Can you explain what smoldering myeloma is?

 Many patients come in to see us because they have back pain or anemia or kidney problems; however, if we know that every single patient who comes to see us with multiple myeloma likely had five years, 10 years of a precursor condition – meaning they were asymptomatic. They did not have any problems, but they also had the same cancer cells and the same protein in their blood. We don't look for it because we don't screen for multiple myeloma and that's something we're changing now with the PROMISE study.

When we identify those patients and they have more than 10 cancer cells in their bone marrow, we call this smoldering multiple myeloma and the name is exactly right. They're almost going to myeloma, they're almost on fire, and the question is what leads to that progression: How often do those patients go on to develop myeloma? Are they at high risk of developing it or not?

So when I see someone who's doing great, who has no anemia, no lesions in their bones and doing well but they have a protein in their blood. They have myeloma cells in their bone marrow. Their first question is: Yes, I have this smoldering multiple myeloma but what's my risk of progression to active disease and should I do something about it?

Can you discuss what monoclonal gammopathy of undetermined significance, or MGUS, is?

 MGUS is the one step before smoldering myeloma. If we look at the spectrum of the disease, people usually have MGUS first and then smoldering myeloma if they progress and then active myeloma. MGUS is basically the number of cells, if there is less than 10, although this is very arbitrary. MGUS risk is very small so that's why we differentiate them because the chance of progression from MGUS to myeloma is only 1% per year .

So what is the risk for smoldering myeloma to progress and how long can this happen after you receive a small during myeloma diagnosis?

We don't know how many people have smoldering myeloma. If we think about the general population, we know that MGUS, or potentially smoldering myeloma, is actually very common – 5% of the population over the age of 50 are more common to have it; the African American population; or first-degree relatives of myeloma.

We start asking, well all of these people who are asymptomatic, how many of them would actually develop myeloma? How can we predict who will progress or not if I am today coming in to see a doctor and I have more than 10 plasma cells, I'm freaking out. I'm saying, okay I have myeloma right now, what are my chances of going in and having a fracture of my bones or having kidney damage.

The first thing to make sure is you don't have active myeloma yet but you're at risk. And the question is: What is that risk we look at clinical factors, what we call clinical markers, of progression – meaning the percentage of bone marrow cells, the light chain ratio, the protein in the blood, how high it is. And now we know that we also have genomic factors, meaning the type of cancer cells, are they aggressive? Do they like to grow very fast or are they just sitting around and growing very slowly? And they don't have a problem of waiting years and years before they cause damage.

 It’s a huge controversy and we still don't have a good answer. I think the most important thing is seeing a specialist, seeing someone who really works in that field especially in the smoldering myeloma field because that's the area where we're all trying to understand how do we predict progression. Are the current markers enough or do we need new markers? And how do we do as far as treatment for those patients? Do we treat them or not? I would advocate that we see a doctor, we consider clinical trials, because there is no right or wrong answer. There are so many questions to be answered in the future.

How often should patients with smoldering myeloma be seeing their doctors?

Watching and waiting is such a hard thing for many patients. In fact, they call it watch-and-worry. If I know that I have some cancer cells in my bone marrow, why do I have to wait until there is a lot of those cells? Do we have the right answer of which treatment should we use is also another problem.

There have been clinical trials of using Revlimid (lenalidomide) and dexamethasone or lenalidomide alone, which have shown benefit, but we don't know who those patients are, who would truly benefit from it. Is there a risk of taking those therapies early on?

So, I would have a discussion with my doctor. And if the answer is, I'm not going to go on therapy now or on a clinical trial, that at least being observed every three months being very careful on knowing that I don't have organ damage. Seeing my doctor all the time is important and that would be true for anyone even if they had 10 years of follow-up because myeloma can happen at any time. Many people will tell me I've been seeing you for five years so I'm going to stop seeing you because the risk of progression goes down after five years and the answer is that's not true. The the risk of progression can still happen at any time.

What is your biggest recommendation for a patient who has received a smoldering myeloma diagnosis?

I think that myeloma is such a rare entity. Smoldering myeloma iseven smaller. And knowing who your expert is in that field is very important, and whether your local doctor wants to refer you for a second opinion is very important, too. I think just having that connection with a doctor. I always say that if you have a problem in your house, you get an expert in that area. And your own body is more important than anything else in the world. You want to be your own advocate. You want to say, I’m going to go get the best of the best and make sure that I'm getting the best treatment for myself. Make sure that this advocacy, whether it's from yourself, from your family members, is available for you. These days, we're doing telemedicine. We're available for many people to give them opinions and making sure that they are on the right track, even if they don't want to come to see us in person.

How can patients with smoldering myeloma learn more about their diagnosis and the potential progression?

There are so many things. One of them, of course, is education. As you said, going online understanding the literature, talking to the experts in the field, getting to be part of some of those webinars and discussions that we have. But also getting your own information and your own data and that comes to the question of what are my genomic alterations? What is going on in my own cancer cells? This is where collaborations we have for the PROMISE study that we've developed at Dana Farber, and the CURE Cloud at the MMRF is the best thing because we are giving back information to the patients so that they can actually get access and empower themselves with that information.

Are there any trials that patients have to look forward to in the future?

