Long-Term Effects of a Transplant Using Your Own Stem Cells (autologous transplant) 

 Download Speaker Slides 

Long-Term Effects of a Transplant Using Your Own Stem Cells (Autologous Transplant)

April 29, 2023

Presenter: Alfred Garfall, MD,  FACP, Hospital of the University of Pennsylvania

Presentation is 42 minutes; Question & Answer segment is 15 minutes

Summary:  Autologous stem cell transplants are a treatment option primarily for patients with multiple myeloma and non-Hodgkin lymphoma. High-dose chemotherapy is part of the treatment and can destroy cancer cells as well as healthy blood cells. Although side effects do occur after an autologous stem cell transplant, most patients can expect a return to normal, healthy life after transplant.

Highlights:

• More autologous stem cell transplants (transplants that use the patient’s own stem cells) are performed each year than allogeneic stem cell transplants (transplants that use stem cells from a donor).
• For patients who have multiple myeloma, an autologous transplant is not expected to cure them of their disease but can extend the period of time before additional therapy is needed.
• For patients with non-Hodgkin lymphoma, the goal of an autologous transplant is to cure them of their disease, but relapse may occur in some patients.

Key Points:

(06:32): In an autologous transplant, the chemotherapy given to patients before the transplant is really the main therapy, not the transplant itself. The purpose of the stem cell transplant is to help the bone marrow recover from the effects of the high dose chemotherapy.

(09:38): After completion of the high-dose chemotherapy, stem cells are infused a few days later, and find their way to the bone marrow where they start to grow and produce healthy blood cells.

(11:24): Patients typically spend a few weeks in the hospital after the stem cells are re-infused, while the blood counts recover.

(14:50): There are fewer transplant-related complications in an autologous transplant, compared to an allogeneic transplant, but especially with multiple myeloma, the disease is more likely to come back.

(15:33):  In the early phase after an autologous transplant, side effects may include gastrointestinal problems, fatigue, dehydration, slow recovery of blood counts, infections and very rarely, autologous graft-versus-host disease.

(18:27): There are potential late effects after an autologous transplant, but the vast majority of patients are expected to return to their prior quality of life after an autologous stem cell transplant.

(22:26): Problems reported by patients five years after an autologous transplant include sexual dysfunction, shingles, cataracts, osteoporosis or osteopenia, needing a joint replacement, and skin cancer, some of which may be driven by the patient’s age.

(23:12): Problems affecting the lungs and heart can occur after an autologous stem cell transplant.

(28:55): A patient’s immune system recovers over a period of years after an autologous stem cell transplant. After a patient’s blood counts have recovered, steps are taken to help prevent infection long-term. Vaccination is an important part of that process.

(40:12): A recent study showed a link between a healthy diet and control of multiple myeloma after an autologous stem cell transplant.

Transcript of Presentation:

(00:01): [Lynne Spina]:  Hello. Welcome to the workshop, Long-Term Effects of Transplant Using Your Own Stem Cells (Autologous Transplant). My name is Lynne Spina, and I will be your moderator for this workshop.

(00:15): Introduction of Speaker. It's my pleasure to introduce today's speaker, Dr. Alfred Garfall. Dr. Garfall is an Assistant Professor of Medicine and Director of the Autologous Stem Cell Transplant Program at the University of Pennsylvania. Dr. Garfall's research focuses on evaluating new multiple myeloma immunotherapies. He is specifically interested in developing new approaches to prevent relapse in multiple myeloma patients. Please join me in welcoming Dr. Garfall.

 (00:56): [Dr. Alfred Garfall]: Hello, everybody. I'd like to thank Lynne and her colleagues at BMT InfoNet for the opportunity to present to this patient symposium. I hope this is informative; please send in any questions, as I will answer as many as possible at the completion of my talk.

(01:16): Outline of Talk. I will present a brief review of what autologous stem cell transplantation is and what it's used for, and then discuss some of the major healthcare and health maintenance issues that arise for patients following autologous stem cell transplant.

(01:35): The number of autologous stem cell transplants performed each year is greater than the number of allogenic transplants (transplant using donor cells) performed. These slides will illustrate who are our autologous stem cell transplant patients. On this slide, the graph tracks the number of autologous and allogeneic stem cell transplants that have been done over the years. This is data collected from the Center for International Bone Marrow Transplant Research, an organization that tracks transplant activity across the US and the world. You can see those autologous transplants, transplants using your own stem cells, are occurring more often, as compared to allogeneic stem cell transplants, in which donor stem cells are used. You see that the number of both types of transplants has increased over the years.

(02:20): There's an interesting story behind the shape of the green line, which is the number of autologous stem cell transplants. You see that there is a big increase in the 1990s in autologous stem cell transplants and then an abrupt fall off. This follows an attempt to use autologous stem cell transplant as a treatment for breast cancer that was initially promising, leading to an increase in the number of transplants done for breast cancer. Some studies then showed that it was not efficacious.  When it was tested in large, randomized controlled trials, it didn’t do any better than standard chemotherapy. Hence, the abrupt drop-off in the number of autologous stem cell transplants at that time.

(03:03): Currently, multiple myeloma patients make up the majority of patients receiving autologous stem cell transplant. In the late 1990s, early 2000s, when the first clinical trials came out, showing that autologous stem cell transplant was helpful for multiple myeloma, we note the gradual increase in the number of transplants performed throughout the 2000s. There is then a slight decline in that trend in 2020. I suspect that is due to a decrease in transplant activity during the COVID-19 pandemic. At The University of Pennsylvania, we put a lot of transplants on hold but, in most cases, those patients went on to get transplants in the subsequent years. I think we'll see those numbers go back up.

