The Importance of Early Diagnosis: Multiple Myeloma, MGUS & AL Amyloidosis

Transcript: Simon Murray, MD: MGUS [monoclonal gammopathy of undetermined significance] is a largely asymptomatic condition. What do doctors and patients need to know about that condition?

Ola Landgren, MD, PhD: The monoclonal gammopathy by its definition is a nonsymptomatic condition. But if you follow a lot of patients, as I do, and people like me who are very specialized, you can actually start seeing that there are certain things that are a little more common in people who have a monoclonal gammopathy, compared with the general population. Things that I see, for example, could be there was a little more of a peripheral neuropathy and a lot of patients complaining about tingling and numbness and things like that. I do think these probably could be early markers for AL [amyloid light-chain] amyloidosis. If you work some of these patients up, you can pick up and see that they have quite low levels of plasma cells in the bone marrow. They could be clonal. If you do fat pad biopsy you can actually pick up AL amyloidosis. You can do echocardiogram and make sure that there is no deposition of AL amyloidosis fibrils into the cardiac muscle. You certainly should also check urine, and you need to do 24-hour urine collection to make sure the patient is not leaking high amounts of not monoclonal protein, but like albumin, they leak a lot of the main proteins in the blood. Because that could indicate that the kidneys are not doing well. So if you have a patient who has tingling, who has these monoclonal proteins, you check the 24-hour urine. You see those a lot of protein coming out. That patient should, first of all, do a fat pad biopsy. If you still don’t see a light-chain amyloidosis, if the patient is leaking a lot of protein, a biopsy of the kidney would be indicated. And that could set the diagnosis that could actually save the patient. If you treat that patient, that’s in this patient’s best interest. If you wait, it could just devolve into very bad renal insufficiency and could result in cardiac problems. So I think early diagnosis is very important. You need to be on top of the game here.

Simon Murray, MD: Will 6 months make a difference? A 6-month delay?

Ola Landgren, MD, PhD: For the most part if you just see these proteins and the symptoms are subtle, 6 months is probably OK. But if someone has high levels of light chains, which you know only if you check, 6 months could be a huge difference. It could actually be the difference between asymptomatic versus showing up in the emergency department with really severe renal failure 6 months later. So you need to check these light chains, and the serum-free light chains would be the way to do it.

Simon Murray, MD: As a patient who has symptoms, what are some of the things that might make me think I should see the doctor, that I could have multiple myeloma? What are some patient symptoms once you have the disease that are important that they experience?

Ola Landgren, MD, PhD: The majority of patients who are diagnosed with multiple myeloma, at least historically, would say that they have some form of skeletal pain. A lot of patients would say that they have fatigue. But if you ask 100 people in the general population, do you ever have fatigue? Most people say yes. It’s not really a very specific symptom. If you ask the people who say they have skeletal pain, many of them say they have back pain. If you ask 100 people in the general population if they’re 50 years old, do you have back pain? Many people say it happens. Most of those will not have myeloma. Again, it’s very unspecific. But if there is some form of continued fatigue out of the ordinary, if there is some form of skeletal pain, those are clearly indicators that something was going on. Those are probably the key features I see. Sometimes you can see individuals having repeated infections, a little out of the ordinary. They could have pneumonia, sinusitis, indicative of immunosuppression. There is another thing that I think, from a more patient perspective, sometimes probably could take the patient earlier to the doctor. It’s like if you urinate, if there is a lot of foam in the urine, the foam comes from protein. And if you have more foamy urine, your doctor checks the total protein and the free light chains, not only total protein. You also have to check the free light chain because the total protein will not necessarily reveal the free light chains.

Simon Murray, MD: And they say you have nephrosis or something like nephrotic...

Ola Landgren, MD, PhD: It could be a kidney disorder. It could also be myeloma or myeloma about to happen. That would probably be, from a patient perspective, something to pay attention to.

