What is Multiple Myeloma?

Rafael Fonseca, MD

Published 2020

Dr. Rafael Fonseca has been a practicing hematologist for almost three decades, now at Mayo Clinic. He shares the basics of what myeloma is, including the different types and standard of care.

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Video Interview: Dr. Rafael Fonseca, Myeloma Specialist

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Introduction

Can you introduce yourself?

My name is Rafael Fonseca. I’m a hematologist at the Mayo Clinic in Arizona. I’m a professor of medicine at the Mayo Clinic. I’m the chair of the department of internal medicine.

My clinical practice my research are exclusively devoted to myeloma and related conditions with the goal of finding new treatment options and improving the care for patients.

Can you talk about the research you’re doing?

Throughout the years, I’ve been engaged in multiple aspects of research surrounding multiple myeloma. I did a lot of research early on with some things that we would consider more basic like understanding the genetic nature of the cells and which genetic markers distinguish myeloma from other tumor types.

I’ve also been involved with a large number of studies that test drugs. Some of those drugs have been taken all the way through to FDA approval, and we use them now for the treatment of myeloma. 

We also do a lot or correlative studies. We sometimes work with a clinical trial where we collect samples of either blood or bone marrow and test for things that might help us better understand why someone responds to their treatment or not. 

There’s plenty of work to do in myeloma research.

Basics of Myeloma

What is myeloma?

Multiple myeloma belongs to the group of diseases we think about when we think about blood cancers. Specifically, myeloma is a form of adult bone marrow cancer that comes about when plasma cells convert into malignant cells.

Under normal circumstances, plasma cells help protect our bodies. They produce the antibodies that give us immunity. Occasionally, those cells become malignant, and that’s what we call myeloma. 

These malignant cells are usually restricted to the space inside the bones called the bone marrow. There are a number of problems that can come about because of the growth of malignant cells from myeloma. The cells grow, and they take up space.

A person may present with fatigue because they have anemia. The cells can also cause problems in the bones. They can erode the bone structures.

This can cause pain or in more extreme cases, even fractures. It also releases some of the calcium that our bones have into the bloodstream. Patients may have a high calcium content in their blood. 

Myeloma cells also produce a type of protein. Fragments of the protein can flow down into the urine. That can cause problems in the kidney in the form of renal failure.

»MORE: What is multiple myeloma?

How is a person diagnosed with multiple myeloma?

For most patients that we diagnose, they’ll come because they’re having some symptoms. Some might come because they have a history of back pain. Sometimes they’re seen in the hospital because of kidney problems and it’s found out that those problems are due to the multiple myeloma.

Maybe a general practitioner finds that the person has anemia and it’s not otherwise explained. Then, the patient would go to a hematologist and would ultimately get diagnosed. 

There is a fraction of patients who are diagnosed with a premalignant condition called smoldering multiple myeloma where they may have abnormal cells and have detectable levels of the protein in their blood and urine but not show symptoms. The majority of those patients will not require treatment.

What are the different types of multiple myeloma?

There is an early step called monoclonal gammopathy of undetermined significance. That’s a mouthful, so it’s usually referred to as MGUS.

That condition is when there’s very discrete growth of the plasma cells, usually that they’re going to be less than 10-percent of the cells in a person’s bone marrow.

Patients with this will not have any of the features I mentioned like anemia or kidney problems. This is actually quite common. More than two-percent of people over the age of 50 have this.

This can evolve a little more. If the number of cells is more than 10% of the marrow, this is called smoldering multiple myeloma. It will remain as such for as long as there is no evidence of complication.

Once we see that someone has complications, that’s when we say they have multiple myeloma, active myeloma or simply, “myeloma.” That’s when people require treatment. 

We spend a lot of our time trying to define the boundaries between those three groups. In fact, where the boundaries are has changed recently.

So much so that we think there are some patients who have more advanced cases of smoldering multiple myeloma who should go ahead and start treatment. 

Is there a standard of care?

There are several guidelines that are published. One of the most common is called NCCN. From a patient perspective, that can be daunting and complex. I recommend starting with a patient organization like one of the ones I mentioned. 

We at Mayo have a set of guidelines we provide. It’s mostly directed towards providers, but it’s simple enough that they can be understood even if you’re not in medicine. They’re available online at msmart.org. That provides a general description of what we would prescribe for patients in different situations.

Can you explain multiple myeloma vs. Waldenstrom macroglobulinemia?

Sometimes they can be really similar, but sometimes they can be very different. If you think of myeloma, it’s a cancer of the very late-stage of B cells. B cells are part of a whole family of cells in our immune system.

Think of myeloma as the seniors in high school. Waldenstrom is like the juniors.

If you look at the genetic makeup of myeloma and Waldenstrom, even though they’re neighbors, they’re completely different. Even though they have proximity because of the process of evolution in the B cells, they’re completely different.