(03:55): This graph shows the different types of diseases and the number of transplants performed for them. In green are the autologous stem cell transplants, while blue are the allogeneic transplants. You see on the left-most column, that multiple myeloma, which is a malignancy of plasma cells or plasma cell disorders - diseases that are in the same family as multiple myeloma- such as systemic amyloidosis - these patients make up the largest number of patients who receive autologous transplants.

(04:30): Patients with non-Hodgkin lymphoma make up the second largest group of people treated with an autologous transplant each year. Second are non-Hodgkin lymphoma patients, this is primarily diffuse large B-cell lymphoma patients. You can see that Hodgkin lymphoma makes up another portion of patients receiving autologous transplant.

There are a few other malignancies for which autologous transplant is sometimes performed. For example, germ cell tumors, which is not a blood cancer like lymphoma and myeloma, is another reason patients sometimes get autologous transplants. There are also a few autologous transplants being performed for non-cancer diseases. For some autoimmune diseases, such as multiple sclerosis or Crohn's disease, there is some experimental use of autologous transplant as a way to reset the immune system in those immunologic diseases.

(05:21): The age of patients receiving an autologous stem cell transplant has increased over time, primarily due to the fact that patients with multiple myeloma tend to be older. You can see that the group in the 65 plus age group has grown over time. This slide looks at the age of our autologous transplant patients. This also reflects the increasing use, over time, of autologous transplant for multiple myeloma, which is a disease of people typically over 60 years old. It also reflects our increasing comfort in the safety of autologous transplants in patients who are in their late 60s and early 70s.

(06:02): This is just focusing on the diseases for which autologous transplant is performed. In the end, this parallels some of the information I was showing you earlier, that multiple myeloma, in the blue line, has been increasing over time, and the use of autologous stem cell transplant for non-Hodgkin lymphoma, in the green, has also been increasing but not quite as much as it has been for multiple myeloma.

(06:32): In an autologous transplant, the chemotherapy given to patients before the transplant is really the main therapy, not the transplant itself. What are we doing in an autologous stem cell transplant? In autologous stem cell transplant - the word 'transplant' makes it seem like the transplant is really the center of the therapy, but it's really the chemotherapy that is the center of the therapy. An autologous stem cell transplant entails removing stem cells from your body before chemotherapy, and the reinfusion of them afterwards.

The purpose of that stem cell transplant is to help the bone marrow recover from the effects of the high dose chemotherapy. Really, the transplant is just a way to make it reasonably safe to give really high doses of chemotherapy. It's the chemotherapy that we think is doing the therapeutic work of the transplant and killing the residual myeloma or lymphoma cells that are still in the patient after they've completed their standard therapy.

(07:29): Autologous stem cell transplants are typically undertaken in patients whose disease is under control from some prior therapy. In multiple myeloma that might be therapies like Revlimid®, Velcade®, Dexamethasone, or Daratumumab, that get the disease under control initially and really reduces the amount of myeloma in the patient's body to relatively low numbers compared to where they started. However, even in patients who go into what we call complete response, we still know that there can be a lot of myeloma cells beneath the surface. The goal of this high dose of chemotherapy, as part of the transplant, is to kill off some more of those myeloma cells to lengthen the amount of time that we can keep the disease under control.

(08:11):  This is also true for lymphoma. Auto transplants are typically used in patients who have had some initial therapy for lymphoma and who, perhaps, had a relapse of their lymphoma and received additional chemotherapy to get the lymphoma under control. Perhaps your lymphoma is in a complete response, meaning you perform a PET-CT and you don't find any lymphoma. But we know that beneath the surface, there are some lymphoma cells that are present even following that therapy. So, we want to come in with higher doses of chemotherapy to try and kill even more of those cells beneath the surface, with the goal in lymphoma, of completely curing that lymphoma and eliminating the chance that it could return.

(08:52): If high-dose chemotherapy was given alone, without a subsequent infusion of stem cells, the diseased cells would be killed, but so too would all the blood cells produced by the bone marrow. If we were just to give high doses of chemotherapy alone, they're such high doses that, while they would kill some lymphoma and myeloma cells, they would also wipe out all the normal bone marrow cells. If you lose all those normal bone marrow cells, your blood counts won't be able to recover after the chemotherapy. In order to make it safe to give these high doses of chemotherapy, we take out some of the bone marrow stem cells from the body beforehand. These bone marrow stem cells are like the seeds of the bone marrow that can completely regrow the bone marrow from scratch. We take them out of your body before the chemotherapy, put them in the freezer, and then give you that course of intensive chemotherapy.

The chemotherapy is usually melphalan, in the case of multiple myeloma. In lymphoma, there are some other different chemotherapies that are used, that I will explain shortly.

(09:38): After you complete the high-dose chemotherapy, we reinfuse those bone marrow stem cells a few days later, in the form of an intravenous infusion. Those stem cells then find their way to the bone marrow and start regrowing there. While the blood counts will still be low for a couple of weeks after this chemotherapy, as those bone marrow stem cells take root in the bone marrow, the normal blood count starts to come back. That infusion of your own stem cells is what makes it safe to be able to give these high doses of chemotherapy without permanently wiping out the bone marrow.

(10:22): For lymphoma, some other regimens of chemotherapy are used, often containing combinations of chemotherapy that I have listed here in black. The two most commonly used regimens currently, are a combination called BEAM that contains four chemotherapies called BCNU, also known as carmustine, the E is for etoposide, the A is for Ara-C, which is also known as cytarabine, and the M is for melphalan. There's another combination called BCV, which is BCNU, cyclophosphamide, and then a medicine called VP-16, which is etoposide. There are some other regimens I've listed here in gray that are not as commonly used currently, so busulfan and cyclophosphamide or just total body radiation, which doesn't involve any chemotherapy, but gives radiation to the whole body. That's not often used for autologous transplants, currently.