There are so many options we are developing right now. There are ongoing

clinical trials including three drugs, including phase three studies, ongoing for registration purposes. But I would say that not every trial is the right trial for that person. And this is where you decide and pick and choose with your doctor or with us if you want help. We can help you in deciding what's the right drug for you. Precision medicine is here. When I have myeloma, I don't want to be on any drug. I want to be on a drug that works for me specifically.

What would you say is your biggest piece of advice for a patient who has been diagnosed with smoldering multiple myeloma?

There’s a lot of controversy. There is a lot of unknown. Every patient is actually helping himself or herself but also helping the future to change multiple myeloma and how we treat patients. I would say get into knowing an expert, working with them closely, being your own advocate because someday we will treat patients earlier and potentially cure myeloma by early interception.

Understanding Smoldering Multiple Myeloma

In simple terms, what is myeloma and how is it different from the other blood cancer?

That's a good question. Multiple myeloma is a cancer of plasma cells. So what are plasma cells? Plasma cells are part of your immune system. They’re the cells that make antibodies. So, every person has hundreds of thousands of different plasma cells. Each one makes a unique antibody that recognizes a virus or a bacteria or other pathogen that the person's been exposed to or may be exposed to. So, myeloma occurs when one plasma cell undergoes changes that causes it to grow and replicate and copy itself out of control.

So, it makes hundreds and millions of copies of itself and each one of those copies secretes the same antibody. So, normally you have lots of different antibodies but now you're over producing one antibody of the protein called the m protein or monoclonal protein that we detect in the blood and these plasma cells live in the bone marrow, which is the factory for blood. So, it can affect blood production, reducing the normal numbers of white blood cells, red blood cells and platelets. And it can also damage bone, from the inside out, it can cause damage to the bone tissue itself.

In a nutshell, it is a cancer of the plasma cells and it has a number of different effects. It's a widespread disease. It can go into any bone marrow space in the body and sometimes it can even go outside of the bone marrow space.

What tests are conducted in order to determine a new diagnosis?

 The diagnosis of multiple myeloma can be very tricky because sometimes the symptoms can be very subtle. Somebody can feel fatigued and their red blood cell count is low. Somebody may experience a broken bone for no unexpected reasons and that's due to damage to the bone. So, when we have a suspicion of multiple myeloma, there's a standard battery of tests that we do in order to make the diagnosis.

There’s blood tests that we look at the blood counts, blood chemistries and we pay particular attention to components such as the blood calcium level and another protein called lactate dehydrogenase, or lDH. We do a bone marrow biopsy, this is a gold standard test. It goes into the bone marrow and samples both the solid and liquid portions in order to identify myeloma cells. And we do additional tests, particularly genetic testing which includes cytogenetics and fluorescence in situ hybridization, or FISH testing. We also do imaging studies to detect bone disease all over the body. In the old days, we did plain X-rays of all the bones but we have much more sophisticated and sensitive tests now.

So, typically for the initial work up for multiple myeloma we'll do something called a positron emission tomography, or PET scan, or an MRI, looking specifically at the bones of the spine and the pelvis in order to identify those bone lesions of multiple myeloma.

Can you discuss what CRAB criteria is and what it consists of?

This is intimately tied to the diagnosis. At a technical level, the diagnosis of multiple myeloma is made when there's 10 or more clonal plasma cells or multiple myeloma cells in the bone marrow. So, that's the diagnosis of multiple myeloma; however, the difference between smoldering myeloma, which you'll hear about in other videos of this series, is this isan active multiple myeloma requiring treatment. The symptoms are codified in the acronym of CRAB.

The “C” stands for calcium. So, if the blood calcium level is elevated or if the patient has hypercalcemia, that is considered a symptom of multiple myeloma. The “R” stands for renal or kidney function. If there's a problem with the kidneys, if the kidneys are not functioning at 100%, this is often due to interference with the monoclonal protein with normal kidney function. The “A” stands for anemia or low red blood cell count. The “B” stands for bone disease. This is a specific kind of bone lesion; it's called a lytic bone lesion. It means there's destruction of the hard part of the bone and those show up on x-rays, PET scans, MRIs.

Now, historically if a patient has greater than 10 plasma cells in the marrow and one or more of those CRAB symptoms, that was sufficient to make the diagnosis of active myeloma requiring therapy. In recent years, we've updated that to expand the diagnostic classification. So, we've added three new criteria. These are codified in the acronym of SLIM. The “S” stands for greater than 60 plasma cells in the bone marrow or multiple myeloma cells. So, if a patient gets worked up and they have more than 60 myeloma cells in their bone marrow and don't have any other symptoms that's considered myeloma requiring therapy. The “LI” stands for light chains. This is a related protein that's part of the antibody molecule. It's called the light chain. And again, those are unique to each individual myeloma cell and they're overproduced in myeloma and there's a ratio that can be calculated of normal light chains to the abnormal light change. So, if the ratio of abnormal to normal light chains is greater than 100, then that is also considered active myeloma, requiring therapy. The “M” stands for MRI. So, if there's lesions that are not visible on a standard x-ray but are detected in one or more locations on an MRI that is also considered symptomatic. So, now we call them SLIM-CRAB criteria. If a patient has greater than 10% in myeloma cells in the bone marrow and has one or more of the SLIM-CRAB symptoms, then those are considered active multiple myeloma.

Are there any biological markers that are associated with a myeloma diagnosis?

