Treatment of multiple myeloma continues to evolve

Exclusive podcast featuring
Prof. Graham Jackson, MBBS, FRCP, FRCPath, MD
Newcastle upon Tyne Hospitals NHS Trust, UK

Multiple Myeloma is a complex disease, but one where scientific research has advanced exponentially over the past decade. With many different options now available for patients at different points of the disease pathway, it is important to continually consider the individual needs of each patient, and ensure patients are able to live the best life possible.

Prof. Graham Jackson, Consultant Hematologist, Newcastle upon Tyne Hospitals NHS Foundation Trust, explains the current treatment landscape in multiple myeloma, including the promising area of personalized medicines and sequencing, as well as future advances. He also highlights the diagnostic approach, and how the treatment pathway changes over time for patients.

Part 1: understanding patient features and selecting multiple myeloma treatment

“We are entering a time where we’re looking at less in terms of fixed duration therapy and more in terms of continuous therapy” 

“We talk a lot about personalized medicine in multiple myeloma and I think I can say this on behalf of all myeloma physicians, is that every single day with every patient that comes in through the door, we practice personalized medicine.”

“It’s very important that we do not harm our patients with each line of therapy and balance the patient’s needs with their comorbidities, their wishes and what we’ve achieved previously”

– Prof. Graham Jackson

Transcript
Welcome to an exclusive podcast about the evolving role of treatment in multiple myeloma, featuring key expert Professor Graham Jackson of Newcastle upon Tyne Hospitals NHS Foundation Trust. In the first of two parts of this podcast, Professor Jackson speaks about the features of patients with multiple myeloma and the selection of appropriate treatment. This podcast has been sponsored by Janssen-Cilag Ltd, a pharmaceutical company of Johnson & Johnson, based on an interview with Professor Graham Jackson. The views expressed here are his own but may have been edited in parts to ensure they comply with the UK's ABPI code of practice.

Multiple myeloma is a very complicated hematological malignancy. The reason it's complicated is that it can impact on a number of different organs such as the bones and the kidneys and it can present in a number of different ways. It also has a variable prognosis and one of the things that we have to think about when patients first present is to try and get a handle on what their likely prognosis is. To do this, I think we obviously have to look at the ISS Staging System and now with cytogenetics and LDH we have the R-ISS Staging System and that's very important to do right at the beginning. The other thing we have to think about when we meet patients for the first time is what are the things they bring to the table. It might be frailty, it might be other comorbidities and clearly, part of our assessment is to assess the frailty and their other previous problems.

I think the third thing that we have to assess is that awareness that patients with disease outside of the bone marrow, extramedullary plasmacytomas or even plasma cell leukemia, those patients have a poorer prognosis and it is very important to recognize those particular issues. We have to assess prognosis. The other thing that is very important when we first meet a patient with multiple myeloma is to have a very full assessment of their disease. One of the sea changes in how we manage this disease is that we previously used to use skeletal surveys and one of the great advents that we've had in multiple myeloma is the use of better imaging such as CT scans, whole-body MRI scans, and PET-CT scans. We get a better handle right at the beginning on how the disease is impacting the patient. Of course, in terms of unmet needs, one of the things that we really want is to get our patients before the disease has started to cause end-organ damage.

We want to get patients with no bone disease if possible. We want to get patients before their bone marrow is deteriorating. We want to get patients before their kidneys start to struggle with the burden of the disease. An unmet need right at the beginning is getting patients earlier and clearly, this is still an issue. Some myeloma patients are still presenting late, they're still presenting in kidney failure and they're still presenting extensive bone disease. That's a very important thing that we need to do as a community to try and get hold of our patients earlier before we get end-organ damage.

I think the other assessment of prognosis that we have to be aware of is clearly we've talked about cytogenetics. The cytogenetic picture is complex and we are becoming more aware that actually, the patients who are destined to do badly are often the patients with more than one cytogenetic abnormality within their plasma cell, so-called double hit or triple hit multiple myeloma and all the data is pointing that one abnormality is much less significant than two or three.

I think the other group of patients where we recognize that there is a significant unmet need are those patients who relapse very quickly after frontline therapy. Certainly, data from Myeloma XI and other studies such as data from Kwee Yong and her team in UCH show that patients relapsing early and in the younger patients, patients relapsing within a year after their transplant are destined to do very badly. This is a poor prognostic group of patients. We assess prognosis at the beginning with cytogenetics, LDH, β2M in albumin, frailty, comorbidity, extramedullary disease but one of the important things we have to add into that is response to first-line therapy in early relapses are patients who are destined to do badly.

We talk a lot about personalized medicine in multiple myeloma and I think I can say this on behalf of all myeloma physicians, is that every single day with every patient that comes in through the door, we practice personalized medicine. We take into account the patient, we take into account their disease, we take into account how they've responded to treatment but also the individual patient's comorbidities, circumstances, wishes and desires.