The majority of Waldenstrom patients have a specific gene mutation. It’s something called MYD88. A lot of them respond to a drug that essentially has no use for myeloma patients.

Some drugs cross the boundaries for both, but that has to do with how some of the cells in both conditions produce proteins. Proteasome inhibitors work in both diseases. 

They’re fundamentally different, but Waldenstrom is kind of in the camp of what myeloma doctors see.

Treatment Opinions

What are your tips for navigating treatment options?

The diagnosis of myeloma is not always necessarily straightforward. The treatments have changed dramatically over the last several years. We have had a lot of new approvals from the FDA for new drugs since the 1990’s.

You have a patient, what their preferences are for treatment and what the logistics of the treatment would look like. Then you have the disease. We want to understand how it’s affecting the organs and things.

We also need to know which of the genetic subtypes it is because that has a significant impact on how we go about therapy. Then you have all the drugs and therapies that are available. Someone has to put all this together for the patient. 

I always encourage patients to have a myeloma specialist as part of their team. They can get their treatment anywhere, and fortunately, treatment can be done very well at community practices, but it doesn’t hurt to have a specialist. There are myeloma centers all over the country, too.

There is a good number of patient support organizations that can provide information for patients. The three that come to mind are the International Myeloma Foundation, the Multiple Myeloma Research Foundation and one I’m working with quite closely called Myeloma Crowd.

These organizations all have resources. They all have hotlines where patients can call and ask questions. This can help them tremendously when they’re making decisions about their treatment. 

We actually just worked in creating a tool that is called Health Tree. These are really neat. Patients go to the website and enter their information. It can be as detailed as the patient wants. Some are very sophisticated and put in their genetic markers and things like that. They can put all their conditions in.

It creates a repository from which we can provide some talking points for patients to take to their doctors. If a patient is on one medication and with that, we know they should be on another preventative medication, we can share that with the patient for them to ask their doctor about. It’s a way to improve the conversation from the patient perspective.

It could also serve as a mechanism through which patients receive feedback and become more informed “consumers” of their health care. They’re going to be better equipped to have conversations with their doctors. 

As a doctor, I can tell you, if I can spend most of my time talking to my patients about the pros and cons of different treatments, it’s much better than me having to sort out the facts of the disease. It makes the encounter more valuable.

They will also lead to research. Patients are going to be able to put in their information, that information can be connected and reports can be generated from that. Health Tree can send queries to users.

Say a patient is on a new drug and says they’re having migraines. They could send a query and ask, “Who else is having migraines?” Suddenly, we know this new drug can cause migraines. 

They become assassins who target myeloma cells, and then they’re shipped back to the patient and given back to the patient in their vein. Essentially, you’re taking T cells, training them to kill myeloma cells and giving them back.

That’s a strategy that has worked and is already commercially available for some other cancer, so we’re hoping that myeloma will have that. An alternative strategy is to use the bispecifics.

It’s kind of the same thing, but instead of taking the cells out, you introduce a molecule into the body kind of like a matchmaker that brings together the T cell and the myeloma cells. I always use the analogy of the frog and the scorpion. 

The frog is going to cross the river. The scorpion says, “Can I ride on your back across the river?” The frog says, “No, you’re a scorpion. You’re going to sting me.”

The scorpion promises not to, and the frog agrees. Halfway through the river, the scorpion stings it. The frog asks, “Why did you do that?” The scorpion replies, “Well, it’s in my nature.”

It’s in the T cells’ nature. When they’re next to a target cell like a myeloma cell, they will attack it. Do a Google search of T cells attacking cancer cells. It’s really cool.

What do you have to say about a cure for myeloma?

If you read every textbook and every article, you’ll read that myeloma is not curable. In order to have that conversation, we first need to define what “curable” means.

If we mean that a patient can get five days of treatment and the majority of patients will never again have to deal with that again, then myeloma is not curable.

If we redefine “cure” as a number of patients being able to enjoy a normal life expectancy even after diagnosis, then there is a number of patients that can be cured. 

I sometimes get in trouble for this because it depends on how the person I’m talking to defines being cured, but there are myeloma patients that are cured from the disease.

A number of patients I have seen in my practice have had treatment 10 or 15 years ago and remain in good condition with or without detectable myeloma.

Unfortunately, this is still a minority of patients. I would like to have a future where we have a treatment that is short, free from side effects, and cures everyone.

When I first started in myeloma, we would tell patients they were looking at two or three years at best and we had almost no drugs. Now, the prognosis is measured in several or many years and sometimes even decades. 

I remind patients of one thing all the time: if I see you today in 2019 and the life expectancy is 10 years, how will we treat myeloma in 2029?

That is what we call the valley of options because with all the research being done, they will have options at that point that don’t exist today.