The biological marker that we commonly follow in multiple myeloma is that M, or monoclonal protein. Now, that's actually not one test because, as I referred to earlier, there's the m protein and then there's light chains. And this can be kind of confusing. An antibody molecule actually is four molecules stuck together: two heavy chains and two light chains. And myeloma cells, for unknown reasons, over produce the light chains. So, in addition to the monoclonal protein, the antibody that's intact, there's also excess light chains frequently detected in the blood. And in some cases, the myeloma cells only make light chain. So, we have to follow the light chain rather than the m protein because we can't detect an m protein. The last point there is we can usually detect these in the blood but on some occasions, only a patient’s myeloma cells only secrete a small amount of the light chain and those can be detected secreted in the urine. So, the light chain is small enough to be filtered out in the kidneys into the urine. So, frequently what we'll have to do if a patient has myeloma but we don't have a detectable M protein or blood light chain, we have to do a 24-hour urine collection and then test the urine for the presence of those monoclonal light chains. So, those are typically the tests that we use to follow patients when they're initially diagnosed.

When they've been treated and if they're in remission, we follow those to detect the disease when it comes back. There are also a rare subset of patients who don't have any detectable protein and the only way we can find them is on some of these advanced imaging tests. So, there are a small number of patients who have what we call oligosecretory or non-secretory multiple myeloma. That means that the myeloma cells do not secrete a detectable protein and for those patients we have to do these types of advanced imaging studies periodically. So, if they're on treatment every three months or six months we'll do a PET scan or an MRI and that can get tricky because funding for that kind of thing is difficult to justify to insurance companies. But we have to do it. So we can usually get clearance for that.

When a patient is diagnosed with multiple myeloma, we use those initial tests to do staging. Now staging in myeloma is very different from staging in othertypes of cancers because typically staging in other types of cancers, particularly solid tumors, means how widespread the disease is. So, if it's ingested in one spot it's stage 1 if it's all over the body it's stage 4, and there's variations in between. But myeloma is different. The staging that we use for myeloma is really a statistical model to predict how aggressive the disease is going to be and how well the patients are going to respond to therapy. So, it's not as an assessment of the extent of the disease. Myeloma can be a very widespread disease. Anywhere there's bone marrow, myeloma cells can go. They can also spread outside the bone marrow. So, staging for us means predicting how aggressive the disease is going to be and how well patients are going to do with different types of treatment.

There was a revised staging system called the international staging system, which was very straightforward. There's two blood tests. One is for a protein called albumin and the other is for a molecule called beta2 microglobulin. And these are proteins that are made in the body and for various reasons they reflect the amount of disease that a patient has. So, we had very simple staging if the albumin was less than 3.5 and the beta2 microglobulin was less than 3.5 that patient is stage 1. And then if a patient has a beta2 microglobulin greater than 5.5, that patient is stage 3 and then stage 2 is in between. That system has been updated to include two new factors. One is lactate dehydrogenase, or IDH. That’s another blood test and if that's abnormal, that upgrades the staging. And the fourth element is what are called high-risk cytogenetic abnormalities.

On the bone marrow biopsy, we do cytogenetics and FISH tests on the myeloma cells from the bone marrow and there's certain abnormalities that are acquired in the cancer cells that can be detected by those tests that predict more aggressive behavior. So, if patients have one of these high-risk cytogenetic abnormalities, that can upgrade their staging. So, now the revised staging system is four tests: the albumin, beta2 microglobulin, IDH and the presence or absence of high-risk cytogenetic abnormalities. So, patients are staged when they're first diagnosed. This is a predictor of aggressive disease and clinical course, but it's not perfect. So, it doesn't change. So, if you were stage 1 when you were first diagnosed, technically your stage 1 for the duration of the disease. So, we don't rely upon staging as much as other practitioners and other cancers. We use this more as a guide, but we often have to tailor our care to the individual patient, the disease course. There’s ongoing research to understand not only the high-risk markers that we're using now for staging but additional genomic and other types of markers that may predict high risk and may predict specific drugs that may be useful to an individual patient.

So, the current standard for risk modeling for staging is more of a guide for how to manage the treatment of the disease. There's ongoing research to understand how additional risk factors, such as genetic risk factors or biochemical risks that we identify, can be utilized to treat individual patients better. So, there's no one risk that is universally agreed upon now. For example, for predicting who's going to require more aggressive treatment versus not, we have a good understanding that there are, for most patients, very good standard care up front. For a subset of patients, they will have more aggressive disease and it's an active area of research to understand what the markers are for this disease, what's the biology behind the more aggressive disease and what we can do to treat these patients. So, they have better outcomes.

What is the current standard of care for newly diagnosed multiple myeloma?

We have very well-established standard care for frontline treatment of multiple myeloma. So, for most patients, their initial therapy will consist of three drugs. The first is an immunomodulatory drug called Revlimid, lenalidomide. This is a pill that patients take at home during the course of their treatment. The second class of drugs are proteasome inhibitors. These are drugs that attack a specific part of the cell protein recycling machinery. Myeloma cells are particularly sensitive to inhibition of the proteasome. There’s two drugs that we use. The one is called Kyprolis, or carfilzomib. The second is called Velcade, or bortezomib. Velcade is the older drug and we have a lot more experience with it. But there was a recent study that was presented at the American Society for Clinical Oncology meeting that showed that essentially triplet therapy with either Kyprolis or Velcade are similarly effective, have similarly good outcomes. The third drug is a chemotherapy drug, a steroid called dexamethasone. So, steroids have been a mainstay of the treatment of multiple myeloma for decades. Myeloma cells are very sensitive tosteroids. It forces them to go from immature to a mature state and then they die. So, we use high-dose steroids as the third component of most triplet therapies for the upfront treatment of multiple myeloma.