It’s very important that we do not harm our patients with each line of therapy and balance the patient's needs with their comorbidities, their wishes and what we've achieved previously, what side effects we've given to them previously and how their disease is evolving, and of course, it's a dynamic situation. Someone may have a relatively low grade behaving disease for first- and second-line therapy but as we get to third- and fourth-line therapy, we do recognize that some patients’ disease evolve into a more aggressive disease clonal evolution and this also marks patients out as having a poor prognosis. They may acquire new cytogenetic abnormalities, they may develop new extramedullary disease or plasma cell leukemia and it's important to watch how the disease evolves as well as how the patient copes with each line of therapy.

When patients present, obviously it's a shock and they often want to get their disease into remission. We are entering a time where we're looking at less in terms of fixed duration therapy and more in terms of continuous therapy. Clearly, at the beginning of treatment, I think the patients and the healthcare professionals want the disease to come under control as quickly as possible because that is associated with better quality of life.

As patients go through their treatment and their disease is controlled and patients have got to a stage where they're in remission, then the question is what is the side effect burden of ongoing therapy versus the benefits of ongoing therapy and that's something that we very clearly have to balance, particularly as I say in the age of ongoing continuous therapy as opposed to fixed-duration therapy. I think as the disease progresses, then patient's priorities may change and obviously we have to be aware that with each line of treatment, the remission duration is generally shorter, the depth of response is generally shorter and often with each line of therapy the patient brings to that line of therapy, the side effects from their previous treatments. We have to be aware of what problems they've had with their last therapy to help guide our next line of therapy.

There is a general move in the direction of continuous therapy rather than a fixed duration of therapy. I think clearly the backbone of most therapies now is going to be a proteasome inhibitor, an IMid and steroid and we are now seeing a number of different agents added on to that particular regime, whether it is chemotherapy or whether it is an anti-CD38 antibody. In terms of sequencing, we're fortunate to have a number of different agents and clearly, in the UK we have to comply with the guidelines that we get from the NHS and particularly from NICE and NHS England and the Cancer Drug Fund.

Professor Jackson also discusses the evolution of therapy in the UK and current reimbursed therapies.

Clearly the therapy in multiple myeloma in the UK has evolved very rapidly over the last 10 to 15 years. Whenever we're considering a line of therapy, there are several things we need to think about. Is there a clinical trial available and some of the questions that we now have to ask is are triplets better than doublets and in general they are and do we want to consider continuous therapy versus fixed duration of therapy? For transplant-eligible patients that would usually be bortezomib, thalidomide, and dexamethasone and for the older patients it would be bortezomib and dexamethasone. Usually, that's of fixed duration treatment.

In the second-line setting, we have three options potentially available to us now. Carfilzomib and dexamethasone for patients who haven't previously had bortezomib in the frontline setting. We have Revlimid and dexamethasone in patients who haven't had Revlimid in the frontline setting, and we have the combination of bortezomib, dexamethasone, and daratumumab. In all three instances, those are continuous therapies until disease progression.

In third-line, we have the ability to use in certain settings, ixazomib, Revlimid, and dexamethasone and again, that is a continuous therapy and at fourth-line we're allowed to use single agent daratumumab. In terms of that single agent therapy, we're only allowed to use that treatment at the third relapse and therefore most people will use that treatment at that time. Beyond fourth-line therapy becomes harder because patients are less well, they've got more side effects from previous treatment and their disease may be evolving but we have the option of pomalidomide and dexamethasone and panobinostat-containing regimens with bortezomib and dexamethasone and beyond that potentially more palliative chemotherapy regimens.

We're often faced with two very different scenarios. The first scenario is the simplest, is that patients’ disease relapsed very quickly, the trajectory of the relapse is fast, they have a rising paraprotein, they start to get new bone pain or potentially their hemoglobin drops so they get renal problems. And those patients, it's clear they need treatment. So clinical relapse is, particularly if it's quick, there is no dilemma about when to start therapy - you start therapy as quickly as you possibly can.

The problem we have is with those patients that are relapsing slowly. Because we have such great tools to measure disease and disease response, we also have great tools to measure disease relapse. In clinical trials, you can measure the re-emergence of MRD so that patients become MRD positive having been negative. But the scenario we're usually seeing in clinic is patients going from CR to relapse or a paraprotein and light chain level that's rising, in patients who are still quite well. And then you have to have a discussion with the patient. Like most clinics, my patients all know their paraprotein level, they all know their light chain level, they're aware that it is increasing. And the skill then is when do you intervene?

Clearly it is critical to intervene before the patient gets any end-organ toxicity. You may want to start as you see a rising paraprotein over three or four measurements. They are biochemically relapsing. You want to intervene before they get a problem. Sometimes we watch the hemoglobin, and that can be the first sign that things are changing. And if we see a fall in hemoglobin, that is another point at which we intervene.

And often it's a personalized discussion with each patient that comes through the door. They know their paraprotein, they know their personal circumstances, and often you're making a decision together. It comes back to that personalized approach, and each person has a different feeling of when you might want to intervene. So relapse is a complex and moving scenario.

This concludes part 1 of the podcast. Listen to part 2 below to hear about the innovations in multiple myeloma therapy in the UK.

