Part 2 - Comprehensive Diagnosis and Management of POEMS Syndrome

00:00 Stephen Hibbs: Hello and welcome to the HemaSphere podcast. My name is Stephen Hibbs. I'm a hematologist and clinical research fellow based at Queen Mary University of London, and I am one of the scientific editors for HemaSphere.

So in our last episode, we were talking with Shirley and Mike who are the two leading authors on a recent piece on POEMS, helping to address some of the complexities of this rare and important subject. It turned out that we had a lot more to talk about than I'd first reckoned on, and so we've broken this into a Part 1 and a Part 2. Please do feel free to check out Part 1 first, if you'd like to, or otherwise you're very welcome to join us here.

This is the second part and I'm glad to welcome Shirley and Mike back again.

1:00 Stephen Hibbs: How do you go about trying to explain what POEMS is, in terms that could be understandable to someone who might not have any kind of medical or scientific training? Yeah. What does that conversation sound like? Shirley, perhaps if I start with you on this one.

01:16 Shirley D'Sa: Yeah. You're absolutely right. There has been a long history, quite often, and patients are feeling somewhat battered and bruised and many of them are not well, they're not functional and they feel a bit let down by a series of doctors.

There's a combination of things. One, we have to be somewhat diplomatic and explain the fact that early on it's often very difficult to join the pieces, because of the rarity. Of course, the more you talk about it being rare, the more patients feel very flustered, because they think "Well, I'm all alone" and "What's going to happen?". So we do have -- We have learned the words to explain the disease over the years.

As a hematologist, I am at pains to -- Because most patients pick up on the fact that POEMS is on a similar spectrum to myeloma. When they read about myeloma, they freak out, actually, because it's obviously quite an aggressive malignant disease.

So I'm at pains to say early on that I believe POEMS is almost bordering on a non-cancer, actually. I really don't think of it as a cancer, because it behaves -- It's an immunological disorder, which is driven by a clone, but there is this spectrum from the "MGUS", as we call it, to something that's much more aggressive. And it sort of almost goes off on it's own path - and it doesn't behave like a cancer.

For example, the bone lesions are not painful. There is a whole range of inflammatory things going on. So I'm at pains to say them that if the sort of survival of people of POEMS is, in my view, as long as you get to grips with the cardiorespiratory compromise, actually is pretty close to normal. That's been my experience. So that is why we want to diagnose it early and get people well.

In terms of neuropathy of course, that is another story and that takes time. But that doesn't really limit their lifespan. So I think I try and tame the negativity by saying "Look, this is something that can improve and it does improve".

We give examples of patients who have been literally fully dependent on their families to gradually becoming independent and actually becoming self-caring. We give examples of people who have been in a wheelchair who have gone from sticks to walking. And we've got some videos of people who have suddenly sort of shown us running and then climbing walls and things like that.

So I'm quite keen on giving the good news stories early on; to give them hope, because, in my opinion, once you treat the disease, it's an upward trajectory of improvement. It takes time. And I think to give them -- to help sustain them through that period of two or three years of improvement; if they can hang on psychologically to this thing that it will improve, then it gives them the wherewithal to actually focus on their rehabilitation and get through the therapies.

So that tends to be my message. It's like, positive. I genuinely have come to believe that, because that's what I have observed and witnessed.

04:35 Stephen Hibbs: Mike, is there anything else you'd say to patients for that kind of first or second meeting, when you're going through what's likely to happen next?

04:44 Prof. Michael Lunn: Yeah, I mean obviously Shirley and I often deliver those messages together in a sort of rather collaborative way, like we're doing now. I think one of the things is helping people recognize that we have recognized this and we have been here before. They feel much more comfortable when they can see that they're in a service where people see what they've got and they can understand it. So that's quite important.

The neurological disability, of course, is the bit that they come to me with. I'm at pains to sort of explain to them that the neurological disability might take two years to even start getting better; and that even then it might carry on getting better for two, or three, or four years after that - and getting better is slow. But, people do get better, as Shirley said. So we'll often paint those pictures or introduce them to other patients, or show them videos or what have you of people who have got better, which clearly makes them feel much better.

The other advantages of having the clinic that we run together is that we might see twenty or twenty-five patients in the clinic - and they have the opportunity to talk to one another. So we're at pains to either have introduced them to the Facebook group or to the other patients in the clinic who are happy to speak to them.