Simon Murray, MD: That’s a good tip. That’s a very good tip. POEMS [polyneuropathy, organomegaly, endocrinopathy/edema, monoclonal protein[AB1] , skin changes] syndrome is skin manifestations of plasma cell disorders. Is it a variation of multiple myeloma, or is that just a plasma cell disorder?

Ola Landgren, MD, PhD: POEMS is 1 of the many acronyms in medicine that we use. It stands for different types of manifestations. It’s the peripheral neuropathy. They have pain in your nerve. You could have endocrinopathy, so there a lot of different types of endocrine markers, including those you normally don’t think of. You have to have a long list of endocrinological markers to look for. That’s the E in the POEMS. The O—I missed the O, the organomegaly; the liver and spleen could be enlarged. So the neuropathy, paraneuropathy peripheral neuropathy?, the organomegaly, the endocrinopathy, and then you have the monoclonal protein as part of it, and they had the skin manifestations.

Simon Murray, MD: It fits in because it has the monoclonal protein.

Ola Landgren, MD, PhD: But I think importantly there is no POEMS syndrome, period. It’s kind of an umbrella for a lot of things. Because there is such a long list of these endocrinological markers, it seems not reasonable to believe that if the sex hormones—if their testosterone levels are high or you have some other neural hormonal markers, up or down, that that’s the same disorder—it’s probably not. And of the skin disorders you could get, there are so many things to look out for.

Simon Murray, MD: Adrenal disease could give you hyperpigmentation.

Ola Landgren, MD, PhD: It’s all over the place. I think all those patients who have a lot of other things fall into that category. That’s a huge research project.

Simon Murray, MD: Are there other consequences of diagnosing this late?

Ola Landgren, MD, PhD: Similar to many other diseases, if you delay the diagnosis it can result in complications that the diagnosis occurs at the time when there is an acute situation. If you could avoid that, obviously that would be preferred. Specifically, when it comes to myeloma, renal failure is 1 of the things you do not want to lead to the diagnoses. You don’t want the patients to end up on dialysis and myeloma at the same time. If you could identify myeloma before this happens and treat it, and avoid the whole renal problem, that would be preferred. But a lot of other things beyond that. I mentioned before that 80% or so could have bone pain, and this comes from the skeleton. And unfortunately, there are some patients who are diagnosed as part of work-up when they have a fracture. Every week I see patients who have compression fractures in the spine. I’ve also seen a lot of pathologic fractures over the years. Patients who could walk around and grab a bag at the airport and when they grabbed the bag on the conveyer belt, the arm could fracture. Subsequently this is being worked up, and now it’s myeloma. A leg could even break, so these were very severe. Even worse, you could have a spinal cord entrapment. I have had patients coming in many, many times to the emergency department, and they have severe back pain. You work them up with MRI [magnetic resonance imaging], and now their spinal cord is at risk. Now we have to send them to a neurosurgeon.

All these things are so unnecessary if you monitor patients. If you have proteins and you monitor, you can catch it much earlier. But there are patients who probably have a rapidly evolving biology that maybe cannot be caught with the current technology. That is also unfortunately part of this kind of situation.

Simon Murray, MD: If you treat multiple myeloma successfully, will renal failure improve?

Transcript Edited for Clarity

Ola Landgren, MD, PhD: Yes. In the vast majority of patients who can revert. I think 1 of the key management things to remember, as a doctor who sees these patients, is that when they come into the emergency department with renal failure, you immediately give them fluid, to give them steroids, and if they have also high calcium levels to bring that down. We use bisphosphonates, or Xgeva if you give that these days. But you could use steroids or fluids for sure. If you have high light chains you can immediately see improvements of the light chains. Once you bring them down, the kidneys can start to relax a little. If you don’t do that, and it goes too long, the kidney turns into scar tissue, and this becomes a permanent kidney damage. So you need to stop this, and then the next line is to start treating myeloma. But the steroids and the fluid immediately will have effect. You can go in with a proteasome inhibitor and the current guidelines say plus or minus a Cytoxan drug. In the future, I would probably be monoclonal antibodies. CD38 antibodies are already in development. But proteasome inhibitors and steroids are definitely in the guideline currently.