So, Velcade plus Revlimid and dexamethasone or Kyrpolis plus Revlimid and dexamethasone are the standard upfront care that we use for patients. They have very good response rates, greater than 80%. They have very deep responses, about a third of patients can go into complete remission on this triple therapy alone. So that's our standard frontline therapy for many patients.

That is followed by what's called consolidation therapy. Consolidation therapy is autologous stem cell transplantation, which is a method to deliver very high doses of chemotherapy to patients who are in remission and use their own stem cells to restore their blood-making capabilities. This has been shown in many studies to deepen remission and extend disease-free and overall survival. So for patients who are eligible for standards for stem cell transplant, the next move after the initial therapy is consolidation with the stem cell transplant. That’s typically followed by maintenance therapy. So, there’s many studies now that have shown that low-dose Revlimid alone as a maintenance therapy following consolidation or following induction for people who are not eligible for transplant improves the remission length.

We use Revlimid maintenance as a standard care after either induction or induction plus consolidation. So, the upfront care for myeloma is very well established. Typically it's induction chemotherapy with a triple regimen, consolidation with the transplant and then maintenance therapy with Revlimid. If a patient is not eligible for transplant and achieves remission on that initial triple therapy, then we can maintain them with revelation.

Are there any exciting trials or treatment options being evaluated right now?

 There’s been a revolution in myeloma care in the last five years with the successful introduction of immunologic therapies for multiple myeloma. So, the first of these drugs was called daratumumab, or Darzalex, and this is actually a monoclonal antibody. So, just like the antibodies that are secreted by the myeloma cells, this is a monoclonal antibody, but it's been engineered to recognize a molecule on the surface of myeloma cells, called CD38. What it does, in a nutshell, is it helps the patient's own immune system to identify the myeloma cells as being bad and then the immune system can kill the myeloma cells. It does this through a number of different mechanisms. In the relapsed and refractory setting, Darzalex has had remarkable results, particularly in combination with immunomodulatory drugs such as Revlimid. In the relapsed setting, there's very good response rates, very deep responses and very long responses. So, there's a great deal of interest in moving daratumumab to the frontline.

There’s a number of different clinical trials ongoing now using a quadruple combination of daratumumab plus an immunomodulatory drug, such as Revlimid, plus plus a proteosome inhibitor such as Kyprolis or Velcade and high-dose dexamethasone as upfront initial therapy for multiple myeloma. Those are ongoing studies. Some of the early results were very interesting and promising. We await the longer term follow-up to see if this is going to become a new standard of care. But I should point out that daratumumab in combination with Revlimid and Velcade has been approved by the FDA for treatment of multiple myeloma.

The other area that's very interesting right now is in CAR T cells, or chimeric antigen receptor T cells. So, this is a method where we take T cells out of a patient, engineer them with a specific receptor that allows those T cells to find myeloma cells and kill them. There's been some really remarkable results in the relapsed/refractory setting for this type of therapy as well.

The other interesting and exciting area in upfront therapy is making that move to earlier settings in therapy, for example, at the consolidation phase for patients who may be at higher risk for early relapse after the transplant. There are ongoing trials now that are comparing induction plus transplant with induction plus CAR-T cell therapy as a consolidation therapy. I think those areas, where we're trying to understand how to incorporate immune-based therapies with conventional chemotherapy are very interesting. That’s paving the way to the future in myeloma care.

Options for Newly Diagnosed Multiple Myeloma

 What is the risk for myeloma becoming relapsed or refractory?

Unfortunately, myeloma is still considered an incurable disease. I always call it a marathon disease because even though you may have five or six years in the first part of your treatment, inevitably all patients will relapse or progress. So, it's almost a 100% risk basically that something is going to happen in the time of myeloma to cause progression or what we call relapsed disease. Refractory really refers to when the disease doesn't respond anymore to treatment and that tends to happen in the later parts of the disease. But earlier on we're able to get a response. So there is basically a 100% chance that the patient will become relapsed and maybe more in the later parts of their disease would become refractory.

Are there any other risk factors that are associated with an increased risk of this happening?

 Almost every patient does have relapse at some point, but the question is who will relapse sooner. Because of that, we know that there are patients that we consider high risk that might have a sooner time to relapse or progression. For example, patients with high-risk cytogenetics or FISH, which is a DNA study, those findings include things like deletion 17p or translocation 4 and 414 or translocation 14 and 16 and these are just chromosome numbers or parts of DNA, if you have any of those or if you've been told that you are revised international staging system score, for example,also known as RISS, is a high score at 3, then there's a greater chance that you'll have relapsed disease sooner than the average myeloma patient. So, that's one of the systems we use to figure out how we should time things and what kind of prognosis we should give patients when they are diagnosed.

What are some of the challenges that are associated with trying to find a treatment for the relapsed and refractory setting?

Relapsed/refractory myeloma is a huge challenge because although we have wonderfully successful drugs that we can use up front, many of these drugs are already used by the time the patient is relapsed and refractory or has had several progressions. So, one of the things that you'll often hear myeloma doctors say is that after you've had a relapse or a progression, they'll try to use a drug that you haven't been exposed to. So, the biggest challenge for us is finding more of those drugs.