(11:24): Patients typically spend a few weeks in the hospital after the stem cells are re-infused, while the blood counts recover. After those chemotherapies are completed, the stem cells are re-infused; that's really the procedure in the transplant. After the cells are re-infused, there's a period of time in the hospital, usually a few weeks, when the blood counts are going down and coming back up. That's where some of the early side effects and toxicities of transplant come into play. Then there's a later phase of recovery after you leave the hospital, or after the blood counts recover, if your transplant is not taking place in the hospital.

(11:56): Autologous transplants are considered safer than allogeneic transplants. When we compare autologous and allogeneic stem cell transplants, we note that they are really quite different in terms of the diseases that they're used to treat and the types of problems that can develop afterwards. Overall, autologous transplants are considered safer than allogeneic stem cell transplants.

(12:16): In allogeneic stem cell transplants, instead of that stem cell infusion being your own stem cells, it's a donor’s stem cells. When you give a patient donor stem cell, those stem cells are going to form an entire immune system in that patient that comes from the donor. That's a good thing, in terms of that donor's immune system being able to fight off some of the residual cancer cells in the patient. However, that also leads to a lot of the complications that can happen after an allogeneic transplant like graft-versus-host disease.

(12:48): In autologous transplant, we don't have to deal with those complications because the stem cells are the patient's own stem cells, and it's the patient's own immune system reconstituting in the patient. In this type of stem cell transplant, we really don't see graft-versus-host disease. Very occasionally, we see something called autologous graft-versus-host disease, but it's a much simpler condition compared to the graft-versus-host disease that develops in allogeneic stem cell transplant patients. As a result, we don't have to give autologous transplant patients immunosuppression after the transplant, no tacrolimus or methotrexate, or prednisone. And that overall reduces the risk of infection after an autologous transplant compared to an allogeneic transplant.

(13:30): Patients with multiple myeloma are not cured by an autologous transplant. The hope is that the autologous transplant will provide a long period of disease control before additional therapy is needed.  In autologous transplant, the main issue that we are concerned about, which is also a concern on allogenic (allo) transplant, but I think especially in autologous transplants for multiple myeloma, it's the underlying myeloma that continues to be a health problem for patients down the road after an autologous transplant. When we implement an autologous transplant for multiple myeloma, we recognize that most patients are not going to be cured of the myeloma. Our hope is to put the disease into a long period of disease control where the myeloma is not growing and is only present in the body at a very low level. You do expect, for most patients, that the myelomas will eventually start re-growing. Hopefully, it will be years until additional therapy for your multiple myeloma will be needed. The issues related to multiple myeloma are really the primary health problems for patients long after an autologous transplant.

(14:25): In lymphoma, we also worry about relapse, although we hope in lymphoma patients that the disease is cured by the autologous transplant. We do think that Hodgkin and non-Hodgkin lymphomas, for the most part, that are treated with auto transplant, are typically curable. We hope for that cure, but in most cases of lymphoma, there remains a risk of relapse for which we are alert.

(14:50): There are fewer transplant-related complications in an autologous transplant, compared to an allogeneic transplant, but especially with multiple myeloma, the disease is more likely to come back. We see overall with auto versus allo transplant, less transplant-related complications, more effects of the primary disease that you're treating, especially in multiple myeloma, where we expect it eventually to come back, and then increases in risk of normal health problems that we see in healthy patients. We test for cardiovascular problems, lung disease, infections, autoimmune disease, second cancers, as well as effects on reproductive and sexual health. These are problems that are also common in the general population without cancer. However, we do see some increases in the risks of these problems in patients who have had an autologous stem cell transplant.

(15:33):  In the early phase after an autologous transplant, side effects may include gastrointestinal problems, fatigue, dehydration, slow recovery of blood counts, infections and very rarely, autologous graft-versus-host disease. When we think about recovering from an autologous stem cell transplant, it entails two or three phases. In the early phase, you're really recovering from the acute side effects of the high doses of chemotherapy. They all have an effect on the gastrointestinal tract, in terms of your ability to take food and drink without pain, diarrhea, and nausea. We watch for dehydration, and we diligently watch for those blood counts to come back. In almost all cases, the blood counts do rebound nicely. As the stem cells take root, we need to make sure of that. In the occasional patient, it takes longer than we expect, and they may need some medications to support that.

(16:18): The immune system recovers over a period of years after an autologous stem cell transplant. I mentioned that autologous graft-versus-host disease happens quite rarely and is very treatable when it happens. That's something that we watch for as the blood cells come back a few weeks after the transplant. We're watching for infections in this early phase. The immune system gradually recovers over a period of years after an autologous stem cell transplant, and the period where it's weakest is in the early couple months after the transplant.

(16:42): We continually watch for gradually improving energy. The two main side effects that we expect patients to have early after a transplant are gastrointestinal side effects and fatigue. Chemotherapy just “knocks the wind out of your sails”. The period of the most fatigue is in those weeks after the chemotherapy, but, really, it's a gradual process over a couple of months before you fully recover your energy. We expect most patients, by about three months after the transplant, to have recovered back to their baseline level of energy and vigor.

(17:16): There are also some late effects that we think of playing out over months to years. There is some continued physical recovery. We still focus on infection, and we carry out a series of vaccines to boost immunity against common illnesses in the year or so after the transplant.

(17:37): We also encourage patients to resume their normal health maintenance routines. Typically, patients who go through autologous stem cell transplant have spent the prior year or so getting therapy for their cancer, where the cancer, the myeloma or the lymphoma, is center stage in their lives. We hope by the time someone recovers from a transplant that the disease is under good control and will stay that way for years. We encourage patients to return to their primary care physicians, to do the things that they might have been putting off for the last couple of years in terms of their routine health maintenance screening: colonoscopies, mammograms, skin exams, getting tested for cholesterol, blood pressure, and blood sugar levels, normal, long-term health maintenance activities.