And then they've suddenly realised they're not alone and that it's not as rare as -- Or it is rare, but there are other people who are coming to the same place for the same thing; and that can be extremely reassuring to patients from the psychological point of view.

And then, of course, the other thing that we have is a very competent small group of clinical nurse specialists, who also can apply a slightly more independent view for the patients. Nurses are always far less intimidating than the doctor telling you "It'll be alright". And actually, we really value our nurses as a part of our team to really help out. Of course, there are the psychologists that we share with the rest of the hematology unit who can really help in the difficult times.

I think helping patients feel warm and understood and explaining and giving them a path of what's going to happen, and really, perhaps, dispelling some of the more difficult sort of ideas of how long it's going to get better...

We often use the phrase of "There is no Amazon Prime in POEMS". Nothing is going to get better quickly here. But it does get better. So it's just a matter of pointing the positives out.

07:35 Stephen Hibbs: Great.

07:37 Dr. Shirley D'Sa: And a shoutout, if I may, to actually the rehab team and the orthotists at Square. I have learned a lot about orthotics hearing Mike describe them to patients. You know, we are lucky that he can make direct referrals and they know what they're doing.

And actually, simple -- You know, I say simple. There's a lot of technology there, but ankle/foot orthoses can make a huge difference to foot prop patients - and also the institution of rehab, in a timely fashion.

You know, when there's been a bit of connection, but from nerves to muscles, and then you can begin to recruit whatever function you've got and move forward. I think that is something that we try and trigger for patients, because functionally that's a huge plus for them.

08:24 Stephen Hibbs: Yes.

08:25 Dr. Shirley D'Sa: I think where there's a slight problem nationally is that there's not such a widespread provision of physio. It's sorely lacking, actually. That's a shame because most of these patients; many are young, they were working and they really want to function - and it would be extremely important if they could get the help to function, because then they could get back into society and get back into their family lives. And so, this is something we try and nudge; starting in our centre but then kind of sending them back to their locals for similar things.

09:00 Stephen Hibbs: One thing that has come up recurrently in this conversation and which I think is really unique, actually, about POEMS, is just how shared the ownership is of patients between you as a hematologist and a neurologist. I can't think of another condition in any clinics I've worked in. I mean, it might happen in the Amyloid Centre. I haven't worked there. But I can't think of anything else in hematology where there's this kind of level of actually sharing a clinic in this way to look after a particular disease area.

I'd be interested to know your reflections on what that's been like, both in terms of some of the benefits of that and some of the challenges. I guess now you're very used to this partnership, but if there was a centre as well that was wanting to set something like this up, what are some of the tensions potentially between the way that neurologists see the world and hematologists see the world? How would you get something like this going? Maybe Mike I'll start with you on this one.

09:59 Prof. Michael Lunn: So it was very interesting, you know, in that journey as a neurologist, at seeing actually how frequently hematology is within neurology. Not always, but quite often, the two are linked - and that's what really set up the clinic. And where it's gone beyond POEMS is non-Hodgkin's lymphomas and Waldenströms and other sorts of diseases.

have clinics with [inaudible: 10:47

And so, it is a real interaction. There are other hematology and neurology clinics now around the UK - a few. I think they've (hopefully) slightly followed our model, or made their own models out of our model. You know, whatever works. I think the process works and it probably would work with anybody, I hope. It works on an understanding that's aimed at the patients.

We're a triangle, me and Shirley and our patients. You know, everything is aimed at them and we're trying to do the best for them in recognizing that, if I see them and I make a decision and then Shirley sees them and then makes a decision, that then we have to talk to each other independently and then we have to get the patient back to communicate.

Whereas actually it's much easier if we all sit in the same room and we have a collaborative thought about things with the patient. The patient is then concordant with any of the hard decisions and they understand why we've made them - and then we can proceed forwards.

It's much more efficient and it's much better in the end for the patient management. It really does work rather well. And of course, it all works on the fact that Shirley and I have become extremely good friends as part of the whole process. You know, I think what COVID taught me was that a lot of my colleagues at work were actually my friends, because when I wasn't seeing them during COVID so much then you miss them.