And that's what drug development is all about. That's what clinical trials are all about. Sort of ironically and happily enough, the drugs that we now use in the frontline settings, such as Velcade (bortezomib), Revlimid (lenalidomide) and other drugs like Kyrpolis (carfilzomib) that we used earlier, those were originally studied in the relapsed and refractory setting. So, patients are actually benefiting from an upfront standpoint now that we've studied those in their relapse setting. So, finding new drugs is always a challenge.

I think the other challenge is the patient's challenge. It's really hard to find out you have a progression. It might just be something that we find on the blood. It's actually not even something symptomatic. And that's hard for a patient to say, “Okay, now I'm going to start this journey again, where I'm going to get a brand new drug with different side effects and a different schedule, And it might work and it might not.” I think that sort of mental stress is something that's really real and something that we try to address at these very important inflection points in our interactions with patients.

Then, tolerating the drug because these do have different side effects. The more you get on with the myeloma journey the drugs that we use for relapse and refractory myeloma further out have more side effects because, of course, these patients have been treated with multiple therapies. So, maybe the bone marrow isn't as strong so there's more anemia or more low platelet counts. Because of that, it can be a little bit tough for patients to tolerate these therapies as we get later and later. So,another very important part of the treatment for relapse and refractory myeloma is supportive care and trying to make sure patients can maintain a good quality of life.

Is there a current standard of care for the relapsed/refractory setting?

Standard of care for a relapse or refractory is based on FDA approvals and clinical trials that have been done. So what we used to say two years ago would be that if someone relapses after their first relapse then they would get maybe a daratumumab, also known as Darzalex containing regimen or a Kyprolis-containing regimen. Even in these past two years, Darzalex has been approved in the frontline setting. So, it's possible somebody may have received that in the frontline and if they don't use it later, there's always a debate do you use all these good drugs up front or do you wait for them when patients relapse? And we really don't know the answer to that because these studies haven't been done.

The good news is the more we have clinical trials the more data we have. The more experience we have, we get a better idea of what drugs we can use in the frontline, what drugs we can only use in the secondline and how patients respond with side effects and other things regarding tolerability.

Hope for Relapsed/Refractory Multiple Myeloma

Can you just discuss some of the medical issues, like bone damage, fatigue, renal renal issues or anemia, associated with multiple myeloma?

The medical issues that are associated with multiple myeloma are really directly related to the effects that the monoclonal proteins have on the body itself. So, these abnormal plasma cells overcrowd the bone marrow, not allowing the bone marrow to do its natural job

of producing your blood cells, specifically your white blood cells and red blood cells. If you have low red blood cells, that causes anemia. We know that the most common presenting symptom of myeloma is anemia, which, in turn, can make people feel very fatigued. The most common physical presenting symptom, aside from the fatigue, is bone pain. The bone pain occurs because the myeloma cells actually upregulate cells in your body called osteoclasts that break down the bone. This imbalance causes issues where the bones become more brittle. They become weaker and easy to fracture without any sort of direct trauma to the bone. These fractures and lytic lesions we can see cause a lot of pain and discomfort for patients, so that's an issue that patients have. Also, this kind of widespread bone destruction can cause the calcium to leach out of the bones into the bloodstream and that's called hypercalcemia, or high calcium levels in the blood. That can make patients feel unwell, too. That can make people have a low appetite, make them feel tired, even a little nauseous or constipated. Sometimes it can even make patients feel a little confused. And the high calcium levels in the blood are actually really toxic to the kidneys, which compounds the issue that these myeloma cells are also toxic to the kidneys. So, there are a lot of body systems that can be affected by the myeloma and can cause a lot of different symptoms and medical issues. Some of these issues can be directly related to each other as well.

How does the disease affect the bone marrow?

So, the bone marrow really is the primary focus of myeloma disease progression. There's properties in the bone marrow microenvironment that allow for infiltration and growth and proliferation and even migration of the myeloma cells itself. The bone marrow microenvironment has these inflammatory molecules that can actually play a big role in supporting the growth of myeloma cells and also play a role in drug resistance, too.

So, as the myeloma cells proliferate and overcrowd the bone marrow space, we can see lowered healthy white blood cells, lowered red blood cells; therefore, the immune system becomes inherently compromised and patients become anemic.

Are there any other issues surrounding the immune system that patients should be aware of?

Overproduction of these monoclonal antibodies are really not functional and not helpful for the immune system. It can also cause suppression of your normal immunoglobulins and that leads to a compromised immune system. So, myeloma patients are particularly susceptible to what we call encapsulated bacteria. These bacteria are in charge of producing respiratory infections like streptococcus, pneumonia, Hemophilus influenza. Treatment of the myeloma itself can compromise the immune system so it's really important for myeloma patients to protect themselves from infection. That’s practicing good infection precautions such as good hand hygiene, good oral hygiene, avoiding sick contacts and obtain vaccinations as directed by your providers.

Now, in terms of COVID-19, we know that patients who are at high risk for complications from COVID-19 are those who are above the age of 65, those who are immunocompromised and those with chronic kidney issues, amongst other many other risk factors. But those three alone that I just described are clear descriptions of the majority of myeloma patients:over the age of 65, immunocompromised. It's really important for myeloma patients to minimize their exposure to COVID-19, wash their hands really well, clean frequently touched areas, practice, social distancing, wearing face coverings when they're around others.