(18:27): There are potential late effects after an autologous transplant, but the vast majority of patients are expected to return to their prior quality of life after an autologous stem cell transplant. While we're going to focus on some of the late complications of an autologous stem cell transplant, I think it's important to mention that we expect the vast majority of patients to get back to their prior quality of life after an autologous stem cell transplant. That's always been our anecdotal experience in the patients we've cared for, but we've gotten, in the last couple of years, some objective data that supports that view.

(18:53): These are results from a clinical trial in multiple myeloma where they were testing a transplant now, versus transplant later approach. If you look at patients who got first line therapy for multiple myeloma, half of them went right to transplant. The other half did not get a transplant and collected stem cells to, perhaps, receive a transplant a few years down the road. In this clinical trial, they surveyed patients about their quality of life in a standard questionnaire, at each step of their participation in the clinical trial.

(19:25): You see here, in red, the patients who got a transplant, and in blue the patients who didn't get a transplant. As expected, around the time of the transplant, the patients who got a transplant had a decrease in their quality of life due to all the side effects of the intensive chemotherapy. However, by a few months post-transplant, these patients were answering the questionnaires in the same way, on average, as the patients who never got a transplant. They really are getting back to their previous quality of life, as if they hadn't had a transplant, within a few months after the transplant. That has been my experience, anecdotally, taking care of patients, many patients who have been through transplant for multiple myeloma. We expect their quality of life to return to normal after the transplant.

(20:08): Side effects of maintenance therapy given to some myeloma patients after an autologous transplant can cause side effects that affect their quality of life. We do see, for multiple myeloma patients who go on maintenance therapy with lenalidomide or Revlimid, which is the most commonly used medication for maintenance therapy after transplant, that there are some resulting side effects. This is another survey where they surveyed patients over time about their quality of life as they went through maintenance therapy. You can see that there are some side effects of lenalidomide that occur at certain time points after the transplant that can affect the patient's quality of life. It's interesting that these emerge early in the course of Revlimid® maintenance and then patients go back to having the same quality of life as if they weren't on maintenance. For most patients, they were able to manage those side effects when they happen with dose adjustments.

(21:03): There is a period of time, when you first start maintenance therapy after a transplant for multiple myeloma, where there's diarrhea, fatigue, and effects of the Revlimid® that we try to treat with dose adjustments and other supportive medications. We're not successful in all cases. Regardless of what these statistics say, I know my experience with many patients is that there are some chronic side effects to Revlimid® in many cases, but not all. And we make a case-by-case decision with patients rather whether they want to continue Revlimid® for the benefits, or whether they want to get rid of those side effects and stop the Revlimid® after some time.

(21:45): Quality of life after transplant for most patients with myeloma does improve, until the disease recurs. These are some results from a similar study showing that, as patients go through the course with their multiple myeloma and a transplant, that quality of life does improve after transplant, during transplant follow-up, and then you see some decrease in quality of life when the myeloma starts growing again. That tells us that what drives patients' quality of life in the long term, at least in multiple myeloma, following a transplant, is the disease itself. We worry about the disease coming back and that's the major health problem that people continue to experience. We are going to talk about this as well as some of the other medical effects of the transplant, during this presentation.

(22:26): Problems reported by patients five years after an autologous transplant include sexual dysfunction, shingles, cataracts, osteoporosis, or osteopenia, needing a joint replacement, and skin cancer, some of which may be driven by the patient’s age. If you ask patients, five years after an autologous transplant, what are some of the common problems that they report, this is a list of the problems that more than 10% of patients in this survey reported: sexual dysfunction, shingles, cataracts, osteoporosis, or osteopenia, needing a joint replacement, and skin cancer. Of course, these are problems that happen in patients in their 60s and 70s, even if they don't have myeloma or lymphoma and autologous stem cell transplant. Nonetheless, we think probably a lot of these problems are more common in patients who have gone through a transplant.

(23:12): Problems affecting the lungs and heart can occur after an autologous stem cell transplant. A few problems that affect specific organ systems are possible after a transplant. There are a couple of problems that affect the lungs early after a transplant. There's a syndrome called idiopathic pulmonary syndrome. Idiopathic, in medical terms, means we don't know what causes it. So this is a condition of the lungs that happens early, usually around two months after a transplant, and it causes inflammation in the lungs and difficulty breathing. This is a little bit more common with lymphoma than in multiple myeloma, and it's rare; overall, fewer than 5% of patients experience this and is usually treatable with a course of steroids.

(23:57): There is also a specific lung problem that can develop in patients who get a chemotherapy drug called BCNU, or carmustine, that is commonly used in chemotherapy for lymphoma patients who are getting a transplant. Up to 20% of patients develop it, usually within three months of the transplant. Your risk of this is a little bit higher if you've previously had radiation to your chest as part of your lymphoma therapy, if you got a higher dose of the BCNU chemotherapy, if you previously had bleomycin, which is one of the chemotherapies that's used in the initial treatment of Hodgkin's lymphoma, and if your age is a bit younger. The vast majority of patients recover from this; if it occurs, it can be treated with steroids.

(24:47): Cardiovascular complications are another set of complications that can develop late after a transplant. It's not clear if these are actually from the transplant or from prior therapy received for the cancer. This is primarily a problem for lymphoma patients because lymphoma patients also receive a drug called doxorubicin, also called Adriamycin, as part of their initial treatment for the lymphoma; it is NOT part of the transplant, but the pre-transplant therapy that lymphoma patients receive.

