[Music] from the JAMA Network this is JAMA clinical reviews interviews and ideas about Innovations in Medicine Science and clinical practice [Music] hello and welcome to this JAMA clinical review podcast today we will be speaking with Dr Edward Libby author of the JAMA paper titled diagnosis and management of multiple myeloma Dr Libby is associate professor of oncology hematology and medicine at the University of Washington he is an expert in clinical research and in the care of patients with hematologic malignancies including multiple myeloma I'll be your host today my name is Ethan Basch and I am a JAMA associate editor for oncology and an oncologist at the University of North Carolina Welcome Dr Libby thank you Ethan in 2022 in your opinion what do you feel is the most common presentation of multiple myeloma and what should General Practitioners be looking out for the most common things that a general practitioner will see in the office one of them would be anemia it could be very mild and slowly Progressive but whenever we're seeing adults with anemia multiple myeloma should be on our differential diagnosis another finding that a primary care physician could see is abnormal renal function in both the cases of anemia and abnormal renal function we should be thoughtful about the differential diagnosis yes they could be due to a bleeding ulcer or the renal function dysfunction could be due to diabetes or hypertension but it's so important to keep other things like multiple myeloma in mind so the differential is so so important and finally and I really want to emphasize this topic is chronic back pain or acute and or chronic back pain back pain is so common in primary care but in adults we have to be thoughtful about whether or not back pain is a malignancy and multiple myeloma loves to involve the skeleton in fact about 70 percent of patients ultimately have skeletal damage from this disease so if you're seeing someone with back pain and it's persistent please evaluate for multiple meloma I think that's such a helpful and practical answer I would say you know as an oncologist myself even though I don't specialize in multiple myeloma it's not uncommon that I'll get an email or a call from a primary care provider colleague of mine wondering about a patient of theirs because of some of those signs and symptoms that you allude to I want to come back in in a few moments to the diagnostic workup that a primary care provider can conduct for myeloma but first I wanted to ask you about one of the key distinctions that you make in your paper patients in clinicians sometimes wonder about the differences between mgus monoclonal gammopathy of undetermined significance versus myeloma versus smoldering myeloma could you just take a moment and talk us through some of the differences in the definitions and the clinical significance of each of these I think an important consideration in this is to think about these three entities as having a difference in progression from premalignancy to a foam malignancy both monoclonal gammopathy of undetermined significance and smoldering myeloma are pre-malignant conditions mgus is a premalignant condition with a low likelihood of progressing to a full malignancy that is multiple myeloma the next stage of this premalignancy is smoldering multiple myeloma that is still a disorder in which a patient does not have end organ damage and is not considered a malignancy but it has a much higher risk of progressing to multiple myeloma the risk for mgus which is well known is one percent per year of these patients progress to multiple myeloma to full-blown cancer requiring chemo whereas smoldering multiple myeloma it's still not a malignancy but the risk is then 10 percent per year much much more perceptible a much more real chance of developing to a full-blown cancer finally multiple myeloma is considered a malignancy and has end organ damage by definition ultimately it's the difference between two premalignant conditions that is mgus and smoldering multiple myeloma and multiple myeloma symptomatic multiple myeloma which requires chemotherapy the key Laboratory Testing that differentiates mgus from smoldering multiple myeloma and from Frank multiple myeloma requiring chemotherapy is particularly related to the bone marrow biopsy in monoclonal gammopathy of undetermined significance those patients have less than 10 percent abnormal plasma cells in their bone marrow and they have no end organ damage that's absolutely key to the diagnosis less than 10 percent abnormal plasma cell population in the marrow and Without End organ damage smoldering multiple myeloma patients have 10 percent or greater abnormal plasma cell population in the bone marrow but they also have no end organ damage and that's key again smoldering myeloma and mgus are not considered a malignancy in multiple myeloma that requires therapy the full diagnosis patients must have 10 percent or more abnormal plasma cells in the bone marrow but in addition to that they have and organ damage which classically is anemia hypercalcemia renal dysfunction bony damage and any combination of the previous four so the big difference between the premalignant conditions and the malignant condition is particularly and organ damage well I think that's really helpful and particularly useful for providers to understand that distinction between the pre-malignancy and the malignancy itself and when treatment might be warranted I think related to that question and also to the prior question I'm wondering what particular tests a general practitioner should think about sending if there's a concern that a patient of theirs might have one of these conditions tests that can easily be obtained by a general practitioner would include the following a complete blood count a metabolic panel that includes renal function and calcium serum protein electrophoresis serum free light chain levels which is a relatively new test that is become essentially required in multiple myeloma in the