How likely are these issues to occur, and what can patients look out for?

Myeloma patients, compared to the general population, because of their compromised immune system, are seven times more likely to get an infection. And once they start treatment, that increases to 11-fold. Infections can be very serious in myeloma patients. They need to report fevers, shaking, chills. Even without a fever, if they have a very low blood pressure, they're feeling short of breath, they have a cough, dizziness, anything unusual should really prompt evaluation and care.

With renal insufficiency, about 20% of patients who have myeloma present with abnormal kidney function at diagnosis and about 60% present with anemia at diagnosis. In terms of the high calcium levels, about 10% to 15% of patients have that in diagnosis but develop it. For the bone disease, we see about 85% of patients develop bone disease throughout their disease trajectory.

Can you describe some of the treatments that are available for patients if they are experiencing any of these medical issues?

Specifically for infection, we know that the best form of treatment is really prevention. With the appropriate infection precautions that we just discussed and also certain antimicrobials are important. For example, there are certain myeloma therapies that can increase your risk of developing certain infections like herpes zoster or shingles and so it's really important for patients to be on antiviral medications to lower this risk.

If patients are neutropenic (really low neutrophils, which is a particular type of white blood cell that's your first line of defense against an infection), you're really susceptible to catching a bad infection and harder to fight it off. Patients who are neutropenic, we can give them growth factor support with injections to help boost their neutrophil count to avoid what we call a neutropenic event.

Vaccinations are also important. Patients should be receiving their seasonal influenza vaccine, their pneumothorax, their pneumococcal vaccine. And, of course, if they get a stem cell transplant, they're going to need to get their post-t transplant vaccination series. there's also the recombinant zoster vaccine that we have available now that patients can receive if it's recommended by their provider.

For the electrolyte imbalances like the hypercalcemia and also the bone lesions, we use bone modifying agents. Those are really important to decrease the likelihood of these skeletal-related events. It can help improve the bone integrity for patients and decrease these high calcium levels.

Then the bone pain that we see with myeloma can really compromise the quality of life for patients. So, pain control really needs to be optimized and there are several things we can do for that. There's prescription medications; surgical interventions; if patients have compression fractures, we can offer kyphoplasty or vertebroplasty; radiotherapy, if it's appropriate; and even complementary alternative medicines such as acupuncture.

In terms of the anemia, if we have anemia associated with diagnosis most often the anemia can actually correct itself once patients are on treatment because we're cleaning out that bone marrow from all that myeloma. But if the anemia persists, ruling out other causes of the anemia are really important. Nutritional deficiencies like iron deficiency, B12 deficiency, folate – we need to look for that. If there's blood loss from bleeding or even hemolysis, we need to look for that. Sometimes. endocrine problems like hypothyroidism can be responsible for anemia and if the patient's really anemic, they may warrant a blood transfusion. That will help improve the oxygen-carrying capacity for the patient.

Fatigue is probably the most difficult side effect that patients experience. It's really multi-bacterial. It's related to the disease itself, anemia, the treatment or even emotional issues such as depression. Exercise, proper rest, psychosocial support, good nutrition, transfusions, if they need it, and even certain medications can be beneficial for the fatigue to alleviate the underlying issue. If it’s truly something like depression or even insomnia, there's a variety of ways we can manage these medical issues for our myeloma patients to really maintain good quality of life.

Are there other types of supportive care that's available for patients?

I’mreally a huge believer in support groups. Myeloma is relatively rare. It only makes up about less than 2% of the population. So, it's really hard to meet another myeloma patient unless you're in the waiting room, sometimes you might meet one but it's really nice to be around your peers and share experiences – see what works for them, what didn't work for them. It’s really helpful for patients to participate in support groups if that works for them.

There's also several organizations such as the MMRF that have wonderful resources for patients and caregivers to learn how best to live well with myeloma. It’s becoming more of a chronic disease. Also, the MMRF helps to find out what the latest updates are regarding treatment of multiple myeloma and other supportive care resources.

What is your biggest piece of advice for a patient who may be experiencing any of these medical issues throughout their treatment or their diagnosis?

I always tell patients to keep a symptom diary. Not every center has intake sheets where they ask specific questions about symptoms so it's really important for the patient to advocate for themselves and write this down. It's very easy to go to your provider's visit and forget to mention all the stuff that you were experiencing a week or two ago before you saw them. So, it's really important to have a symptom diary. Write the symptoms down, if you are taking medications or certain interventions that are recommended by your provider to alleviate their symptoms. If it’s not working, you know record that, document it. Did it help a little bit?Did it help a lot? Did not help at all? It's really important for you and the provider to understand how you're experiencing these symptoms and what interventions we're doing that could be beneficial or not beneficial because we might need to try something else. And if it's related to treatment, we might actually need to dose reduce your treatment to improve toxicity but not reduce efficacy.

Supportive Care Options for Patients with Multiple Myeloma

What is the rate of myeloma diagnoses in the US each year?

Myeloma is the second most common blood cancer behind non-Hodgkin lymphoma in the US, but with that said, it really is only 1.8% of the cancers that are diagnosed every year. So, it can be considered rare compared to other cancers such as breast and lung cancer.