(25:30): If you've received chemotherapy regimens like CHOP or EPOCH or ABVD, you've received some of this doxorubicin medication. The thought is that this medication increases the long-term risk of developing heart failure. Although heart failure is a scary term and, certainly, heart failure can be a severe condition, it's important to keep in mind that many, many patients have some form of heart failure. Heart failure is an unfortunate term since it connotes that something is failing. Really, there are many patients with heart failure, or that diagnosis, who can be managed with medications and have perfectly normal quality of life. It doesn't mean that that's a chronic medical problem that needs to be managed in coordination with the cardiologist. In most cases they're milder cases. But, of course, there is some risk of severe heart failure that can develop in patients who had doxorubicin and it can develop in the later years after the initial therapy.

(26:42): Long-term lymphoma survivors have a long-term risk of infection and autoimmune disease, even long after the lymphoma has been cured. There's an increasing appreciation of a concept called immune health, which is the health of the immune system. We think of the immune system as being really important in fighting disease, but it also has a role in fighting cancer. Dysregulation of the immune system is also the cause of autoimmune disease. In looking at immune health long after transplant, as with heart failure, it's difficult to disentangle what's caused by the transplant, versus what's caused by the fact that the patient had hematologic cancer, a blood cancer. which is essentially a cancer of the immune system, versus what was caused by prior therapy that the patient had before the transplant for their cancer. If you look at patients who are long-term lymphoma survivors, you do see some deficiencies in immune health that's reflected in an increased risk of infection and autoimmune disease, even long after the lymphoma has been cured.

(27:43): There was a comprehensive study that looked at this and did not find a big difference in the immune health parameters between lymphoma patients who did, and did not, receive a transplant. Perhaps these late effects on immune health that we see in transplant survivors with lymphoma are actually from the fact that they had lymphoma to begin with and had prior therapy for lymphoma even before the transplant. Nonetheless, we do see an increased risks of infection and autoimmune disease compared to the general population.

(28:17): There are a number of steps that can be taken to manage the risk of infection early and late after transplant. How do we manage infection risk? In the early phase after the transplant, we utilize preventative antibiotics. Most patients will receive, in the early days after their chemotherapy, a host of antibiotics to prevent bacterial, fungal, and viral infections. We treat fever very proactively in those early stages. We don't wait. If you have a fever in those early days after a stem cell transplant, we don't wait until we find an actual infection to start some more intensive antibiotics. We just give you more broad-spectrum antibiotics to prevent any full-blown infections from developing.

(28:55): After a patients' blood counts have recovered, starting a couple of months after the transplant, we start thinking about long-term prevention of infection; vaccination is an important part of that.

(29:10): There is also, for some patients, whose immune system is a little bit sluggish after transplant, antibody replacement therapy. This is just like giving a red cell or a platelet transfusion. We can also give antibody transfusions from other patients. This takes the form of a medication called intravenous immune globulin, which is a formulation of antibodies that's collected and purified from different donors, the way platelets or plasma might be. It can be given as antibody replacement every one to three months after transplant for patients who have not recovered the full antibody producing capacity of their immune system and are dealing with repeated infections. This is really a rare thing to have to go on IVIG after autologous stem cell transplant, but does happen occasionally, and it can be helpful for patients who are suffering from recurrent infections, such as pneumonia and sinus infections.

(30:07): There is a series of vaccines that are recommended after an autologous stem cell transplant, and there is some variation in practice from transplant center to transplant center; how intensely people are revaccinated and how intensive vaccines are given. The recommendations are the same from the guideline agencies for allogeneic and autologous stem cell transplant, in terms of the number of vaccines that are received. This is the schedule that's recommended from the National Marrow Donor Program, which you can find at bethematchclinical.org. It lists re-vaccination, both with some childhood vaccinations, but also focusing on illnesses that are common in adults. This includes pneumonia, which is the main one that we worry about.

(30:55): In addition, we recommend vaccination against shingles; there is a shingles vaccine called Shingrix® that has been specifically studied in patients who have had autologous stem cell transplants, which has been shown to be highly effective in reducing the risk of shingles after a transplant. That's a two-dose vaccine. We recommend avoiding the alternative shingles vaccine called Zostavax, which is a live vaccine. It is worth just keeping in mind that there are two out there, and the one that you want to get after an autologous stem cell transplant is the Shingrix® one.

(31:38): Finally, several agencies, including the National Comprehensive Cancer Network, recommend repeating your COVID mRNA vaccine series after a transplant. So that's a total of the two primary vaccines and two boosters after the transplant. With COVID vaccines, it does seem like the guidance changes very frequently and so this is what's recommended right now. I always advise patients and other physicians to consult the latest guidance from the CDC, FDA, and the National Comprehensive Cancer Network for how to manage COVID vaccination in immunocompromised patients.

(32:20): The risk of a second cancer after transplant can be reduced by diligent cancer screenings and lifestyle choices such as avoiding smoking and using sunscreen to protect against sunburn and skin cancer. Risks of other cancers late after an autologous transplant are difficult to study since it's difficult to disentangle what that risk comes from - the transplant versus the patient's prior therapy for cancer, and whatever post-transplant therapy, like maintenance therapy in the case of multiple myeloma, might be causing it. Some general guidelines are to be diligent about your normal cancer screening for patients of your age group. It's easy to forget about mammograms and colonoscopies when you've just been through such an intensive process for another health problem, but it is really important to stay on top of these things after your transplant. So get back into the routine for normal cancer screening for your age.

(33:15): I recommend yearly skin exams for my patients after autologous stem cell transplant, even though that's not necessarily a part of regular primary care. I recommend an annual skin exam with a dermatologist as well as staying on top of oral cancer screening. That's usually part of your routine dental health maintenance that you should be doing every six months. Of course, avoid lifestyle choices that increase your risk of cancer; avoid smoking and enjoy the sun, but do it with sunscreen so that you don't get sunburn, all which increases your risk of skin cancer.

