outpatient because we think that keeps our patients more mobile and in better physical condition.

(11:58) Additional cells may be harvested for a second transplant if needed. So in general terms, we'd like to collect stem cells after no more than four cycles of induction chemotherapy, and the most commonly used regimen in the United States is called VRd, which stands for Velcade, Revlimid and Dexamethasone. And increasingly, Daratumumab or Darzalex, the monoclonal antibody directed at CD38 on myeloma cells is added. We like to collect more cells for the rainy day, at least sufficiently for two transplants or even a third transplant or to be used for replenishing the bone marrow when the patient has been heavily treated.

(12:42) There's a variety of treatment regimens for relapse. Standard dose of Melphalan is 200 milligrams. We need to square it within older patients or less patient, the dose can be reduced. And sometimes you make Daratumumab concoctions for an individual patient. Two transplants are especially considered at this time for high-risk disease.

(13:11) Survival is better with transplant than with novel drug therapies alone. So do we still need transplants for myeloma with all these novel drugs? It's a question which is often asked. There's a study which is French-American study in which VRd or eight cycles followed by Revlimid maintenance, was compared to an approach which includes a transplant on top of VRd regimens. And there was an option to do a delayed transplant in the non-transplant arm of the study. So we look at the left-hand side here, the progression free-survival, that is the survival without relapse occurring, was better in patients who received a stem cell transplant. So this study is often quoted as the reason for incorporating a transplant in the upfront approach to transplant-eligible patients.

(14:11) Two transplants may be appropriate for high risk patients. The issue of two transplants in a row, or tandem autologous stem cell transplantation, is still somewhat contentious and some studies have shown benefit and others have not. This is an example of a European study where there is actually a difference with two transplants, both in progression-free and overall survival and the overall survival is shown on the right-hand side. However, this has not been demonstrated in all patients and in some centers, two transplants are confined to patients who only have high-risk disease.

(14:58) Using medications like daratumumab may improve the response rate and overall outcome. Introduction of daratumumab, the anti-CD 38 monoclonal antibody, has offered the opportunity to incorporate this in transplantation approaches. And one of the induction regimens which has been used is called DARA, Daratumumab-VRd or RVd, which is done followed by a transplant, then consolidation with VRd and the maintenance with Daratumumab regimen. So this is a randomized study and patients in the control arm received exactly the same treatment but not the Darzalex drugs at all stages of the therapy as an induction consolidation and maintenance.

(15:41) Now this is probably my most complicated slide. So this is organized, on the left, you can see the patients who received daratumumab-VRd or Rvd and on the right, patients who only received RVd. And then you see the different treatment stages, end of induction, end of transplant, end of consolidation, and after 12 months of maintenance. And the bars represent response.

(16:13) And just look at the orange and the purple bars. These are patients who are in complete remission or better. And you compare the two sides of the slides in terms of end of induction, the daratumumab-RVd, 19.2% of patients are in complete remission and only 13% of patients who did not receive Daratumumab. Last 12 months of maintenance have been completed. The complete remission rate is 81% in patients who receive Daratumumab-RVd and only 60% of patients who received RVd or VRd. So the response and the depth of response were much greater for patients who received daratumumab. And at this moment in time, the bars start to separate in terms of progression-free survival. So we hope that in future we are not only going to see better response rate, but that these will translate into better outcome.

(17:19) So this particular study showed better response rate, follow-up is not long enough here to see differences in progression-free survival. Also, it should be said that daratumumab-VRd seem to be having less benefit in patients with high-risk disease. Adding the Daratumumab for a bit caused some extra toxicity, particularly in terms of infections, and there was a little bit more difficulty in terms of collecting stem cells with more patients requiring a second drug like Mozobil.

(18:01) Maintenance therapy is better called extended therapy because it is used not only to maintain remission and prevent relapse but also to eradicate residual myeloma. Just to say a few words about maintenance therapy. The goal of maintenance therapy is to keep patients in remission and to prevent relapse. I personally think that maintenance therapy is a misnomer, I like to call maintenance therapy, extended therapy because the maintenance is really not intended just to keep the patient where they are in terms of disease burden, but to gradually help to eradicate residual myeloma cells as well.

