POEMS: A Rare, Often Misdiagnosed and Disabling Condition if Not Properly Treated
Jack Khouri, MD, hematologist oncologist at Cleveland Clinic Cancer Center, who specializes in rare plasma cell disorders within the Rare Cancers and Blood Diseases program joins the Cancer Advances podcast to discuss POEMS (i.e., polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes). Listen as Dr. Khouri talks about how the early recognition and diagnosis of POEMS is key to effective management.
POEMS: A Rare, Often Misdiagnosed and Disabling Condition if Not Properly Treated
Dale Shepard, MD, PhD: Cancer Advances, Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Jack Khouri, a hematologist at Cleveland Clinic specializing in rare plasma cell disorders within the Rare Cancer and Blood Diseases Program is here today to talk to us about POEMS. So welcome, Jack.
Jack Khouri, MD: Hi Dale.
Dale Shepard, MD, PhD: So tell us a little bit to start out about your role here at Cleveland Clinic. What do you do?
Jack Khouri, MD: So I'm associate staff here in the department of hematology and medical oncology. I mostly see patients with plasma cell disorders. So namely multiple myeloma, AL amyloidosis and rare plasma cell disorders, such as POEMS.
Dale Shepard, MD, PhD: All right. So we have a pretty broad audience here and so we're going to talk about POEMS. So let's start really simple. What is POEMS?
Jack Khouri, MD: So, Dale, POEMS is a rare plasma cell disorder that's characterized by demyelinating polyneuropathy and clonal plasma cell proliferation. So the acronym stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin changes. So Dale, as you know, the plasma cell is the most differentiated cell of the B cell lineage of the immune system. And we think that in POEMS, this cell is really the cell that's responsible for a surge of inflammatory cytokines, like of VEGF, vascular endothelial growth factor interleukins and FGF. And at the same time, the same cell suppresses other anti-inflammatory cytokines, like transforming growth factor beta one, or TGF beta one, where this imbalance of cytokines that's elicited by this plasma cell is actually what's responsible for the multitude of clinical manifestation of the disorder.
Dale Shepard, MD, PhD: And so just to give us some perspective, how common is it? How many cases are there and do we know what sort of triggers it? What's the cause?
Jack Khouri, MD: So POEMS is very rare. So honestly we don't really see more than three patients per year here at the Cleveland Clinic and we're a major referral center. And now there isn't a lot of studies on the epidemiology of the disease, but we think that the prevalence can a range as in the order of 0.3 per 100,000 people and mostly Japanese studies and US studies. So it's very rare.
Dale Shepard, MD, PhD: And so we're not really sure what triggers it?
Jack Khouri, MD: We still don't really know. We think that it's a combination of chronic antigenic stimulation of the plasma cells, changes in the marrow microenvironment, and some changes in actually the way plasma cells make their antibodies, especially the lambda light chain antibody. A lot of those things together trigger this plasma cell to initiate this inflammatory imbalance and cytokines.
Dale Shepard, MD, PhD: You sort of described what this is based on sort of the things like polyneuropathy in large organs and things, but what kind of signs and symptoms would people typically have if they're coming to see us?
Jack Khouri, MD: Peripheral neuropathy is the main symptom of POEMS, Dale. And this is how people come to medical attention. They have neuropathy going on for a long time. It's usually long standing. They see neurologists and neurologists in combination with hematology. So neurology and hematology end up diagnosing these patients. So people usually have long standing demyelinating polyneuropathy. The way this neuropathy starts is with sensory symptoms in the feet that works its way up and becomes more motor over time with consequent weakness and muscle atrophy. There are other manifestations of the disorder and it can involve the skin with multiple rashes being reported in the literature. There is hardening of the bones with what we call sclerotic bone lesions that we can see on imaging. There is enlargement of the liver, the spleen, the lymph nodes. Some people can have what we call Castleman's disease, which is a special type of lymphoproliferative disorder. So there's a wide area of symptoms, but usually people come to our attention when they have this long standing polyneuropathy that goes undiagnosed.
Dale Shepard, MD, PhD: So, the lack of diagnosis seems like that must be a really tough component of this disease. So I would guess that patients have had a pretty long journey of seen lots of different people. And you really quite honestly may have to stumble across the right person that thinks of it and makes the diagnosis. Somebody may see a dermatologist, but not really make the connection or a neurologist and neuropathy being standard. So how's the actual diagnosis? Is it from bone marrow? What's the process here?
Jack Khouri, MD: Right. So usually patients get referred to us by neurology. So neurologists are the frontline kind of specialty that sees these patients. They usually get EMG studies on them, so electrodiagnostic studies on their nerves. And they check more lab work, including they screen them for plasma cell disorders with serologic testing, and they get VEGF levels, vascular endothelial growth factor levels. And if they feel that there is a question of POEMS or they feel that the diagnosis is really POEMS, they send them our way and then we confirm the diagnosis here and start treatment.
Dale Shepard, MD, PhD: And what is that treatment?
Jack Khouri, MD: So the treatment is very similar to what we do in myeloma. So it's either radiation therapy, autologous stem cell transplantation, and or a combination of other plasma cell directed therapies. And the treatment really depends on if the patient really is eligible for stem cell transplant. A lot of patients come to us really debilitated from their neuropathy, they're not really eligible for high dose therapy and transplant. And so we either do radiation depending on how many lesions they have in their bones, or depending on how many clonal plasma cells they have in their marrow, or we do other therapies that we borrow from the plasma cell, the myeloma armamentarium.
Dale Shepard, MD, PhD: So when we think about POEMS, how does that differ from CIDP?