Clinical Trials

What advice do you have for a patient who is interested in a clinical trial?

I would recommend they go to SparkCures. There’s clinicaltrials.gov. That’s sort of the central source, but if you go there, you’ll notice it’s not really that easy. There are many trials listed with no way of knowing if you are eligible or not. 

With SparkCures, you put in your information. You can tell them how far you’re willing to travel, and it will suggest trials you could be eligible for. It has a really neat tool that tells you about centers of support.

Let’s say you live in LA but have a family member living in Atlanta. As it turns out, Atlanta has a great myeloma center. Suddenly Atlanta is now an option because you might be able to stay with your family. 

As a doctor, I can tell you that we’re always thinking, “Is there a trial that could be good for this patient?” If I don’t talk about a trial, it’s maybe because there’s nothing that would be better than what we’re going to recommend.

Trials often open up new avenues for patients to consider. These new avenues could be adding a drug to an existing course of treatment. For example, there was a trial for adding Darzalex to the standard induction treatment VRd.

With this, they were able to greatly increase patient responses. 94-percent of patients in the trial were able to reach a complete response at the end of the consolidation period. This is going to lead to more clinical trials. 

Trials can also help you by bringing in drugs that aren’t yet approved but show some promise. There’s a new antibody out now from GSK. It has a warhead attached to it basically.

It has a molecule that’s going to be toxic to myeloma cells, and it seems to be working. It has some toxicities, and we’re trying to figure out how to best use it. It seems to work even when nothing else is working, and that’s only available through clinical trials right now. 

Never think of trials as being exposed to random things. They’re very well thought out. More often than not, you have a high level of reassurance.

What phases do clinical trials go through?

There are three key clinical trial groups people need to know about. There are more than that, but the popular ones to know are phases 1, 2 and 3. 

Phase 1 trials are typically small clinical trials. A drug is being tested for the first time against a certain condition and sometimes for the first time in humans.

The only focus of that trial is to find safety and make sure there are no unexpected safety hazards before opening the trial up to more people. Typically, these trials will start with low doses and gradually increase.

The next step is to see if what you’re doing has any activity. That’s called a phase 2 trial. They usually are small to medium-sized. These people are given the dose that was determined to be safe in the first phase.

What they’re looking for here is what fraction of patients respond to a specific treatment. It’s pretty straightforward. Phase 1 and 2 clinical trials are done with drugs that aren’t yet available. 

If a phase 2 trial is successful, there’s some hope that what you’re seeing is going to be better for the disease. That’s where you go to phase 3. That’s where they would prove that a new drug is going to be better than what’s considered standard or that it can improve patient outcomes when added to the standard.

This is considered the gold standard because in this phase, you can test rigorously whether or not something adds to the care of patients. This is where they ask questions like, “How long does it control the disease or improve survival?” It looks at all sorts of metrics.

Would you say that phase 3 trials are better to look at getting into than 1 and 2?

Not necessarily. In phase 3, you probably have the lowest risk as far as clinical trials, but you also have a less innovation, too. There have already been some advancements. 

Phase 1 and 2 give you options for things that aren’t yet being considered for phase 3. There have been myeloma drugs approved on the basis of phase 2 because it’s just so obvious that patients who didn’t have any other options were responding.

In fact, that has and will be the case for some of these new immunotherapeutics. They can sometimes save individuals who would otherwise have not had any options. 

Even phase 1 trials are interesting. If you go back about 40 years, people used to think of phase 1 clinical trials as, “Well, let’s just see if something works.” Now these things are quite different. You don’t see what the low levels of responses like you would back then. They’re very well thought out.

Final Word

Do you have a message for newly diagnosed myeloma patients?

Everything you’re going to read is much easier to hear directly from a doctor. Under normal circumstances, I’d like to see patients in person. I’m cognizant of the difficulty that a diagnosis places on a person and their family and how it changes our whole view of the world. 

Don’t give up. There’s no time to be nihilistic in myeloma. I will always respect patients’ choices, but we have a lot of good opportunities, and there is a very good possibility that a person’s life can be extended very significantly with effective treatment.

I sometimes get the statement from patients, “I am about quality, not quantity.” Well, good news because with myeloma they both go hand in hand. That’s not to dismiss the possibility of side effects and toxicities that will occur sometimes with treatments, but for the most part if we can control the disease, the quality of life increases substantially. 

Seek out opportunities and connections whether that’s in the form of patient support organizations, information like The Patient Story, resources like Health Tree or looking into clinical trials. 

I have no doubt that an informed patient ends up being a better patient for themselves and for their family. There’s nothing wrong with being a sophisticated patient. 

I would rather see a patient in my office who knows a lot about their disease where we can spend our time talking about specific aspects of treatment rather than waste their time having to go back to the basics with them. It’s a better return on investment for you.

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