(18:36) Deciding when to stop maintenance therapy and its toxicity is challenging. Obviously, once you give maintenance therapy which is acceptable in terms of toxicity and not too much impact on the quality of life, there's a lot of discussion about whether one should be doing ongoing maintenance and you don't stop it, or perhaps it's fixed duration maintenance. I think there is a lot of new data on minimal residual disease and there are trials going on at this moment trying to test whether you can stop maintenance therapy based on minimal residual disease negativity. So in other words, if a patient has sustained minimal residual disease, negativity, you could stop the main therapy early. So that's I think, where are we going in the future.

(19:29) There are several options for maintenance therapy. So what are the options for maintenance? First of all, there's a Revlimid, which is the most commonly used maintenance therapy. Then there are the proteasome inhibitors like Bortezomib and Ixazomib or Ninlaro. Daratumumab is in a number of clinical trials at this moment. And then there are also combinations of drugs like Velcade, Revlimid, and Dexamethasone, or Revlimid and Daratumumab combined.

(19:59) This is a very large study, looking at three trials, lumped together, of maintenance therapy which shows that patients who received Revlimid as maintenance have significant improvement in overall survival at seven years. 62 versus 50%. And this is a very large study incorporating more than a thousand patients.

(20:35) The oral proteasome inhibitor called Ixazomib, and which many of you know as Ninlaro, has also been tested in a clinical trial and compared to placebo or fake drug. The maintenance with Ixazomib improves progression-free survival by about eight months. So overall, maintenance therapy in myeloma improves the progression free-survival. However, it doesn't always improve overall survival. There are some downsides. There's the risk of second cancer, also that of the bone marrow, which is bone marrow dysplastic syndrome. It can sometimes impact on quality of life and affect the blood counts.

(21:35) Relapses can occur sooner or later and slower or faster. Now turning over to managing relapse. The first thing to say is that not every relapse is the same. There are patients who relapse many, many years after their initial therapy, they relapse very slowly. Sometimes we call them biochemical relapse or incipient slow relapse. And many of these do very well with a second therapy. Very often monoclonal antibodies such as the daratumumab drug are used in that setting. Other patients will relapse very early or whilst on treatment and those relapses are very often more difficult to manage.

(22:16) There are a number of new myeloma drugs now available. Now, a number of new myeloma drugs have been approved since 2000 and these are depicted here in blue. We have the proteasome inhibitors, Bortezomib, Carfilzomib, Ixazomib or Ninlaro. In purple are some antibodies, Daratumumab, Elotuzuma, Isatuximab. And then more recently, an antibody has been approved which is called Belantamab which carries a chemotherapy agent. And then there are CAR-T cells, very recently approved, a drug which was called Ide-ce,l and I'll talk about this later.

(22:57) Treatment for relapse is highly individualized. It's very important to realize the treatment of relapse is very often very individualized. There is no one shoe fits all. Treatment is very often determined by previous toxicity that occurred as a result of prior therapies or even complications due to myeloma. Or even function, how good the blood counts are, how strong the marrow reserve is. And also as I alluded to, when the patient relapses, many years after initial treatment or whilst on active therapy.

(23:37) So it's exciting that we have a number of novel drugs approved for multiple myeloma which utilize the immune system. And I won't discuss all of them I will confine myself to drugs which have been recently approved for the treatment of relapsed myeloma.

(23:58) Several drugs are available for relapsed myeloma. The antibody drug conjugates which is called belantamab or Blenrep delivers a cytotoxic drug bound to the antibody directly to the myeloma cell. So the working ends of the antibody recognizes a molecule at a cell surface of myeloma cells called B cell maturation antigen or BCMA. So the antibody docks to this BCMA. The antibody and the cytotoxic drug cargo get internalized into the myeloma cell, the chemotherapy drug gets released and kills the myeloma cells. So you can see it's a little bit like silver bullet, an antibody precisely delivering the drug where it's needed, and that is in the myeloma cell. So this drug is approved for patients who have at least four lines of prior therapy which have included an anti-CD38 antibody, like isatuximab or daratumumab. And we've seen drugs in the class of proteasome inhibitors like Velcade and Bortezomib or we've seen immunomodulatory drugs like Revlimid or Pomalidomide or Pomalyst.