Jack Khouri, MD: Again, CIDP is chronic inflammatory demyelinating polyneuropathy, and POEMS also has this component of demyelinating polyneuropathy. And if you do EMGs on people, electrodiagnostic studies on people, you see that 70% of the POEMS patients fulfill criteria for CIDP. So it's really hard to differentiate both entities. However, I think there's a couple or a few clinical EMG features that can help differentiate both of them. So for example, there is more axonal loss on EMG on POEMS patients than CIDP. And there tends to be more lower limb involvement and more leg pain, which can be a really severe in POEMS than CIDP. And there's really more distal muscle weakness in CIDP. Also, muscle atrophy in the lower limbs tends to be more pronounced in POEMS. Another thing is there's more neuropathic pain in POEMS more than CIDP and there's way less cranial nerve involvement in POEMS. So it's really a combination of EMG features and clinical features, mostly pain and lower limb involvement that tends to be more common in POEMS patients.
Dale Shepard, MD, PhD: So you mentioned that we don't see very many patients in a given year. We have this program set up for rare cancers, blood disorders. How are we able to most appropriately take care of patients?
Jack Khouri, MD: We do have care paths here for bones. I've put together a care path for the community, for the regionals sites. And for us here at main campus, I've seen a lot of referrals coming from the community for stem cell transplants so I think there is more awareness in the community about this disorder, probably because of the care path and because people just know about it more than before. So I'm seeing more patients with POEMS in general.
Dale Shepard, MD, PhD: And I guess it's that awareness part that I guess I was going to ask about. So, it seems like certainly from a patient frustration, going to numerous doctors trying to get a diagnosis being called they don't really know what that diagnosis is until they reach the right diagnosis. But then when you mention on top that not only the long wait to get a diagnosis, but then maybe not being able to get a transplant because their disease has progressed, it sounds like more awareness by primary care, neurology, dermatology, how do we raise awareness in what's really a rare disease, but really, really important they get diagnosed faster?
Jack Khouri, MD: Honestly, I think it starts with primary care and neurology because they're the main people or the initial people that see patients with neuropathy. And neuropathy really is the most debilitating manifestation of the syndrome. And so really recognizing POEMS early on is really important. So I think neurologists, when they have a patient with possible CIDP, they're not very convinced that it could be CIDP, they should look for POEMS. Or if a neurologist sees somebody with CIDP, they start treating CIDP with plasma exchange, or IVIG, which is a totally separate or different treatment than what we do for POEMS.
And they feel that the patient is not really getting better, they should look for POEMS. So they should revisit the diagnosis. So I think it really starts with the neurologist. They should screen patients for POEMS with simple serologic testing for plasma cell disorders and VEGF levels to start with. And then if they're really suspicious that this could be POEMS, they could always consult with hematology. We can help them make the diagnosis. Or if they've been treating somebody for CIDP and they're not getting better, they should revisit the diagnosis.
Dale Shepard, MD, PhD: What about the role of support groups? Are there particular like patient advocacy groups or anything that we work with to raise awareness?
Jack Khouri, MD: So, actually there aren't many support groups. I know when patient of mine told me that there was a group on Facebook, I'm not really aware of the name of it. But it's a rare disorder, I think NORD, N-O-R-D, is also involved in awareness and supporting patients with it too.
Dale Shepard, MD, PhD: What do you think are the biggest gaps? Is it awareness we've talked about? Is it research into new treatments? What do we need to do to make this better?
Jack Khouri, MD: I think making the diagnosis is really important. I think we can treat POEMS very well. A lot of our patients do well when we treat them, like for example, with transplant, more than 90% of the patients respond and the mortality is very low from the procedure. And the side effect profile is really, I mean, we know a lot about it and we can do it very safely, the transplant. And the progression-free survival, overall survival data are really good. However, it's all based on cohort studies, we don't really have to have therapeutic trials. And so I think we can treat it very well. We don't have a lot of research about the treatment, but from the experience of a lot of centers that have been treating POEMS patients, they do improve and their symptoms get better. They can walk again, but it takes time for that to happen, but we can really get them better.
So I think it's really making the diagnosis, that's the issue here. And currently there is an ongoing study at the University of Arkansas that's looking into the role of other treatments like Darzalex, which is what we use commonly in myeloma and the treatment of this disorder. And I'm in discussion with another pharmaceutical company about starting potentially another clinical study, a single arm study, in rare plasma cell disorders, which will include POEMS to study a novel agent in myeloma. Hopefully that's also promising, but I think even with what we have right now, we can treat people very well and get them better. It's just getting them to hematology is honestly the issue.
Dale Shepard, MD, PhD: Yeah. That sounds like a big barrier. And it sounds exciting that there's some new therapies potentially in the works. But that is a tough area to study. Other than the awareness and research, is there anything else we need to be thinking about in terms of other mechanisms? Or do we think that there's anything else that might improve our ability to treat these patients?
Jack Khouri, MD: Well, I think just having more seminars or giving more talks to neurologists and hematologists in the community, because honestly our neurology department here at main campus is very good at recognizing POEMS and referring people to us. I just feel that we probably need more work in terms of spreading the awareness in the community, especially amongst neurologists and hematologists in the community. So maybe just more webinars, more talks like this, more podcasts and things just to kind of shed more light on the importance of referring early on. And when in doubt, just refer them. We can help you figure it out.
Dale Shepard, MD, PhD: That makes sense. Well, thanks Jack. I appreciate your insight. It's always difficult with rare diseases to sort of build the right programs to do the right things and awareness is huge. So hopefully your ability to inform us is going to help people think about it when they have patients that they're not quite sure what's going on and we'll have some positive outcomes here.
Jack Khouri, MD: Thanks, Dale. Good talking to you.
Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You'll find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinic Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.