[00:00]
Prof Simon J. Harrison: Hello, my name is Simon Harrison, and I’m the Chair of the Medical and Scientific Advisory Group at Myeloma Australia. I’m also a myeloma doctor at Peter MacCallum Cancer Centre.
[00:13]
As you probably know by now, myeloma is a cancer of some of the blood cells called plasma cells that live in the bone marrow and normally produce antibodies. These cells become damaged, and the genetic damage produces an abnormal malignant plasma cell that makes a nonsense protein called an M protein. We can detect this in the blood, and it is often a way in which we can look for myeloma without doing a bone marrow.
[00:46]
The proteins in the blood are called M proteins, and they are structured like a normal antibody, so they look like a Y-shape. The parts at the top of the Y can detect antigens on the surface of bugs to prevent infection, or on cancer cells. The large parts of these molecules are called heavy chains, and that is where the G, M, A or E name comes from. The smaller parts are called light chains, and they are called kappa and lambda. This helps explain what people mean when they say “IgG kappa” — it describes the structure of the molecule that the myeloma is making.
[01:33]
I’ll talk about light chains in a little more detail shortly. When we do a blood test looking for the paraprotein or M protein, you can see a separation and curve showing the normal proteins that are in the plasma, the liquid part of the blood. In the gamma region, a very high peak can be seen. This is the abnormal antibody that the myeloma cells are producing, and it is called either a paraprotein or an M protein, standing for myeloma protein.
[02:15]
Small fluctuations in these levels do not mean a great deal because the test is not especially sensitive. There generally has to be a significant level in the blood, such as 5 grams per litre, to make a diagnosis of myeloma. A change of somewhere between 5 and 10 grams per litre may indicate that the myeloma is changing significantly and that treatment may need to be started or adjusted.
[02:45]
Some patients do not make a detectable protein. They may be making only light chains, which we will discuss in a moment, or they may make no protein at all. This is called non-secretory myeloma. It can be more difficult to monitor over time and may require more frequent scans and bone marrow tests.
[03:08]
Here we can see light chains, which are the small parts on the side that combine with the heavy chain to form the antigen-binding site. Light chains are produced in people without myeloma and can be detected in everyone’s blood. Kappa and lambda light chains are usually present at approximately the same level.
[03:33]
Light chains are quite small and can be filtered through the kidneys, where they appear in the urine. This is called Bence Jones protein. It was one of the earliest ways in which myeloma was detected, more than 100 years ago.
[03:54]
To measure light chains in the urine, urine needs to be collected over 24 hours, which can be difficult. The light-chain level in the blood also has to be above a certain threshold before it passes into the kidney and is not reabsorbed. Measuring light chains in the blood is therefore much more sensitive and accurate. Light-chain levels can also change much more quickly than heavy-chain levels because they are excreted through the kidneys very quickly.
[04:21]
These are myeloma cells in the bone marrow. You can see large cells with a very large nucleus, the purple area in the centre of the cell, surrounded by the lighter-coloured cytoplasm. There is also a very light area, which is the factory where proteins are produced. This is much more obvious in myeloma plasma cells than in normal plasma cells or other normal white blood cells.
[04:57]
One of the things doctors examine is the nucleus. Normally, it is very dark and uniform. In this micrograph of the bone marrow, there are many lighter, open areas, which tells us the cells are very active and producing large amounts of protein.
[05:22]
A bone marrow procedure is performed by inserting a small needle and drawing some liquid from the back of the pelvis. A small piece of bone is then taken using a different type of needle. A little sedation can be used to make the procedure more bearable. It is a very important tool for making the diagnosis and for performing complex genetic tests to understand how the disease is likely to behave in the future.
[06:00]
One of the things we need to decide when we meet a patient with a protein in the blood and plasma cells in the bone marrow is whether they need treatment. One way we determine this is by asking whether the myeloma is causing damage. This is where the CRAB features come in. Patients with a high calcium level may need treatment. Patients with abnormal kidney function, often because light chains are becoming stuck in the kidneys, may also need treatment. Low haemoglobin, or anaemia, can indicate that the myeloma is active, either because it is taking up space in the bone marrow or affecting the kidneys. Bone pain, fractures, bone disease or lumps outside the bone marrow that are identified on scans and X-rays are also important signs that treatment may be required.
[07:15]
When examining the bones of people with multiple myeloma, several techniques can be used to identify damage. Historically, plain X-rays were the main method. Dark patches in the skull can create what is known as a “pepper pot skull”, a classic feature of multiple myeloma. Disease may also appear in the long bones as dark holes, expanded areas of bone or fractures, including in the tibia. CT scans can identify holes in the bones of the spine. In adults, bone marrow is mainly found in the spine, ribs, pelvis, sternum and the tops of the long bones, so damage can often be identified using these imaging methods.