(33:53): Thyroid problems can develop after an autologous stem cell transplant and cause fatigue. Other problems can also develop, such as thyroid gland dysfunction. About 10% of patients will have some degree of thyroid gland dysfunction. I check the thyroid hormone levels in my patients because, when you hear that patients are experiencing fatigue, you have to be mindful that they could have developed a hypothyroidism (low functioning thyroid). Thyroid hormone is one of the main things that regulates our metabolism and energy level. Of course, fatigue is very common, and most patients who report fatigue do not have a thyroid problem.

(34:24): Peripheral neuropathy is common after an autologous transplant, usually caused by therapies patients received before they had an autologous transplant. We are also alert for peripheral neuropathy. This doesn't usually come from the transplant as much as the therapy that patients have received for myeloma and lymphoma before the transplant, but it can be made worse following transplant. The name drugs that could contribute to this pre-transplant neuropathy include bortezomib, also called Velcade, the treatment for multiple myeloma, and brentuximab, which is an antibody drug conjugate used in the treatment of some patients with Hodgkin lymphoma.

(34:54): Gabapentin is often prescribed to deal with peripheral neuropathy. I would encourage everybody to think about another medication called duloxetine, which also goes by the brand name Cymbalta. This has been well studied in chemotherapy-related neuropathy and in patients who don't get relief from gabapentin. It may be the answer as a first-line agent for patients with neuropathy and can be very effective.

(35:21): The risk of cataracts, problems with the lens in the eye, can also increase with stem cell transplant. Cataracts are a common problem in people as they age, but it’s more common in patients who have had a lot of steroids. Multiple myeloma patients and lymphoma patients all receive steroids as part of their cancer therapy before the transplant. That likely increases the risk of cataracts. If you're having trouble seeing, make an appointment with your eye doctor as it may be the formation of cataracts. You should maintain routine eye exams so that these are identified early. Cataracts can be treated with lens replacement, which is a very routine surgery.

(36:02): Other problems, such as fatigue, depression/anxiety, and cognitive dysfunction, are all problems in cancer patients and should be monitored and attended to. I'm not going into detail about some of the therapies for these, but you should not be afraid to bring these symptoms and concerns up to your physicians, your oncologist, your transplant doctor, and your primary care physician.

(36:31): As I mentioned, it's very important to return to routine healthcare and pay attention to some of the routine health maintenance parameters. Stay alert and aware of your cholesterol, diabetes, maintain a healthy body weight, and get regular exercise.

(36:46): Patients who had an autologous stem cell transplant should get sufficient calcium and vitamin D daily to protect against osteoporosis. In terms of bone health and risk of osteoporosis, you should maintain vitamin D and calcium intake. If you don't get this in your diet, consider adding calcium and vitamin D supplements. Follow your primary care doctor's guidelines for the monitoring of bone density with DEXA scanning and treatment of osteoporosis if it's diagnosed.

(37:11): Most female patients will be postmenopausal after an autologous stem cell transplant.  Male and female fertility after autologous stem cell transplant is often foremost in many patients’ minds. Most female patients will be postmenopausal after the transplant. The potential to recover fertility after the transplant depends on age and the prior cancer therapy. There are a minority of younger female patients who do recover normal ovarian function after autologous transplant. It's important to keep in mind that just because you're not having regular periods does not necessarily mean that you're infertile. You should still think about contraception if you don't want to become pregnant. If you do desire to become pregnant, you should seek OB/GYN consultation in advance to receive some specific counseling about the risks and monitoring that you should undertake as part of a pregnancy. In patients who do get pregnant after transplant, there does not appear to be any increased risk to the health of the mother or the baby.

(38:16):  Fertility preservation before transplant is easier for men than for women. Fertility preservation is easier for men because sperm banking is usually feasible, even in a newly diagnosed patient who hasn't started chemotherapy. Similar measures for females are more difficult because egg harvesting or embryo storage are more time-consuming procedures that take a longer time to plan and perform, which may not be feasible in a newly diagnosed patient who has a new lymphoma that needs to be treated urgently. This should be considered on a case-by-case basis. A lot of medical centers have obstetricians and gynecologists who are focused on this area and can consult with patients, prior to starting therapy, about some of these options and their feasibility.

(39:12): Sexual difficulties are common problem after an autologous stem cell transplant. Sexual health is one of the more common things that patients report problems with following transplant. Both men and women report less sexual activity after transplant than would be expected for their age, based on surveys of patients who haven't been through transplant. Reported reasons for lower sexual activity among patients include reduced sexual function; erectile dysfunction for men or vaginal dryness for women, and/or overall reduced interest. These can be addressed. In the case of men, for erectile dysfunction, medications like sildenafil (Viagra), can be prescribed; for women, topical estrogens that are often effective in alleviating vaginal dryness, can be prescribed by primary care doctors or gynecologists.

(40:12): A recent study shows a link between a healthy diet and control of multiple myeloma after an autologous stem cell transplant. One of the most common questions that I get from patients is whether diet matters in the long-term control of the lymphoma or the multiple myeloma, and how to handle post-transplant diet. I always tell patients to just maintain a healthy diet. We don't really have a lot of information about which diet is better or worse for controlling cancer.

In the multiple myeloma field, we have some interesting data from clinical studies that has emerged in the last couple of years from the group at Memorial Sloan Kettering Cancer Center which gives us the first hint of an interaction between diet and long-term control of the multiple myeloma, specifically in the post-autologous stem cell transplant setting. The good news about this is that it actually doesn't point us towards any special particular diet or special food. Instead, it points us towards the same dietary guidance that we have routinely been giving.