Every year, just over 30 000 people in the United States are diagnosed with myeloma and there's about a little under 13,000 people who pass away from the disease every year. Currently about 100,000 people are living with myeloma in the US.

Why is it so key to make sure that patients are seeing the right team or the right health care provider that's a specialist for multiple myeloma?

 This is really super important and one of the main reasons for that importance is because the relative rarity of multiple myeloma. Some oncologists may only see one or two myeloma patients every year because it's not that prevalent of a disease. These oncologists, because they see so few myeloma patients, might not be aware of the most modern and recent treatments and testing protocols and may not be aware of the best clinical trials that are available to their patients. Myeloma is a very complicated and heterogeneous disease and every patient's disease is different so it's really important for the right care team to be very aware of all of the most modern treatments and testing. Some patients do not have the resources available to them to travel to major academic medical centers and to see a myeloma specialist as often as is necessary for them but it's really important for every myeloma patient to get at least a second opinion from a myeloma specialist who sees a lot of myeloma patients and is really up on the latest and greatest in myeloma. Then, if patients continue to be treated locally, it's great if their oncologist can certainly be in touch with this myeloma specialist and really stay abreast of this patient's treatment. Then maybe they can see a specialist once a year just to stay on track with their disease.

Can you discuss the MMRF’s Right Track Program?

The Right Track is something that our founder and chief mission officer Kathy Giusti had been working on up at Harvard Business School, with five other non-profit cancer organizations. They came up with four steps that every cancer patient can take to make sure that they're moving toward their best possible outcome for their cancer.

The steps are seeing the right team, having the right testing done, being placed on the right treatment and then sharing data at every step.

We were saying previously about the importance of the right care team. It's really important for cancer patients to be seen by a specialist, either at an academic medical center or at an National Cancer Institute-designated cancer center, where the doctor sees a lot of patients who have their same type of cancer. They can be assured that their doctor knows a lot about the disease.

Then once they're with the right care team it's really important to have the right testing done. That includes genomic testing to enable your doctors to learn more about the subtype of your disease, which can be especially important for myeloma patients and that can help to potentially inform treatment options for patients.

Being on the right is what patients will move to after having the right testing done. The right treatment can be based on the subtype, the level of risk associated with their specific disease and previous outcomes that they may have had on other therapies.

The other important part is sharing their data at every step. We always encourage patients to share their data because that will really accelerate new therapies for all patients.

How can patients learn more so they can be their own best advocate?

Certainly, in the case of myeloma patients, it's really important to learn as much as you can about myeloma and what treatments are available out there. The MMRF has a lot of education programs for patients. We have live education programs; patient webinars; materials such as our patient kits; a lot of resources on our website. Those are all great resources for patients to learn about their disease so they can advocate for their own care.

We always encourage patients to have substantive discussions with their doctor whenever possible and ask as many questions as it takes for you to get the answers that allow you to understand exactly what's happening and why you're being treated with a certain therapeutic. We also encourage patients to reach out to resources such as our patient navigation center at the MMRF and ask our experienced myeloma nurses any questions they might have as well. That can really help them advocate for themselves and for their disease.

Why is it important for patients to consider joining a clinical trial?

We always talk about clinical trials and how important they are to move new therapies forward for patients to approval. There's no new therapies approved and no new treatments unless patients volunteer for clinical trials.

Patients seem to be a little bit afraid of what's going to happen and there can be some factors that may prevent them from being on a trial, such as being close enough to a center or not being able to see the doctor as many times as is necessary for the protocol. But in general, being on a trial means that you're being watched by your care team even more closely than normal. So you're getting even better care than normal and you might receive an active therapy that's not available to other patients and it might be really great. We always encourage patients to consider a clinical trial if it's appropriate for them at their stage in their disease journey. They can talk about it with their doctor and they can make that decision together.

The MMRD also recently launched its Cure Cloud. Can you discuss this a little bit further?

The Cure Cloud is a huge effort at the MMRF and we have been working on this non-stop for several years now. It's great because it finally launched on July 14. We’re really excited. We’ve always been a huge proponent of collecting as much patient data as possible because we know that having that data and having it available for researchers means better treatments and potentially accelerating a cure for this disease.

Leading up to the Cure Cloud, our COMPASS study was a great example of this. We've been monitoring newly diagnosed patients in this study for eight years and this study has been pivotal in the advancement of knowledge about myeloma and development new therapies.

We always encourage patients to donate their data because we know how important that is. I often hear from patients that they want to donate their data but they don't know how to donate their data or where to donate their data but now the MMRF has created a way for patients to do this and every patient can donate their data.

The Cure Cloud is a direct-to-patient effort we launched where patients can donate their own data to become part of the Cure Cloud study. This is an effort to create the largest database of clinical and genomic data for myeloma patients to accelerate new treatments and hopefully lead to a cure. All data that is collected will help all myeloma patients.

There’s a lot of firsts in the Cure Cloud. This is the first direct-to-patient effort in the myeloma community. We have the first at-home genomic testing for myeloma patients and the first CLIA grade liquid biopsy or blood test that can sequence patients by looking at myeloma DNA that's circulating in the blood without doing a painful bone marrow biopsy. This is free testing. It doesn't cost anything for the patient and it doesn't cost anything for the clinician.