So you know, it was obvious from how Shirley and I get on that we're good friends as well as colleagues; and I think if you can find a good friend, either way, and you can see the purpose of what you're doing, then it all pretty much works, really.

12:43 Stephen Hibbs: Any thoughts on that at all, Shirley?

12:44 Dr. Shirley D'Sa: I think one has to want to collaborate for the patient's sake, to be honest. I think both Mike and I genuinely feel that. We also have other colleagues at UCLH who have been very keen to join.

So Professor Stephanie Baldeweg in endocrinology, we had meetings years ago with her. She enabled one of her senior clinical fellows -- She would have loved to join herself, but unfortunately the clinic clashed with one of her regular clinics. So we have had the input of a senior endocrine fellow throughout the years, and they themselves have done research into the endocrinopathy of POEMS. But they're also vital in the clinical follow up and advice of these patients, because I am terrible at the endocrinology.

The fact is, endocrinopathy produces a lot of morbidity. Whether it's hypogonadism, hypoadrenalism. You know, people who have premature menopause and stuff like that. I mean, that all adds up to the health of the patient and what they feel.

So if someone is hypogonadic, they are tired. There's erectile dysfunction. There's infertility. And one mustn't forget those things, because it really -- You know, in terms of, for example, bone health; if you ignore that, you know, that's bad news for the patient. These are young patients. They've got a long life ahead of them. So we mustn't leave these sort of stones unturned. So that's been another great help to our service.

Likewise, we have an andrology clinic, which again is really helpful for the management of the erectile dysfunction side of things. So I think before anything it has to be this feeling of collaboration that has to come forward, with the patient at the centre of everything.

And that then; you then find people who are interested. And I think there are very few people who are not interested in POEMS once they get to know it, because it really is fascinating. And when we go and speak to people elsewhere and things, they are equally fascinated. I think, you know, whenever we get people contacting us, they are literally -- They find it very interesting. I think it's just -- It's come out of that. So I tend to think --

-- People have asked how to recapitulate the service and we're always happy to lend whatever experience we've had to try and build something up locally as well.

What I would say is that I guess my experience of neurology is a bit like general hematologists. There are a lot of general neurologists. Correct me if I'm wrong Mike, but they are the kind of core of neurology in the UK. Most are generalists. They see a lot of referrals in district generals, from GPS who may refer people with small symptoms which probably fill up a neurologist's clinic and they may get a bit like "Ugh", you know? "It's probably just..." You know?

So it's a crowded clinic for them - and to then set themselves time to think about peripheral nerves... My experience is that there are relatively few peripheral nerve specialists in neurology, and I am very lucky that Mike is one of them and one I work with, because that is -- The nuancing of peripheral nerve disease, I have discovered, is a real craft, and it's down to the consistent systematic examination. I think that is something that is really worth putting across.

I'm kind of commenting on the neurology side, but it's what I have observed. I think hematology is a bit more numbers and sort of -- But it's also spotting other features. So I just think it's us -- We're trying to get a message across, and that's certainly the paper we published. We have published in neurology journals as well, to try and highlight neurophysiological features and VEGFs and various things.

We're just keen to get the message across as much as we can, because it tickles the imagination, it plants a seed and then people go off and think "Ooh... Maybe this could be POEMS" or whatever. I think the key message is that it's so responsive to treatment. I think as hematologists we do see people respond a lot to the treatments we give; not necessarily all of them successful. But I think a lot of neurologists don't have that benefit in many diseases.

Again, I'm sure things have moved on. But I think it is super rewarding. And, if we're looking at professional satisfaction as well as patient reward, I think that is the way to kind of sell it to colleagues, you know; that if you make this diagnosis, you feel like a winner and you can see patients improving (which is brilliant, really).

17:33 Stephen Hibbs: Yes. So final question for you both, then. This is a rare condition, and probably for that reason as well as some others, there are a lot of uncertainties that remain about all parts of POEMS, both in terms of its underlying pathologies but also its treatment and follow-up.

And so, if I could give you both an infinite pool of money and access to the data of every POEMS patient in the world, what would be the one research study that you'd each like to do that would address what you feel is the kind of most important unanswered question?

So maybe, Shirley, do you want to start on this one?