(41:13): There is real evidence that the standard healthy diet that you hear about from the Center for Disease Control (CDC), one that is rich in fruits and vegetables, whole grains rather than refined carbohydrates and emphasizes protein coming from fish and beans and legumes is an excellent nutritional regimen. This is not necessarily a vegetarian diet but, perhaps, a plant-focused diet that seems to modify the bacteria that live in our gut and suggests there may be a favorable interaction between that bacterial composition of our gut and the immune system's ability to fight off and maintain long-term control of the multiple myeloma. This is an emerging area, but I think we finally, just in the last year, have some real data, as opposed to just general guidance. Fortunately, it points us in the same direction that our prior general guidance did, which is just to eat the same healthy diet that we all should eat. That may be helpful for your long-term control of your multiple myeloma also.

(42:16): Summary of Talk. In summary, even though we talked a lot about late complications, it's important to remember that most patients return to their prior quality of life following autologous stem cell transplant. There may be long-term impairments in immune health and risk of infection, and there may be increased risks of otherwise common health problems, such as sexual health, bone density, and infections. Important interventions to maintain your health after an autologous stem cell transplant include vaccinations, getting back to your routine primary care, medical care, including cancer screenings, and measures to address sexual health. There may also be an emerging role for plant-based Mediterranean-style diet to potentially improve long-term multiple myeloma control. Thank you for the opportunity to present, and I would be glad to take questions.

Questions and Answer Session

 (43:16): [Lynne Spina]: Thank you, Dr. Garfall, for your excellent presentation. Our first question is: “What do studies show about stopping maintenance versus continuing maintenance for a longer remission?”

 (43:50): [Dr. Alfred Garfall]: I assume you're talking about multiple myeloma there. This is an area of uncertainty. We have the best evidence for maintaining maintenance therapy through a couple of years after the transplant. Beyond that, it's a little uncertain. The best data we have are from two clinical trials that had the same design. One was conducted in Europe, and one was conducted in the U.S. The only difference between their designs is that, in the U.S, they used continuous maintenance until the disease started growing again, and in Europe, they cut off the maintenance at two years. From those trials it looks like patients had better control of the myeloma, if they continued the maintenance therapy beyond two years, but that still doesn't tell us about two years versus three years, three years versus four years.

(44:44): And in both those clinical trials, patients stopped maintenance therapy if they couldn't handle it anymore and they were having significant side effects. So I still think our goal in the maintenance phase of therapy after transplant for multiple myeloma is for you to be able to get back to your normal quality of life. So if you stuck it out for a year or two of maintenance therapy, and you're really struggling with the side effects, I'd certainly consider stopping maintenance therapy in my patients in those circumstances and tell them that they put in an honest try with a couple of years of therapy. But if there are only mild side effects, and you find them manageable, there's perhaps a hint in the clinical trial data that continuing it for longer may help with control of the myeloma. But exactly how much longer and for how long, we're not sure.

 (45:31): [Lynne Spina]: The next question is,”(1) after stem cell collection, how many years do the frozen stem cells typically remain viable for a subsequent transplant? (2) What are the risks for the development of other cancers after a stem cell transplant?”

(45:55): [Dr. Alfred Garfall]: (1) In terms of how long the stem cells last, different centers will have different policies about this; it hasn't been extensively studied. Our center has felt comfortable using stem cells that have been stored for up to a decade. Sometimes, if we are going to use stem cells that are older than that, we'll try to do another collection of fresh stem cells just to have as a backup. But the stem cells do last for years, probably a decade, if not longer.

(46:25): (2) In the context of multiple myeloma, we do think there's an increased risk of second cancers in patients who are receiving the transplant plus the Revlimid® maintenance. There seems to potentially be an interaction between the Revlimid® maintenance and the transplant that increases the risk of other cancers over time. That increase in risk is small, only a few percentage points. We think, in myeloma patients at least, that the benefit of the maintenance therapy and controlling the myeloma, which is the main threat to our patient's health, outweighs the risk of other cancers. It's been shown in the long-term clinical trials that, on average, people who get Revlimid maintenance live longer with the myeloma than people who don't. So that tells you the net benefit of the maintenance is worth the small risk of second cancers.

(47:24): Remember, a second cancer is not necessarily the end of the world. A lot of these second cancers that have been reported after transplant might be early-stage cancers, like a skin cancer, that can be removed with minor surgery, or even early-stage breast cancer that can be treated and does not become a long-term threat to the patient's health. That said, there are life-threatening cancers that can develop after transplants, such as leukemias, but they are, fortunately, very rare.

(47:55):  I can't quote for you the statistics for patients in these studies transplant versus no transplant and the risk of second malignancies. However, in those trials, the primary threat to our patient's health remains the underlying cancer that we're treating with the transplant. The concerns about second cancers are minor. Hence, when you look at the long-term outcomes in the diseases where transplant is regularly use, it looks like getting the transplant has improved long-term overall survival for patients such that the benefit in controlling the underlying lymphoma and myeloma outweighs the risks associated with the other cancers.

 (48:39): [ Lynne Spina]: "I lost over 60 pounds in my second stem cell transplant." I'm thinking they mean during my second stem cell transplant is that normal?

 (48:56): [Dr. Alfred Garfall]: It's not common to lose that much weight after a stem cell transplant. Tere is often a substantial amount of weight loss. This varies from patient to patient. I've had many patients who lose no weight, a lot of patients who lose a lot of weight, and that's often related to the effects on the gastrointestinal tract of chemotherapy, and sometimes infections that can develop afterwards. Most patients do recover.