(25:10):  So this is the first study which was done with the Belantamab or the Blenrep drug and you can see here that there was a median progression-free survival in this patient of about 12 months, somewhat less than patients who were refractory to daratumumab but it still has activity there. And many of these patients have seen a lot of different drugs including both the proteasome inhibitor and immunomodulatory drugs. The overall response rate in these patients was about 30%. Now what's interesting to know with this drug, its that's very often one can evaluate whether a patient is going to respond to therapy after one or two doses. And then many of the patients who do respond, seem to have fairly sustained responses which can last up to a year and in some patients longer. So one little note with this drug, whether the patient responds very quickly and very often, those who do respond, have fairly durable responses.

(26:43) One of these medications may have side effects on the cornea and should be closely monitored. Now, the principal side effects of the Blenrep drug pertained to the cornea. It affects the corneal stem cells and it can cause the cornea to look abnormal under examination by the ophthalmologist. And it can cause reduction in vision or blurry vision. Now this is reversible but it can interfere with the quality of life such as reading or sometimes even driving.

(27:18) Another side is blood count suppression. Now in the first study, these clinical events we reported in about 63% of patients. Time to onset of occurrence of the side effects was about 23 days and time to resolution 30 days.

(27:40) Now, this drug is available under what is called a REMS program. So the patient needs to have a corneal exam by an optometrist or an eye doctor prior to every drug and the effects of on the cornea needs to be graded. And depending on that, the drug can be given or not. So it is inconvenient that patient needs to have an eye exam before you can get the drug. Those reductions or those delays are fairly common but fortunately, patients do not seem to lose their response during those delays. So if the patients who do respond and who have significant dose delays, 80% continue to maintain their response.

(28:35) CAR-T cell therapy also shows promise. And then there are the CAR-T cells. Now CAR stands for chimeric antigen receptor T cell and the first set of products approved is called Ide-cel previously known as bb2121. And these are immune cells from the patient that have been genetically modified using a virus, smuggle some DNA material into the immune cell of the patients and expresses an antibody fragment which attaches to the BCMA molecule on the myeloma cell, and at the same time, activates the immune cell. And the immune cell then goes on to kill the myeloma cell.

(29:26): So the way this works is, the patient gets apheresis. Patient does not get chemotherapy to collect the immune cells like we do for stem cell, but the patient does get connected to an apheresis machine., The cells get sent off to the manufacturing laboratory where the cells are genetically altered to express this CAR receptor They are multiplied and then infused into the patient after the patient has received what is called lymphodepleting chemotherapy. It is chemotherapy which reduces the number of immune cells present in the patient, prior to return into the patient, of the genetically altered and activated immune cells. The purpose is to generate space for these anti-myeloma immune cells to expand.

(30:29) These are responses which were recently published in The New England Journal of Medicine and the bars here are organized by the number of cells given. So here 300 million cells were given and 70 patients received such therapy. And you can see that the complete response rate which is in the light blue and dark blue bars, those are in the order of 28%. For the highest cell dose for 50 million which 54 patients receive the complete response rate is in the order of 40%.

(31:16) This next slide demonstrates progression-free survival according to cell dose, and patients who receive the highest dose fared better. It is fair to say that the follow-up of each patient is still somewhat short and that we need to see whether these responses remain durable.

(31:42) CAR-T cell therapy can have significant side-effects. So what are the side effects of CAR-T cell to therapy? You obviously have heard about cytokine release syndrome. This is a systemic inflammatory response due to the activated immune cells releasing what we call cytokines, things that you've may have heard about, things like interleukin-6 and gamma interferon and these can give rise to fevers, chills, low blood pressure, problems with breathing and in severe cases, organ failure and even death. Neurological toxicity such as lethargy, difficulty concentrating and in more severe cases, agitation of seizures or even swelling of the brain can occur. This is called neurological toxicity and the technical word is immune effector associated neurotoxicity syndrome or ICANS syndrome, some of you may have heard this term.

