Updates and Inspiration Regarding Multiple Myeloma

My name is Dr. Sherilyn Tuazon and I am from the Fred Hutchinson Cancer Research Center at the Seattle Cancer Care Alliance. It is a very exciting time for myeloma. And in the next 20 minutes, I will review the current information on the role of stem cell transplantation

Multiple Myeloma is a cancer of plasma cells in the bone marrow, and it is the second most common blood cancer in the United States.

The uncontrolled growth of plasma cells can lead to organ damage such as bone and kidney disease.  Infection is also a notorious complication, and it is the leading cause of death in myeloma. Despite therapeutic progress over the last decade, the sobering truth is that myeloma remains an incurable disease.   Thankfully with use of newer potent myeloma drugs, stem cell transplant, along with post-transplant maintenance therapy, survival for myeloma has improved tremendously with patients. Those with multiple myeloma can typically expect to live seven to ten years or beyond.  What is important to understand about myeloma is that it is markedly diverse disease such that each person’s myeloma is different.

Multiple Myeloma also changes or mutates within the same individual through time, which is incredibly challenging and given the significant heterogeneity of myeloma. It is important to recognize that one size does not fit all in the treatment of myeloma and that individualized therapy is key.

The initial choice of therapy depends upon the patient’s health, age, ability to undergo stem cell transplantation, and the aggressiveness of the cancer whether the disease is considered high risk or standard risk.

Most patients will be treated with III drug regimen and one popular regimen is RVD, Lenalidomide, Bortezomib, and Dexamethasone (RVD) Regimen.

After this initial therapy is given for about 4 months, we encourage patients to proceed directly with stem cell transplantation rather than to delay this procedure until the time of disease progression. Transplant performed early on shows longer duration of remission. Marrow transplantation can be done using one’s own stem cells (autologous) or using stem cells from a close relative or matched unrelated donor (termed allogeneic stem cell transplant.)  Although not curative, they have been shown to prolong remission and life in some patients.  Experienced centers like ours have a less than 1% mortality rate for these autologous transplants.

Another type of transplant that is sometimes offered to patient is called a tandem transplant or a double autologous transplant. This involves the use of two consecutive transplantations done within six months of each other.  Overall, double transplant does not appear to offer additional benefit to most people with multiple myeloma, however, in some patients with high-risk multiple myeloma, it is sometimes offered because they have worse outcomes with single transplant or any standard therapy. Allogeneic stem cell transplant on the other hand, as I mentioned uses stem cells from a donor with a matching tissue type.  In approximately 20% of cases, results show long term remissions that are suggestive of cure.  Unfortunately, approximately 15 to 20 percent of people who undergo allogeneic transplantation died from transplant related complications such as infection and graft-versus-host disease, which is a condition in which the donors transplanted stem cells attacked their body.  

Primarily because of these complications as well as the lack of clear benefit, allogeneic stem cell transplantation is only offered in patients who are young and have high risk multiple myeloma now.

In recent years, we have learned the importance of our own immune system in fighting cancer, and we have developed multiple immunotherapies.  

We now have something called car T-cell therapy or chimeric antigen receptor. T-cell therapy is a more specific way of teaching the immune system to recognize and target myeloma cells to capitalize on the potency of the immune system, without having the unique complications we see with an allogeneic stem cell transplant.

Car T-cell therapy involves the use of a patient patient’s own T cells which are a type of white blood cell to fight cancer. It begins with a collection of the patient’s T cells.  These T cells are then engineered to become cancer-fighting cells called car T cells. These car T cells are then grown in the laboratory until there are millions.

Once infused into the patient, the car T cells are now able to recognize and destroy myeloma cells.  Chemotherapy called lymph or depletion chemotherapy is typically given for a few days prior to car T therapy.

There is currently no approved car T-cell product for myeloma. At this time, car T cells are offered in the context of a clinical trial, often for patients who have failed standard myeloma therapies.

However, there are several ongoing trials using BCMA or B cell maturation antigen. The B cell maturation antigen or BCMA is a protein that is expressed exclusively on plasma cells and in particularly large quantities on plasma cells turn myeloma cells BCM a conductor.

Important for myeloma cells growth and survival and it is expressed in virtually all patients with myeloma.

Car T cell trials have a striking response rate among patients with highly advanced myeloma.  The majority of whom had had multiple prior therapies and had no other meaningful treatment options and the largest carT cell trial published to date.