last 10 to 15 years serum free light chain levels a 24-hour urine for urine protein electrophoresis X-rays of any areas of bone pain and a primary care physician should consider obtaining full body skeletal Imaging with either a CT or an MRI I would say that it's reasonable it's more than reasonable for a primary care physician to do everything but the full body skeletal x-rays those are often done the vast majority of the time by the hematologist oncologist the other testing would be critical and expected and easy to do in a primary care setting though I wonder if you could just take a moment before we move to the the next question just to focus on the serum free light chain levels for a moment because this is a test that your providers especially those who may have trained some time ago will have familiarity with could you just speak for a moment about the tests and its utility in the not too distant past 10 plus years ago 10 or 15 plus years ago the way we measured free light chains the only way you could measure them was to get a 24-hour urine looking for what's called Vince Jones proteins they could not be measured in the bloodstream a significant percentage of myeloma patients don't have a full protein in their blood and therefore the serum protein electrophoresis is negative in those patients if you don't look for free light chains in the bloodstream or bench Jones proteins in the urine you will miss the diagnosis and that's perhaps 15 or 20 percent of patients so the serum free light chains in many ways almost can replace the 24-hour urine but not completely they're very easy to obtain and they're inexpensive please remember that when you're measuring the monoclonal protein in myeloma in general you're looking at an intact antibody and intact monoclonal protein that has both heavy chains and light chains attached to each other two heavy chains and two light chains for each intact monoclonal protein many myeloma patients or mgus or smoldering myeloma patients secrete only or primarily the free light chains alone they do not secrete the intact immunoglobulin and therefore you will not measure it in the serum protein electrophoresis free light Chains Are excreted by the kidneys and therefore you can measure them in the 24-hour urine with a urine electrophoresis but the free light chains are much easier to obtain in the bloodstream that's so helpful and I I think a really essential tip for contemporary workup of these patients so once all this has been done when should a patient with mgas or multiple myeloma or a smoldering myeloma diagnosis be referred to a Hematology Oncology expert specialist I was a academic internist for a number of years before I fell in love with hematology and oncology and decided to become an oncologist and so I've been on both sides of this fence I think really that as hematologist oncologists we really want to protect patients from the often severe consequences of this disease so we are delighted to see these patients early we don't want the primary care physician to be stuck trying to dig into how to evaluate or treat multiple myeloma we want to help we want to get these patients diagnosed early so I think if you have a suspicion contact your hematologist oncologist and get their advice for what test to order and they will be delighted to see them in the office in general the two complications that we really fear for this disease are number one bony destruction which can impair a patient for the remainder of their life with severe compression fractures sometimes a patient can even have neurological compromise from collapse of the spine and the other thing that we really want to avoid and we can only do this by diagnosing this disease early is renal failure and a significant percentage of patients 10 or 20 percent of myeloma patients develop Frank renal failure from this disease and it's a disaster if we can diagnose the disease early we can avoid these complications so please contact us early we'd love to hear from you so Ed in general in 2022 what is the treatment Paradigm for multiple myeloma we're very fortunate in 2022 to have a standard therapy that's excellent for multiple myeloma ten years ago this therapy was just in development and difficult to obtain and to get paid for and now it's available all over the country easy to administer by the vast majority of hematologists oncologists and I am really pleased that this is now available for our patients this therapy is called a triplet therapy meaning that patients receive three agents to control this disease one of them is called lenolidomide and this is an immunomodulatory drug the other is bortazumib which is a proteosome inhibitor and the final one is steroids and interestingly why give steroids steroids you can actually treat multiple myeloma with just steroids and many many years ago it was one of our only therapies it is anti-plasma cell and it enhances the response or the effect of the other two drugs so it's a triplet therapy combining linolidomide bortezumib and dexamethasone it's abbreviated as either RVD or vrd I usually refer to it as RVD now this therapy surprisingly unfortunately is quite well tolerated by patients even very elderly patients can tolerate RVD or vrd if necessary in patients who were quite frail one could reduce this to either lenolidomide and dexamethasone or mortiseumib and dexamethasone to a double it to just two drugs in very elderly patients it's not uncommon to do that but the standard is RVD and we can give that even to quite elderly patients after receiving this therapy RVD or vrd for approximately four to six months then in patients who are in good physical shape who have a good performance status we then move on to a stem cell transplant and this is an autologous stem cell transplant using the patient's own stem cells this is much better tolerated much fewer complications than when a patient receives someone else's stem cell so it's an autologous stem cell transplant in patients who are physical