18:17 Dr. Shirley D'Sa: First of all, I think from a general looking after the patients point of view, we need a system which enables quick diagnosis. So we need speed with investigations. We need regular education; because, you know, doctors, they come and go. You know? People get old and they retire. So we need to capture doctors in training to make sure the message is hammered home on a regular basis, across specialties. Okay?

So we need some sort of -- Almost like an academy of some sort. Because you said the sky's the limit, so I'm going for a POEMS Academy. Which, you know, these days one can deliver like this! Digitally. You don't have to have people coming in. You can have a POEMS podcast where people can pop in and listen to the cases.

Secondly, we need quick diagnostics. We need more availability of diagnostics. A lot of people do have to send VGEF to Queen Square, for example, and the neuroendocrinology lab that actually Mike heads up. You know, it does a great job and it responds to patients. We have little sort of "PS: If your VGEF is high, please feel free to get in touch with the POEMS service and discuss the patient".

On the hematological side, I think there's a great -- I have to say, another colleague that's joined our service is Dr. Jonathan Sive. Because I have become a bit more distant from day-to-day myeloma therapy, we have -- He's a myeloma specialist at UCLH. He actually runs our POEMS treatment clinic. Because there are so many therapies in myeloma, which we can and are already applying to POEMS because they really can make a difference.

Gone are the days where we used to make a diagnosis and transplant everyone. Well, we still do that, but they're now relapsing, or they need other treatments, you know? So it's much more nuanced. So having a clear understanding and availability to anti-myeloma therapies, of which there is a huge number, would be fantastic, so that we can give people treatment. The kind of treatment they need that matches their morbidity that they may already have, you know?

I guess the other thing is the genetics. You know, why do people -- Why do some plasma cell disorders express themselves as POEMS? Why is it LAMBDA-restricted? What is the light-chain usage? You know, what is the genetic profile of these patients, in terms of in the bone marrow?

And again, myeloma has -- There's a lot of, you know, mileage in those treatments and in those fields. In POEMS, we have a small amount of global disease to work with.

20:55 Stephen Hibbs: Yes.

20:56 Dr. Shirley D'Sa: So we need to make the best of that. And we would love to do that. That is something that I know my colleague Jonathan Sive is looking into. How do we get these marrows, even if there's a very low burden disease; whether it's next generation sequencing or other omics, you know?

Because this, I think, will unlock some information as to why the disease behaves in this way. Why is it neurotropic? Why is it inflammatory, etcetera? And it could unlock appropriate delivery of therapies for the right patients; because there are subgroups within POEMS. Some do better than others with different therapies.

In terms of the neurology, I will hand over to Mike.

21:37 Stephen Hibbs: Yeah. So Mike, what's your number one unanswered question?

21: 39 Prof. Michael Lunn: Yeah, so in Shirley's POEMS Institute, I want to know what it is; what serum factor it is, that damages the nerves. That's the major disability that patients have. It's not a direct invasion of that plasma cell clone. It is something that happens as a result of the toxicity that is in the serum and that is produced by that plasma cell clone, or what that plasma cell clone drives.

And so, my major interest would be: How does that factor get into the nerves? What is it doing to the nerves? Because for me, that's the way that we intervene in the major disabilities as early as possible.

One goes to the other end of the problem, of course, and that's what Shirley said. What is it about that very tiny plasma cell clone (as if often is) that is unique and individual, that should drive POEMS rather than just being multiple myeloma or plasmacytoma.

There is something extraordinary about those cells in those patients that drives the non-clonal disease; or maybe it's the non-clonal cells that are extraordinary that are driven by a small clone that's there anyway.

But there's something at that end of the pathogenesis as well, that leads to understanding why POEMS patients get POEMS. And again, opens the window to any other disease often at an earlier stage.

So I am very much - in Shirley's POEMS Institute - looking at both ends of that pathogenesis. What drives it and what the toxicity is that results in the disability.

We've got some way to it in these last few years; collecting a big enough group of patients. But we always need more patients, and we definitely need more money and support, for any of you out there who are willing to give me some money.

23:45 Stephen Hibbs: Thank you so much, both of you, for this great discussion today. It's been really useful. I want to just direct our listeners to that paper as well on the HemaSphere website, that will tell you even more useful hints and tips about both how to understand, how to diagnose and how to treat POEMS.

So thank you both and thank you to all our listeners for joining in today. We'll be back with another episode soon.