The study has treated a total of 128 patients with a carT cell product called VB 2121. There were almost 75% of patients who responded to this car T-cell therapy and one third of them had a complete response meaning disappearance of all signs of their cancer.

Some of these patients have not relapsed more than two years after car T-cell therapy. These outcomes compared well to standard treatments for relapse myeloma as a reference point patients with myeloma who failed three main classes of myeloma therapy.

That is immunomodulatory drugs, inhibitors such as bortezomib and daratumumab. The only have a median progression-free survival of three to four months and the median survival is only eight to nine months. The car T Cell trial reported overall survival was 19 months.

These are the promising results of BB 2121.  An application has been submitted to the Food and Drug Administration for approval of Ide-cell as standard therapy for patients with relapse or treatment-resistant myeloma. A decision on the application is expected by the end of this month.

In general, the preliminary results of car T-cell trials are exciting. However, until we have a more conclusive results the position of car T cells in the treatment of myeloma remains to be determined. There are also other strategies that I would like to share with you. These include the use of other targets on myeloma cells using Cartesian.

Earlier in the disease course, we use donor T cells to manufacture car T cells to provide what we call an off-the-shelf product.  At our Center, we have a clinical trial that incorporates a small molecule called gamma secretase inhibitor to increase expression of BC.  This B cell maturation antigen and this is a concept developed by Damian Green at the Seattle Cancer Care Alliance.

Car T Cell Therapy is also associated with serious complications that may be life-threatening. And this is something that is important for us to remember and the most common side effect is what we call cytokine release syndrome or CRS.

This is caused by a large rapid release of inflammatory substances or molecules from immune cells affected by the car T cells. CRS manifests as fever with or without low blood pressure, low oxygen levels, and organ dysfunction. Another common complication after car T-cell therapy can be headache, confusion, speech disturbances, and in severe cases can lead to seizures, brain swelling, or a coma

Todd Brown is now here to share his personal experience with multiple myeloma.to you.  Todd is a 67-year-old professional Forester from Idaho. He is married and has two adult daughters. He was misdiagnosed with osteoporosis after a certain fracture from a “friendly chest bump” as he says that refused to heal in early 2012.  He is a two-time stem cell transplant recipient with multiple myeloma, and he will be sharing his uplifting message that focuses on resilience staying positive and finding balance post-transplant. 

I am competitive and in my first diagnosis there was a bit of a “why me”, but then I changed gears. I said,” you know what I’m going to beat this thing.” I am going to hit it head-on and take every option that the physicians offered to me.  I am going to beat the odds. After some chemo with a local oncologist, I did go to Seattle in late 2012 and I had an autologous transplant.  I went through the chemo and conditioning pre-harvest. I am a bit of an overachiever and I was able to produce 36 million stem cells in one sitting.  I sat there for 8 hours.  Other than sitting there or lying there on the bed, the actual stem cell harvest was relatively benign. 

My caregiver wife constantly reminded me to keep ice chips in my mouth. I was able to avoid any mouth or throat sores that typically infects patients going through treatment prior to stem cell introduction.

The actual stem cell is the introduction was again relatively benign much like getting any other IV treatment.  I will admit that that following week was a bit of a fog, I do not remember a whole lot about it other than being led around by my wife to the appointments and making sure that I was fed and hydrated.  I slowly started to come back into normal being and each day became easier and other than a skin infection.  I became fully engrafted on day 25 and was able to come home just before Christmas in 2012. I did not tolerate Revlimid as a maintenance drug. I had to stop that after three months and managed to go almost five years before the multiple. myeloma cells started to re-emerge.

I went back on oral chemo and then in the fall of 2018 went back to Seattle for my second transplant did not need to do the harvest because I still had stem cells frozen in the in the in the bank.

Everyone at Seattle had told me that the second transplant would be more difficult than the first but neither my wife nor I felt that.

I understand that there is no cure for multiple myeloma, but again, I thought “I’m competitive, I’m going to beat this thing.”   I have told my grandchildren I fully expect to see them graduate high school/ college, get married, and maybe meet my great-grandchildren.

I think that having a positive mental outlook has been extremely beneficial to me. I kind of view this as a poker game. I am going to play the hand I was dealt but as in poker, I was able to turn one card back to the dealer and get a new card.  Then, I turned a second card back to the dealer. I got a new card, and I am going to keep on doing that.