candidates once the patients have recovered from the stem cell transplant and the full process of a stem cell transplant is roughly three months so three to six months of induction treatment with RVD then a stem cell transplant if you're a candidate and that stem cell transplant process takes about three months you're not on RVD while you're getting the transplant and the transplant utilizes a chemotherapeutic agent called milfalan and then once you've recovered from the stem cell transplant then patients go on maintenance therapy maintenance therapy is a lower dose and often less frequent administration of one of the agents in the RVD therapy the most common maintenance therapy is lenolidomide alone at less than half of the dose that's given during induction the reason for the lower dose is we want patients to have a high quality of life we don't want them to have to be coming into the clinic in the long term for maintenance therapy you can use bortazemib as maintenance therapy and it is done in certain patients dexamethasone is not used as maintenance therapy so maintenance therapy is either portasomib or lanolidomide without dexamethasone I do want to mention that RVD slash vrd whichever term you choose to use is simple to administer the mortiseumib is an injection Under the Skin given once or twice a week for those first three to six months lenolidomide is a capsule so it's simply an oral agent and the dexamethasone is a capsule so it's very simple chemotherapy easy to get and pretty darn well tolerated well thank you very much that was extremely clear I think considering how complicated it can be sometimes to manage or oversee the treatment in this population of patients who can be quite ill and on that note I'd like to ask you just to speak a little bit about the complications both of the disease itself but also the adverse sequelae of the treatment that one should be looking out for in this population the complications of the disease itself in particular are the four classic ones that we abbreviate as crab the C for high calcium are for renal dysfunction a for anemia and B for bony destruction the high calcium essentially is probably the least problematic and it's not particularly often that we diagnose patients on the basis of a high calcium but certainly we do on a regular basis renal dysfunction as I mentioned earlier is a terrible complication because as we all know as primary care physicians as physicians in general renal failure has a huge impact on patients quality of life when a patient presents with renal dysfunction in multiple myeloma it is a medical emergency and it should be addressed immediately not the following day or the next week and that's because of very significant percentage of these patients who arrive with severe renal dysfunction or even renal failure can be salvaged and their renal dysfunction can even return to normal if they're treated very aggressively so that's a very very important complication that we want to avoid if at all possible and treat very aggressively when we see some in the clinic or urgent care of the emergency room with renal dysfunction and suspected multiple myeloma you can reverse that renal dysfunction bony fractures are a terrible problem for these patients and as I said roughly two out of three patients will at some point during their Journey with this disease have bony fractures many patients present with back pain and severe compression fractures it's quite common for patients to have severe pain from compression fractures for three to 12 months after diagnosis it's not uncommon for patients to have permanent back pain from compression fractures for multiple myeloma much less commonly you can see patients who have neurological compromise from compression fractures and occasionally you will see patients who are frankly paralyzed from a compression fracture anywhere in the spine another complication that is not uncommon is what's called plasmocytomas in general multiple myeloma resides primarily in the bone marrow but occasionally and fairly commonly I don't have a good percentage but we'll say at least a third of patients if not higher the disease presents as tumors so patients have tumors just like a breast cancer tumor or a lung cancer tumor myeloma tumors that can present anywhere in the body they may or may not be associated with bone most commonly they are associated with bone and they're called bone plasma cytomas but they may be unassociated with bone and they can be highly destructive completely destroy a bone or even destroy an organ so that is another complication of the disease rarely the disease can go to the brain that's quite uncommon and uncommonly we see patients where the disease enters a leukemic phase and they have multiple myeloma cells floating in the bloodstream this is defined as 20 percent or more of the white cells in the blood are plasma cells that is a very very aggressive form of multiple myeloma now there are also complications of therapy unfortunately even though these drugs are well tolerated there are some complications and I think probably the one that we fear the most or that we dislike the most is neuropathy the drug bortezumib the proteasome inhibitor can cause neuropathy in the peripheral nerves and a significant percentage of patients at least 10 to 20 percent of patients who get bortazumib even as it's administered today subcutaneously it used to be intravenously can develop permanent peripheral nerve neuropathy primarily in the feet and that's a very disturbing complication that affects quality of life so we really dread that and we stopped the drug early and or modify the dose when patients develop peripheral neuropathy another complication that is associated with mortasium even steroids is shingles so it's quite common to reactivate your viral status when you're on vertazamib and dexamethasone fortunately we've learned that taking prophylactic acyclovir is highly effective at preventing shingles in these patients and so routinely