Options for Newly Diagnosed Multiple Myeloma



Kristie L. Kahl: In simple terms, what is myeloma and how is it different from the other blood cancer?

Dr. Hearn J. Cho: 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.

Kristie L. Kahl: What tests are conducted in order to determine a new diagnosis?

Dr. Hearn J. Cho: 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.

Kristie L. Kahl: Can you discuss what CRAB criteria is and what it consists of?

Dr. Hearn J. Cho: 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.

Kristie L. Kahl: Are there any biological markers that are associated with a myeloma diagnosis?

Dr. Hearn J. Cho: 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.

Kristie L. Kahl: What is the current standard of care for newly diagnosed multiple myeloma?

Dr. Hearn J. Cho: 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.

Kristie L. Kahl: Are there any exciting trials or treatment options being evaluated right now?

Dr. Hearn J. Cho: 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.

Transcription edited for clarity.

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