One thing I think that helped me was that I posted often on the CaringBridge blog site and being able to explain to friends and family what the medical professionals were telling me.

I needed to understand the process and become kind of my own advocate. In addition. I think that having a strong and loving caregiver with me every step of the way was a huge benefit towards me.

I am not sure who does the hiring at Seattle Cancer Care Alliance, but every member of their staff greeted me with a smile, greeted me by my first name and did so even after my repeated visits.  They helped me maintain a positive mental outlook.

And as I have ended most of my conversations, my blogs on Caring Bridge, or my emails to friends and family, I maintain “life is good.” I am lucky to be where I am.

And we will go to our first question.

Yes. Hello. I am a cancer survivor of multiple myeloma. I have had both transplants and I am about four years since the second transplant from a donor. My question is since I have had both transplants. The first one was with my cells. It failed. I got one with another with a donor my sister. It did work. Is car T therapy available to me in the future if I need it?

Yes, you will still be eligible after an allo transplant.

I have two brief questions for you regarding Car T therapy. If a patient can have more than one stem cell transplant. Can they also have more than one car T therapy and also after a car T, is a patient discharged from the hospital? How is their recovery the same or different from the stem cell transplant recovery?

Yes, it is likely that you would still be eligible for another car T-cell therapy. If the first car T-cell therapy. However, patients who received a second car T Cell infusion after the first one has failed only had about 21 percent response rate and the responses were much shorter. Which range from about 2 to 7 months. The responses are not as robust as the first one and we still need a lot of work in terms of making these car T Cell responses last longer.  Although we have seen striking responses to up to 100% of patients with refractory highly advanced disease, the remission rate is still short at less than one year. So, we really need more work in figuring out how to make these car T therapies last longer. 

How is the recovery the same or different from the stem cell transplant recovery to the car T therapy? Car T-cell therapy has a better side effect profile after 30 days then transplant.  It seems like most of our patients can function normally after a car T-cell therapy. 

Hi, my name is Alan. I had an autologous stem cell transplant to treat my multiple myeloma about 30 days ago.  I was released from the hospital two and a half weeks ago. My question relates to the side effects, which seem to leave me much more fatigued, groggy, and foggy.

That fog will lift in time. Usually patients recover within three months, the fatigue and maybe the mental fog improves as well. But what is important is to try to do more of the usual or normal activities to improve the fatigue as well as a mental fog. If you can, exercise a, try to engage with people or try to live normally as much as possible.  That could help the recovery, but usually patients feel better within the first three months and I have to say 30 days is still early.  Do not feel discouraged, keep going and stay positive.

Stay on maintenance therapy for as long as possible. 

I would say in general we offer a second transplant. If you have had a great remission from the first one. Usually what we like to say is about minimum of 18 months remission from the first one without maintenance or about 36 months or about three years while on maintenance therapy and typically what we what we find is that patients get about half of the remission.

Listen from the from the first transplant. Let us see as an example Todd Brown who was her patient guest had about five years about five to six years. I think or permission from the first one so roughly in general he will get about two and a half to three years remission from the second one. 

Typically, harvested stem cells are still good for about 10 years.

I would say it is hard to predict how long someone will be in remission just from the drug because every patient with myeloma is different and that is something we really want to emphasize because you know, it really depends on the biology of your disease

Todd on those days when it felt rougher than others. What would you say to you the most positive?

I think that probably is some physical activities just getting up moving around, playing cards, walking, and doing something which then caused me to be a little hungrier and a little thirstier.

It is kind of like a snowball. I mean not going downhill of course, but the more I did within reason, the better I felt. The more I ate, the more I was able to do.

You could get a covid vaccine around three months after transplant, the flu shot six months after transplant, as well as the rest of your childhood vaccinations at one year after transplant.

You can take walks as much as possible as early as you want after transplant.

If you have got an opportunity to walk outside just a walk around the block to the end of the street. That is really going to help you move forward both physically and mentally.

What is the standard number of Cycles for RVD for multiple myeloma?

So usually about four to six Cycles. We would like you to have at least a very good partial response what we call or about a 90% reduction from your initial monoclonal protein. Historically, we do not want patients to get about more than four to six cycles of RVD because we think that it is going to be harder to collect the stem cells because the increased exposure to Revlimid.