(32:56) Now, these are the side effects by grading. The severe forms of cytokine release syndrome occur only in a very small percentage of patients, that's less than 1%. In fact, the onset is one day and the median duration of this cytokine release syndrome is about five days. There is treatment obviously available. Very often an antibody called tocilizumab can dampened down the cytokine release syndrome. The neurotoxicity is, with this particular product, also usually not severe. If it occurs, it occurs early after treatment and it can be treated with steroids and other measures. So overall, this cytokine release syndrome and neurotoxicity side effects are usually not severe and quite manageable with these products.

(33:57) The decision to use CAR-T cell therapy turns on several factors. So what do you choose? Do you choose an immune cell or an antibody therapy? Now what are the pros and cons? Now, if you're giving the CAR-T cells, you need to give this lymphodepleting chemotherapy.  It's usually three doses of a drug called Fludarabine and three doses of a drug Cytoxan which means that you do need to have reasonable blood counts to start with, otherwise your marrow goes on strike for quite a bit. And in fact, in the study that I've just mentioned, three patients required stem cell rescue.

(34:32) When you make the CAR-T cells, it also depends on the patient's own immune cells. And if you've had a lot of therapy to beat up your immune cells, you can't produce high-quality CAR-T cells in the laboratory and they're not as effective when you re-infuse.

(34:55) Also, the CAR-T cells are usually given in a hospital or an academic hospital. And The CAR-T cells are hospital-based and the antibody therapy, like Belantanamab, can be given by the community oncologist.

(35:13) The CAR-T cells are often a single-shot dose and it's obviously rather complex to make. Having said that, the response rate is higher and there are more side effects which is cytokine release syndrome and neurological abnormalities.

(35:38) There are advantages and disadvantages of antibody vs. CAR-T cell therapy. Now when you're done look at an antibody like Belantamab, you don't need to give prior chemotherapy, it can be given to even very elderly patients. So the physical fitness of a patient is not that important. You still need to have some reasonable blood counts but it doesn't depend on the quality of the patient's immune system.

(36:02) So the antibody will work even if the immune system of the patient is not in such good shape. It can be given by the community oncologist, in multiple doses, and it's off-the-shelf. It's not as complex to manufacture but it does require monitoring by an eye specialist or an optometrist. The response rate is lower than what you see with the CAR-T cells and side effects are principally related to vision. So there's a different spectrum of side effects which permits you select a certain product or a specific patient.

(36:50) Newer therapies are mostly used for relapse. So overall, I think that the new therapies are very exciting. At the moment, they're mostly used in the relapse setting. Obviously, there are clinical trials ongoing to try and move this therapy earlier on in the treatment approach and it's likely that we're going to see this perhaps even for patients with very aggressive disease early on in treatment and hopefully improve outcome.

(37:25) Transplantation remains important though CAR-T cell therapy may partially replace it in the future. I personally do think that there is going to be still room for stem cell transplantation in many patients and, at least, at this moment in 2021, we're not ready to abandon stem cell transplantation and replace it with CAR-T cell therapy. However, it's not inconceivable that with further improvements in CAR-T cell therapy in terms of efficacy and tolerability, that in due course, it may at least partially replace stem cell transplantation.

(38:00) So overall, these are exciting times with many new therapies becoming available for myeloma. And hopefully in future we'll continue to improve the outcome of multiple myeloma. And I'm going to leave it there with 40 minutes into the talk and we're going to open it up to questions.

Question & Answer Session

(38:23) [Sue Stewart]     Thank you, Dr. van Rhee, that was an excellent presentation that covered a lot of ground. Lynne, I'm going to ask you to take over managing the questions for a moment. Can you do that?

(38:37) [Lynne]     Yes, that'll be fine. Okay. The first question we have is: Would you please discuss the re-vaccination protocol for childhood diseases after transplant. It differs from program to program I have found, and I don't mean the new COVID vaccine.