[08:26]
More recently, MRI scans have been used to examine the soft-tissue component of the bone marrow or disease outside the bone marrow. Areas shown as dark or light using different scanner settings can indicate that the bone marrow has been infiltrated by myeloma.
[09:02]
Here, you can see a patient with extensive disease in the bones and particularly in the liver. Myeloma living outside the bones can be a relatively aggressive feature. It is unusual at the beginning of the journey but becomes more common after a patient has received more treatment. In this example, some of the myeloma was reduced over time, but the disease in the liver was difficult to treat until aggressive therapy, including a bone marrow transplant followed by CAR T-cell therapy, brought it under control.
[09:47]
A PET scan uses radiolabelled glucose that is injected into the patient. After waiting for the rapidly replicating cells to take up the glucose, areas of myeloma and other cancers can appear as dark regions on the scan. Other organs also use glucose as a major source of energy, including the brain and heart. The kidneys excrete the dye, so the kidneys and bladder can also light up.
[10:40]
These are the types of tests we perform when we think a patient may have myeloma. The most important starting point is meeting the patient, taking a thorough history and performing an examination. We carry out a full blood count, biochemistry testing to examine kidney and liver function, paraprotein and light-chain tests, a bone marrow procedure and imaging to complete the staging.
[11:23]
When we request a full blood count, we look at the haemoglobin level and whether the patient has anaemia. We also assess whether the rest of the haematology system is functioning properly, including the total white blood cell count, the individual types of white blood cells and the platelets that help stop bleeding.
[11:48]
When blood is examined under a microscope, one classic feature of myeloma is called rouleaux. This looks like a stack of coins, with red blood cells sitting on top of one another. It is caused by the high level of protein in the blood.
[12:07]
More rarely, we look for myeloma plasma cells in the blood. This has become increasingly important as treatments have improved because plasma cells in the blood can be an aggressive or high-risk feature. Their presence may change the treatment a patient requires.
[12:31]
We combine this information with tests such as beta-2 microglobulin, albumin and LDH to calculate whether a patient has standard-risk, intermediate-risk or high-risk myeloma. This may affect the treatment available and provides prognostic information, such as the likelihood of remaining in remission or being alive at five years following standard treatment.
[13:19]
Unfortunately, myeloma is a journey of peaks and troughs. Some people we meet have MGUS or smouldering myeloma and do not need treatment. At some point, however, some people progress. Their paraprotein may rise and they may develop other features, such as fractures or kidney problems, that require treatment.
[13:49]
When assessing response, we examine several factors in the patient’s blood and bone marrow. If the patient produces a paraprotein, M protein or light chain, we consider how much is present, how quickly it is changing and the degree of change. This acts as a surrogate marker for what is happening in the bone marrow and helps us avoid performing bone marrow procedures more frequently than necessary. If the paraprotein changes by less than 25%, this is called stable disease.
[14:27]
A fall of more than 25% but less than 50% is called a minimal response. A partial response is a reduction of more than 50%. If the level falls by more than 90%, this is called a very good partial response and suggests that the patient is having a very good remission and may remain in remission for a long time.
[15:00]
The gold standard is to achieve a complete response. This means there is no detectable protein in the blood, the light-chain ratio has normalised and no myeloma cells can be detected in the bone marrow.
[15:19]
However, this is only the beginning of the response story. What we can see in the blood is like the tip of an iceberg above the water. Modern myeloma therapy aims to target the disease that remains hidden below the surface and achieve much deeper responses over time. If a patient achieves an MRD-negative response, meaning we cannot find any myeloma cells in the body, they are likely to remain in remission for much longer than someone who remains MRD-positive.
[16:10]
There are different levels of sensitivity that can be used to detect how many plasma cells remain in a patient’s body. New techniques such as mass spectrometry can detect tiny amounts of paraprotein in the blood that are invisible using standard testing.
[16:40]
Once the blood has been cleared, the bone marrow can be examined. We do not only look for visible myeloma cells; we can also use highly sensitive techniques such as flow cytometry. This uses fluorescently marked antibodies and a machine capable of counting millions of cells.
[17:14]
We can also identify a genetic sequence that is characteristic of an individual patient’s myeloma and search through millions of cells for any remaining disease. These tests can detect fewer than one myeloma cell in a million, and sometimes one in several million cells, depending on how many cells are processed.
[17:46]
I hope this has helped you understand some of the tests we use, why we use them and how they help us explain what a patient’s myeloma is like, how it may affect them day to day and how it may influence treatment. We also use these tests to modify treatment and achieve the best possible result, ideally reaching a point where we cannot find any myeloma in the body.
[18:14]
There are a number of resources available on the Myeloma Australia website that explain these tests in more detail. I hope this has been helpful for you.