(49:28): Our center, and I think a lot of others, have been a lot more proactive about using what we call parenteral nutrition. For patients who are having a hard time eating during the transplant, switching over to receiving nutrition through the vein can help reduce the calorie deficit that leads to loss of lean body weight. Even if it's just for a few days, it can help control the loss of muscle mass when patients are experiencing these extreme side effects from chemotherapy. Perhaps more proactive supplemental nutrition has been helpful in mitigating some of the weight loss; that is a real problem. Most patients do regain that weight with time.

 (50:09): [Lynne Spina]: Another question; “How prevalent is secondary cancer for women in their reproductive organs 10 years or more post-autologous stem cell transplant; I developed both breast and endometrial cancer?”

 (50:28): [Dr. Alfred Garfall]: I don't have the exact statistics about those specific cancers. Of course, breast cancer is a very common cancer in women, and so it's going to be the top of the list for any list of cancers that develop in women in any circumstance, either after an autologous stem cell transplant or not. So, I'm sorry, I don't have specific statistics on this that might come for that.

 (50:53): [Lynne Spina]: “What about long-term fatigue and weakness? I am four years post-auto and struggle with significant levels of both.”

 (51:05): [Dr. Alfred Garfall]: That's an important question. I showed you the average statistics for patients recovering their energy level and quality of life after a transplant. But, of course, that's not everybody. Everybody is not in that average group, and there are, I think, outliers who continue to struggle with late complications or late fatigue.

(51:25): If you're a multiple myeloma patient, I would think about if you're on Revlimid maintenance therapy and how that could be contributing to your symptoms. It's very safe, from my perspective, to stop maintenance therapy for a month or two just to see if that's the problem. Because with fatigue, it's hard to sometimes disentangle what's the medication, what's lingering fatigue from the transplant, what's other factors or other health problems in my life. If it's not related to Revlimid maintenance therapy, there are some supportive things that I would encourage you to think about.

(52:03): There's a medication called methylphenidate, which also is called Ritalin®. That's a medication that's used to treat attention deficit disorder. It also, though, has been specifically studied in cancer-related fatigue, and I would put this kind of malaise and fatigue in that category. I've had a lot of patients who have been on myeloma therapy for years and have that cumulative fatigue. It doesn't work for everybody, but there are some people for whom it's been a game changer in terms of increasing energy level.

(52:34): It's a very safe and short-acting medication. You can use it on an as-needed basis. And the standard routine that I recommend for patients is to take it in the morning and at lunchtime, and you can get effects even with very small doses, the same doses that you might use in a young kid with attention deficit disorder. So safe doses, and it's been studied for this indication. So I encourage patients to think about that if this is a problem.

 (53:03): [Lynne Spina]: “Do you recommend tandem transplant if you have high-risk cytogenetic factors?”

 (53:25): [Dr. Alfred Garfall]: There are clinical trials that point to potential benefit of tandem autologous stem cell transplant in patients with multiple myeloma and high risks that are cytogenetics (the study of inheritance in relation to the structure and function of chromosomes.)

We do not currently do that in our practice. The data supporting that primarily come from studies in Europe where the patients did not receive the same type of initial therapy for multiple myeloma that we typically administer in the United States. If you received our typical induction regimen in the United States of Revlimid, Velcade, Dexamethasone, maybe with the addition of Daratumumab, it's not clear without more intensive first line therapy, whether two transplants are better than one transplant for high-risk multiple myeloma. That has not been shown. The data from the clinical trials in the US that have compared two transplants to one transplant did not show a substantial benefit, even in the high-risk subset, when they were receiving what we think of as the standard first-line therapy for myeloma in the US. However, you can certainly read those trials another way, so if your doctor is talking to you about a tandem transplant, it's not a crazy thing to consider. There is evidence suggesting that it's safe to do tandem transplants, and if you read clinical trials a certain way, you can see some potential benefits for high-risk patients in those trials. It is still an area of uncertainty. It's considered an acceptable thing to do if you look at some of the guidelines, like the National Comprehensive Cancer Network® guidelines. My personal practice, though, is not to recommend that.

 (55:16): [Lynne Spina]: “If I am having gastrointestinal issues four to five months out from BMT for lymphoma, when do I need to see a gastro doctor?”

 (55:30): [Dr. Alfred Garfall]: I would say four to five months out, it’s not uncommon to still have some lingering gastrointestinal symptoms at that point. If your GI symptoms are improving week to week and month to month, I think you can be patient with it. If they're not improving or if they're getting worse, it might make sense to think about seeing a specialist. A gastroenterologist may be able to recognize reasons that are unrelated to the transplant that could be causing this and recommend more advanced diagnostic procedures like endoscopy or colonoscopy.

 (56:13):[ Lynne Spina]: “If you still have neuropathy in fingers and toes a year after your transplant for non-Hodgkin's lymphoma, will it eventually go away without taking drugs?”

 (56:27): [Dr. Alfred Garfall]: Maybe, maybe not. I would have some additional questions about when you first noticed it and how long you've had it. There is a good chance that your peripheral neuropathy will improve with time, but there's also a good chance that it won’t completely resolve. It makes sense to give it some time if it's not crippling, and if you're adverse to taking some medications. The medications that I mentioned for peripheral neuropathy, especially duloxetine or Cymbalta, are not necessarily a long-term commitment to take them. You can start them; if it helps, you continue. If it's really helping and you want to see if you still need it, you can always stop a few months later. But I think it is also reasonable to just watch and wait a little longer.

 (57:16): [Lynne Spina]: “Does stem cell collection impact bone health such as increased osteoporosis?”

 (57:38): [Dr. Alfred Garfall]: I can't say. I don't think I've seen evidence that the stem cell collection procedure has any adverse effects on bone health.

 (57:50): [ Lynne Spina]: On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Garfall for a very helpful presentation and thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way. That's help@bmtinfonet.org.