(39:06) [Frits van Rhee]     It does indeed vary from program to program. Some programs only use Revlimid as maintenance after stem cell transplantation and Revlimid does not affect the immune response adversely. In fact, it may slightly stimulate it. So if you're on a regimen where you're only getting Revlimid as maintenance, it does make sense to re-vaccinate patients. We very often use multiple drugs as maintenance like a combination of Velcade, Revlimid and Dexamethasone, or even for higher risk-patients carfilzomib, Revlimid and dexamethasone. And then you put drugs into the mix which are immunosuppressive and you wonder how effective it is to give these childhood vaccines. And we usually don't do it.

(40:05) This is also based on the notion that we see very few problems with childhood illnesses fortunately in our transplant population, and we've done over 10,000 transplants here. So these childhood illnesses fortunately, are not a problem, even if you don't re-vaccinate. I won't belabor the COVID-19 vaccine which we give to everybody, we usually do recommend the flu vaccine and the pneumonia vaccine, as well, regardless of maintenance therapy.

(40:43) [Lynne]      All right, thank you very much. We'll go on to the next question. And this gentleman says: I'm currently on maintenance treatment, eight months post-transplant, how likely am I to get cancer in other areas of my body after transplant such as in the colon?

(41:01) [Frits van Rhee]      Okay, so there is only a risk of secondary malignancies which is a couple of percent. Colon cancers are really not common, you definitely should do all your routine care as well such as having your colonoscopy as indicated. And the risks of second cancer are small and the benefits of maintenance therapy far outweigh the risks. So the general recommendation is to definitely do your maintenance therapy. You're much more likely to derive benefit than having the small chance of having a second cancer.

(41:49) [Lynne]      All right, thank you. This person would like to know if you can explain the difference or the advantages of Kyprolis Carfilzomib versus Velcade in extended therapy?

(42:01) [Frits van Rhee]     Okay, I think that's a really important question. So in some clinical trials, it appears to be that Kyprolis is doing better than Velcade. However, there has also been a clinical trial which is called the Endeavor Clinical Trial where Carfilzomib and Velcade produced equally, although the criticism of that trial is that this was more selected for standard-risk patients. Kyprolis can be still effective in patients who relapse after Velcade and many of us do think that Kyprolis is a somewhat more effective drug. Kyprolis has a small incidence of cardiac side effects and we monitor the patients for tha,t and the many of us reserve the Kyprolis drug for patients with more high-risk disease.

(43:14) [Lynne]      All right, thank you. This individual said that he had a stem cell transplant in October at age 62. He started Revlimid maintenance in February and he knows that some people stop Revlimid after two years but his oncologist is recommending that he stay on it for life. Can you explain why some patients might be on it for only two years and others might consider being on it for life?

(43:42) [Frits van Rhee]      Well, the idea here, obviously is that there continues to be a... That there is a significant risk of relapse and a prolonged Revlimid therapy can prevent relapse. So the question between sustained therapy versus limited therapy is a very important one. There, for instance, has been a trial, this was admittedly a non-transplant patients, or the first trial where the patients with a long Revlimid Dexamethasone therapy fared better than patients who had fixed duration Revlimid and Dexamethasone. So there is difference in clinical practice in the United States and I think in the future that this is going to be guided by minimal residual disease-testing. And the patients who have multiple minimal residual disease tests which are negative, for instance, two years apart, that these patients are going to be selected for early discontinuation of maintenance, while those patients who continue to be MRD positive perhaps should continue with their maintenance therapy.

(45:05) So at this moment in time, there's not quite a right or wrong answer. There are no clinical trials mature enough at this moment to guide patients on the duration of maintenance, based on minimal residual disease-testing, so those are data which are still being awaited. The two types of minimal residual testing which are available, there is one called flow cytometry and the other one is a molecular test called clonoSEQ, slightly more sensitive and the patient should discuss with their clinician whether this test can be performed on their bone marrow. And preferably, I think ,serially to get an idea of whether he is what we call minimal residual disease negative or not. So it's a very important question, but as yet not fully answered.

(46:09) [Lynne]     Thank you for that answer. The next person wants to know how long she can expect fatigue after an auto transplant for myeloma. She's been out for three years and is still experiencing fatigue and is wondering if you have some suggestions on how to manage that.