all patients getting a proteosome inhibitor should be on acyclovir prophylaxis or valacyclovir prophylaxis to prevent shingles the drug linolidomide is a pro-coagulant and a high percentage of patients will develop usually deep Venous Thrombosis it can be an arterial thrombosis when they're taking linolidomide fortunately it's very simple to avoid this in the great majority of patients with simply giving an aspirin a day usually a baby aspirin so it's very effective in preventing thrombosis in these patients but we have to be cautious in people who are at high risk for thrombosis when giving lenolidomide which is part of that triplet therapy because it can induce arterial or Venous Thrombosis primarily venous and finally I want to mention rash the drug limit often causes a rash in patients it's usually when they're starting the therapy in general we can stop the drug let the rash dissipate and then restart the drug it's very unusual for patients not to be able to continue lenolinomide due to a rash yeah it really underlines how ill this patient population can be the complications that individuals can experience that's the importance of making a diagnosis early as well as a referral to a hematologist oncologist I think the other point that we increasingly talk about in patients with malignancies is the importance of the partnership between oncology or Hematology Oncology professionals and Primary Care Providers as patients often continue to see their Primary Care Providers through their cancer treatment and following the cancer treatment so I do think that awareness of these complications is is really germane to our discussion the final question I wanted to ask you about and I I think it would be impossible to have a discussion in 2022 without asking about this is whether patients with myeloma are at particular risk if they're infected with covid-19 either related to the disease or to the treatment whether they were susceptible in a premalignant state during treatment after treatment notably there have been some examples in the news of prominent individuals with myeloma who suffered consequences of covid-19 infection so I wonder if you could provide some detail on that one thing that's important in myeloma patients if we think they have covet is to ask ourselves whether we're primary care physicians or oncologists how immunosuppressed is this patient because the question of immunosuppression in general is critical when we decide how to approach their care what agents should be administered to treat them for covet if any so many myeloma patients now fortunately I'm very happy to say their disease is well controlled for years just taking the maintenance drug lenolidomide for instance or bortazemid and they can go for many years on just those drugs and the disease is in wonderful control those patients they're not on steroids they're just receiving these drugs that are not markedly immunosuppressive if hardly at all and therefore those patients who have a covet infection I would not necessarily treat them in a different manner if they're highly stable and they're on very simple therapy that's not immunosuppressive now if they are on immunosuppressive antimyeloma therapy steroids an obvious example but another example would be a drug that I have not mentioned yet called duratumumab and duratumumab is an anti-cd-38 antibody cd38 is an antigen on the surface of the myeloma cell this is a wonderful relatively new drug for myeloma that is very significantly immunosuppressive so in a patient who was on duratumamab for instance I would be quite concerned if a patient contracted covet and would consider using more aggressive therapy if someone was on very complex antimyeloma therapy with three or four drugs say they're in the middle of the RVD induction therapy that we talked about earlier and they developed covet I would have concern about much more concern about their immunosuppressive state and consider treating them more aggressively so I'm pleased to say that not everyone with myeloma is severely immunosuppressed and therefore we don't have to treat them in a super aggressive fashion we'd monitor them very closely but there are still a significant number of patients who are on multiple therapies that are highly immunosuppressive so you really have to address each individual patient and their status now what about the role of the plasma cells themselves in immune response should that be something that providers think about regarding viral infections in general I would say no it's a great question you know in in somebody who's being successfully treated with myeloma their plasma cell level is low their level of normal plasma cells is low as well because the these drugs affect both Normal and abnormal plasma cells so yes they are relatively immunosuppressed but to a mild degree much of the time in patients who have multiple myeloma who are untreated they do have a mild degree of immunosuppression but it's not severe this is in the untreated patient in the treated patient to judge their level of immunosuppression I think it's really all about what agents are we administering rather than the disease itself if the myeloma was out of control they're being treated but they're relapsing and the disease is not in control yes I would say there probably are significantly immunocompromised both from the disease and the treatment I'd like to thank our guests today Dr Ed Libby for a rich and informative discussion on the diagnosis and management of multiple myeloma and its complications I'm Ethan bash it's been a pleasure serving as your host today for this podcast this episode was produced by Jesse mccorders at the JAMA Network the audio team here also includes Daniel Morrow Shelly stefans Lisa Hardin Audrey foreman and Mary Lynn fercalook Robert golub is the executive Deputy editor for Jama to follow this and other Jama Network podcasts please visit us online at jammandnetworkaudio.com thank you for listening foreign [Music] foreign foreign