CP-131126 December 2019

Part 2: a spotlight on multiple myeloma innovations in the UK

“There is now a wealth of data to show that MRD negativity is associated with an improvement in progression-free survival and an improvement in overall survival for our patients. And increasing evidence that the deeper the MRD negativity, the better that patients are likely to do.” 

[This gives] us the opportunity to really change how we treat patients. If we can achieve the very deepest MRD negativity, how do we approach those patients if they’re still on therapy?”

“If we maybe get to 1 in 10 million cells or MRD negativity to 1 in 100 million cells, then we really are starting to think about eradication of the disease. And with these new tools and the tools we already have available, I can see that potentially happening in the next decade.”

– Prof. Graham Jackson

Transcript
In Part 2 of this two-part podcast, Professor Jackson shines a spotlight on the innovations in multiple myeloma therapy in the UK. This podcast has been sponsored by Janssen-Cilag Ltd, a pharmaceutical company of Johnson & Johnson, based on an interview with Professor Graham Jackson. The views expressed here are his own but may have been edited in parts to ensure they comply with the UK's ABPI code of practice.

Over the last 15 years, we've seen dramatic improvements in the treatment of multiple myeloma, and that has led not only to better therapies and better outcomes but also it has had to change the way we think about assessment of response. 15 years ago, we measured response by getting a patient to a plateau phase. Their paraprotein went down, it then got stuck, we accepted that was the best we're going to do, and generally stopped treatment. We've seen a succession of papers over the last 10 years that have shown that deeper responses are becoming increasingly important. We've gone from 'VGPR is better than PR' to CRs being better than VGPRs, and then we've moved on to stringent CRs.

I think we have now seen over the last 5 to 10 years a shift towards minimal residual disease assessments. Obviously, this has only become important because we have such powerful tools in terms of treatment, and there is now a wealth of data to show that MRD negativity is associated with an improvement in progression-free survival and an improvement in overall survival for our patients. And increasing evidence that the deeper the MRD negativity, the better that patients are likely to do.

Quite clearly, this holds out for us the opportunity to really change maybe how we treat patients. If we can achieve the very deepest MRD negativity, how do we approach those patients if they're still on therapy? Is there a question about maybe they don't need to continue therapy or maybe they should still carry on with therapy? So MRD negativity has become an absolutely vital part of any clinical trial.

What we've seen with our new regimes is that MRD negativity is very achievable both in the frontline setting, but what we've also seen with some of the really novel combinations including anti-CD38 antibodies and powerful IMiDs and proteasome inhibitors is that we can achieve MRD negativity even in the relapse setting. And that is an amazing change from 15 years ago.

One of the questions that we get asked in clinic and at meetings is, "Is MRD negativity relevant in the clinical setting outside of a trial?" And that's a harder question to answer. MRD negativity is not routinely used in the clinical assessment of a patient, but I can see that changing over the next five years, and in the United States we're already seeing that happen. So MRD negativity is currently a clinical trial tool, but I think if we had this interview in five years' time, we'd be using that as an assessment of the patient's response.

And as I say, this is going to really affect how people are treated. Some people are really going to look at that question of, if you get patients to very, very low levels of MRD negativity, and I'm sure we'll see the MRD negativity assessment tools becoming even more sophisticated, we might actually get to a point where we're talking about functional cures in people where the myeloma is simply undetectable. I don't think we're there yet, but we're clearly seeing that the deeper response the better the patients are going to do, so that's very, very important. And we're going to have more tools to achieve that MRD negativity. I think it's an exciting time going forward.

We've seen the evolution of anti-CD38 antibodies, which have really added to the treatments we already have available. And I think we've also seen newer agents such as selinexor and venetoclax potentially going to have an impact on the disease. CAR T-cell therapy is going to be important, and other anti-CD38 directed therapies such as BiTE antibody therapies and also loaded anti-CD38 antibodies, and potentially other treatments which will impact on the disease.

I think, in parallel with that, in the research setting, we are going to learn a lot more about the relationship between the plasma cell, the malignant plasma cell, and the bone marrow microenvironment and the immune system. And I see that as being one of the research areas of development which will really lead to or encourage the paradigm shift we're already seeing, where the move is away from chemotherapy, and let's face it, chemotherapy is virtually a thing of the past in myeloma, towards immune-directed therapy.

There are agents such as BCL-2 inhibitors, SINE inhibitors, and then more specific interactions with the immune system, so bispecific antibody therapies, CAR T-cell therapies, and antibody-drug conjugates. So we have a number of new therapies coming along. I think if we can then really assess MRD negativity to the deepest levels, we can already go down to less than one in a million cells. If we maybe get to 1 in 10 million cells or MRD negativity to 1 in 100 million cells, then we really are starting to think about eradication of the disease. And with these new tools and the tools we already have available, I can see that potentially happening in the next decade.

This concludes our two-part podcast series with Professor Jackson, thank you for listening. For more content on multiple myeloma, MRD and video interviews with Professor Jackson, follow the links below.

CP-131137 December 2019

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