(46:26) [Frits van Rhee]      So fatigue is a common problem after cancer therapy. Sometimes the Revlimid drug, if the patient is still on that, can cause some symptoms, sometimes some diarrhea, sometimes a fogginess in the brain, we call that chemo brain, sometimes patient doesn't quite feel right. I think it's important to try and be physically active if feasible, try to be in good physical shape to do some exercise. Obviously, you don't need to run the marathon but be physically active, do what you can, eat a healthy diet. Also, try and be positive.

(47:14) Many of our patients do very well and they have very good long-term outcome. So a positive attitude, healthy diet, vitamin replacement, I think are all very important. And sometimes, if feasible, patients would also consider going back to work if they're still in working age because I think work also distracts and helps people to feel a productive member of society. And that's really the goal of therapy to have patients fully functional.

(47:54) [Lynne]      Thank you. And I might also add that tomorrow at the symposium, Dr. Manzullo will be doing a session on fatigue. So if you're interested in learning more about fatigue management, that might be good for you to check out.

(48:08) [Frits van Rhee]      If I'll make one more comment. Sometimes patients cope with depression after the stem cell transplantation and these treatments. And sometimes talking with a friend or a pastor or talk about their worries with their doctor or whoever they trust in, can really help. And sometimes even some counseling can help. So there are a number... And this all is very patient-dependent. A support group can be of a lot of help as well and joining a support group I think is very important too.

(48:49) [Lynne]      You're right, good ideas. Alright, we have a number of questions as you can imagine about COVID. People are wondering whether they should get the vaccine, at what point during their treatment they should consider getting the vaccine and if there is anybody who should not get the vaccine if they're undergoing treatment for myeloma.

(49:12) [Frits van Rhee]      Okay, if the patients are about to get a transplant, there is probably not much point doing the vaccine. Everybody else probably should have the vaccine at least starting 100 days after transplant. If patients are on ongoing therapy which may suppress the immune system, like Velcade or Dexamethasone or Daratumumab Darzalex, then the recommendation is to still give the vaccine. Maybe the antibody responses are a little bit less than in a normal individual, but the patient may still derive some protection from the vaccine. So I strongly encourage patients to be vaccinated. If feasible, and that depends very much upon the patient, one can sometimes generate a little window of therapy for the patient to receive their vaccines. Drugs like Revlimid don't actually actively suppress the immune response and don't necessarily need to be stopped for vaccination.

(50:27) Now patients often ask me, "What vaccine should I take?" I usually tell them to take one of the two-shot vaccines, that is the Moderna, AstraZeneca or Pfizer vaccine. If your immune system is not in tip-top shape, as it can be after or during myeloma therapy, it makes sense to give a priming dose and a boost dose.

(50:57) So overall, these vaccines are very safe. There has been a lot of news about blood clots in the brain which have been described with the Johnson & Johnson's and AstraZeneca vaccine. They occur at very low incidence and primarily in younger females and I am not against patients being vaccinated with the AstraZeneca vaccine. And obviously, any of these serious but very rigorous side effects have not described with both RNA vaccines, that is the Pfizer and the Moderna vaccine. So the answer is yes, we recommend vaccination for patients and also for the family members.

(51:45) [Lynne]      All right, thank you. I'm sorry, excuse me. How often do you see peripheral neuropathy develop after a stem cell transplant when the patient has not been on any drugs that are associated with neuropathy?

(52:02) [Frits van Rhee]    Okay, Melphalan by itself does not cause neuropathy, so the transplant itself does not induce neuropathy. Drugs like Revlimid can cause neuropathy. Velcade is more often the culprit.

(52:22) There are also other reasons why patients can develop neuropathy. I mean, diabetes is obviously a very common cause of neuropathy. And finally, if a patient has a very short disease course and hasn't been diagnosed very long, very occasionally, and if patient is not on remission, the myeloma protein can affect the nervous system and also cause neuropathy. But I think the issue is to look at the medical history, to look at other diseases and direct exposure. But the stem cell transplantation process in itself or the high-dose Melphalan is not instrumental in causing neuropathy.