In order to be eligible for the study, patients need to have active disease and that's because we need patients to have enough myeloma DNA circulating in their blood so that it can be detected in the test. So, patients need to have active disease. And certain smoldering myeloma patients will be able to join the Cure Cloud as well if they've already enrolled in the Dana-Farber PROMISE study or the P-CROWD study and receive a code from that study. Their enrollment in Cure Cloud will hopefully begin later this summer…

For Cure Cloud, active myeloma is defined as having an M spike of 0.3 grams per deciliter or greater and also a kappa lambda light chain ratio of 8 or more. Now, if patients don't have this information, they should talk to their care teams or they can call our patient navigation center at the MMRF. If patients are in remission or if they're on maintenance therapy, this is great news for these patients, but because they have a very low disease burden when in remission or when on maintenance therapy, the testing would not work on them because there's just not enough DNA circulating in their blood. But we still want those patients to sign up for the Cure Cloud. We're going to track everyone who signs up. We're going to be in touch with them and

keep track of how they're doing and if their myeloma begins to relapse we certainly will have them donate their blood sample at that time and donate.

If patients are deemed eligible and they sign up for the study online, then they need to have their doctor sign a form which gives consent for the blood draw. Then a mobile phlebotomist (a person who draws blood) will come to their home and safely do the blood draw. The blood will be shipped to our lab for sequencing. At the same time our partners in the study will be collecting all of the patient’s medical records from all the doctors and centers that the patient has been to. These two pieces of data are joined together but they're de-identified so they cannot be linked back to the patient. All of this data is stored in our very secure cure cloud database and the data is also collected on the patient's own secure dashboard which is within our Cure Cloud database. They can also access it. Patients and doctors will both receive results of the genomic testing so when the patient's blood is sequenced the result will come back to the patient. The result will also go back to the doctor. They will have a listing of clinical trials that might be appropriate for them based on their genomics and that will also allow the patient and the doctor to have more useful data-driven and substantive discussions about future therapeutic options for them. Data will also be available to certain researchers.

This is going to certainly accelerate new therapies for all myeloma patients and hopefully a cure for this disease. In the future, as Cure Cloud begins to gather more and more data, our goal is to

put together the data of at least 5,000 patients in the cloud database. As we gather more data, the clinical data, the genomic data and the immune data on patients, patients and doctors everywhere will have access to visualization portals where they're going to be able to see treatments and outcomes for patients who look like them and that's going to help patients and their care teams make more informed and data-driven decisions on what therapeutic options might be best for them.

Are there any other additional resources that the MMRF has available?

We have three great things for patients. First and foremost, we have a patient navigation center that is second to none. We have three very experienced myeloma nurses working in our patient navigation center. Our nurses can be reached at 888-841-6673 or they can be reached by email at 

. They’re there every day during the week from 9 a.m. to 7 p.m., to answer any questions. They’re a fantastic resource for for all patients.

Secondly, we have a brand new program that we just started called Myeloma Mentors. We have about a dozen specially trained myeloma patients who can act as mentors to other patients. We have a great page for them on our website where you can see the mentors, you can see where they are in their disease. We have some smoldering mentors, some newly diagnosed mentors, mentors with relapsed/refractory disease who are just interested in speaking to someone who may be going down the same road that they're going down with their journey or maybe they've been through a procedure that this patient is thinking about they want to really find out you know how it was and what their experiences were like. They can contact the patient navigation center and be matched to a mentor who they can then talk to on the phone and they can share their experiences and share their journey, which is a great resource.

. It just underwent a complete modernization overhaul facelift. It’s reallygreat now and I encourage patients to go to the website. All of our educational resources are there. They can listen to webinars, patient summits, order our patient kits or read them or download them.

What is your biggest piece of advice for patients with multiple myeloma?

Three thing. First, I recommend that patients learn as much as they can about their disease so that they can be active partners in the decision-making process with their doctors. This is so important. And then they become an educated medical care consumer so that they really understand what the doctor is treating them with and why. And if they have questions, they know how to ask them and get the answers that they need so they feel comfortable with the decisions that are being made on their behalf.

Second, I recommend all patients take full advantage of organizations – like the MMRF – trusted third parties, trusted sources of myeloma information. We can help you find the resources that you need. Certainly call the patient navigation center and whatever you need we can certainly help you with.

Finally, if you're diagnosed with myeloma or if you've been in treatment and you've relapsed, my best advice is don't lose hope. Developments happen really quickly in myeloma and there's been a lot of amazing advances in the myeloma field just over the past few years. There's a very active community of physicians and researchers in myeloma. Many new treatments are on the horizon. There’s great efforts like our Cure Cloud that are in place. Data being collected that can help identify precisely the right treatment for each patient and hopefully help cure this disease in the future. The future is really bright for myeloma.

Learning About Resources in Multiple Myeloma | CURE^® Speaking Out

Understanding Smoldering Multiple Myeloma

Options for Newly Diagnosed Multiple Myeloma

Hope for Relapsed/Refractory Multiple Myeloma

Supportive Care Options for Patients with Multiple Myeloma

Resources from the MMRF

Latest News

Learning About Resources in Multiple Myeloma | CURE® Speaking Out

Understanding Smoldering Multiple Myeloma

Options for Newly Diagnosed Multiple Myeloma

Hope for Relapsed/Refractory Multiple Myeloma

Supportive Care Options for Patients with Multiple Myeloma

Resources from the MMRF

Latest News

Learning About Resources in Multiple Myeloma | CURE^® Speaking Out