(53:07) [Lynne]      All right, here's a question about preparation for CAR-T cell therapy. Can treatment with Blenrep compromise the response to subsequent CAR-T cell therapy? Do antibodies bind to the same BCMA antigen on cancer cells?

(53:27) [Frits van Rhee]     Okay, that's just an excellent question and we don't quite know the answer to that. So the idea is that lambda targets BCMA, it sits on myeloma cells. And if you subsequently give CAR-T cells, the CAR-T cells will also try to recognize BCMA but the Blenrep drug is there and shields the myeloma cell from the attack by the CAR-T cell. There have been a number of patients allowed into clinical trials who have received prior BCMA therapy with the Blenrep drug and there have been incidental responses. However, we do not know overall how important it is to avoid Blenrep therapy prior to CAR-T cell therapy and we definitely need further data in that area.

(54:33) There's also an issue how far away the Blenrep therapy is. In general terms, it would take four to six months for an antibody like Blenrep to completely disappear. So if the therapy with Blenrep has been four, six months ago, then certainly it would also be very reasonable to do the CAR-T cell therapy. But it's an excellent question, but it's unanswered.

(55:03) [Lynne]     Okay. The next question comes from a 63-year-old woman who's 18 months post-transplant. Will you please talk about gain of 1q? I have this marker and it's still very unclear on how it affects my overall prognosis.

(55:21) [Frits van Rhee]      Okay, so gain of 1q, that is multiple copies, three or more copies of the long arm of Chromosome 1 where genes where located which stimulates the myeloma cells to grow and help myeloma cells to survive. In general terms, t three copies alone of Chromosome 1q is not that important. If you have four or more copies, then it does confer in general terms, worse outcome, particularly when there are other higher-risk abnormalities there. And there is deletion 17p or other high-risk abnormalities.

(56:17) Having said that, it is also true to say that many patients with more than two copies of Chromosome 1q, do have good clinical outcome. You have to realize that all of these are risk factors. If you have one of these risk factors, it doesn't necessarily mean that you are going to have a bad outcome. So all of this needs to be interpreted in context and also in the context of which other abnormalities are there. And then, another issue is that if you do have higher-risk abnormalities, you can consider adjusting your post-transplant therapy. For instance, instead of doing one drug, giving three drugs like Velcade, Revlimid and Dexamethasone. So these are all things that one could take into consideration.

(57:17) [Lynne]      All right, thank you. The next question are we'd like to know what dosage of Revlimid you recommend for maintenance.

(57:25) [Frits van Rhee]      The standard dose is 10 milligrams, it's either 15 or 10 which are commonly used. Revlimid, when given chronically, tends to reduce the platelet count somewhat. The platelets best reflects the robustness of the marrow and how well the marrow is functioning, how well the stem cells are faring, so to speak. And very often we look at platelet counts to see whether we need to dose adjust the Revlimid or not. So 10 milligrams is the standard dose. I like to give 15 milligrams very often if the blood counts are good. We've shown in prior studies, that the total dose given in maintenance. that the cumulative dose given in maintenance, overall does impact on outcome, emphasizing that maintenance is really active therapy and continues to suppress and eradicate multiple myeloma cells.

(58:25) [Lynne]      All right, and then our last question because we are coming to the end is about whether there is any reason to take or not to take Tylenol after a COVID vaccine depending on whether or not you're having symptoms.

(58:42) [Frits van Rhee]      First of all, taking Tylenol is not going to interfere with the response to the COVID vaccine. So if you do have some aches and pains or fever, it's perfectly okay to take Tylenol. Some people even take some Tylenol prophylactically a few hours after they get the vaccine. So if you have symptoms, by all means, take some Tylenol and you don't need to be worried that it's going to affect the antibody response.

(59:25) [Sue Stewart]     Closing. Thank you, Dr. van Rhee for the terrific presentation and I'd like to say on behalf of BMT InfoNet and our partners, thanks again Dr. van Rhee and also thank you audience for all those excellent questions that you brought into this discussion. Have a good day.