Following NICE guidelines | An interview with Ceri Bygrave

Ceri Bygrave is the Myeloma Lead at the University Hospital of Wales, Cardiff, UK, which serves as a tertiary referral center for Multiple Myeloma (MM) patients in South Wales. In this role as Myeloma Lead, Dr Bygrave has helped to establish the myeloma service and to develop all clinical and research aspects of the department. She is also a valued member of the MUK CTN (Myeloma UK Clinical Trials Network) and an elected executive member of the UK Myeloma Forum. The MM Hub were delighted to talk to Dr Bygrave at the Clinical Advances in Myeloma meeting held in London UK on 31 January 2018, where she presented a talk on the topic: ‘Navigating the latest NICE guidance for Myeloma’. The slides from Dr Bygrave’s presentation can be viewed here.

I was delighted to secure an exclusive interview with Dr Bygrave to follow-up on some of the points from her talk and to expand on some of the interesting discussion points that arose at the London congress. The interview is detailed below (FC: Fiona Chaplin and CB: Ceri Bygrave).

FC: What are the biggest revisions in the 2016 NICE guidelines in terms of diagnosis?

CB: In terms of diagnosis, there is a difference between when NICE says consider and when NICE says ‘perform’ – meaning do this. In the case of myeloma FISH analysis, this has now been upgraded from consider to perform. This will help those labs around the country where currently routine diagnostic FISH is not funded, which is often the case outside of big centers. Knowledge of a patient’s cytogenetic status by FISH at diagnosis is crucial to be able to calculate their Revised-ISS score, which should be done for all patients and the prognostic implications discussed. Also, NICE now recommends that all patients have serum-free light chains measured in addition to electrophoresis, which is a breakthrough for diagnostics and for monitoring, particularly, for those with light chain only myeloma and patients with renal failure, and to minimize the damaging effects of light chain escape. Tertiary centers will perform these for smaller provincial hospitals, but funding level agreements need to be put in place.

FC: You talked about the importance of communicating the R-ISS score to patients. How important is it to be honest about a patient’s prognosis and do you think that most UK doctors have the necessary support to do this effectively?

CB: It is a vital component of having an honest conversation with the patient about the implications of their diagnosis.  I think that many UK doctors lack the support needed to do this as they do not have a dedicated myeloma clinical nurse specialist, and without mine, my job would be much, much harder. Often, we have limited time in the clinic to go beyond cold hard facts and myeloma patients benefit from having a team of nurses and other health professionals to help assess their holistic needs.

FC: Does this means that many doctors will have to explain a poor prognosis without support?

CB: Yes, they will, and that is very cold. Patients don’t always understand their prognosis, but it is important that they are able to, to the best of their capability and desire. If we have time and the right staff around us, it is far easier to share this information. In Cardiff, we have a Clinical Nurse Specialist (CNS) who is also supported by a trials nurse, and who can provide support in the main clinic. Together they run a nurse-led quality of life clinic and work across palliative care clinics. So patients in our clinics receive a well-rounded package of care, but unfortunately, this is not something that all doctors will have access to.

FC: You strongly advocate the use of bortezomib (Velcade) as a frontline regimen. However, it was commented [at the London MM meeting] that this then eliminates the possibility of using carfilzomib second-line due to the specification of the treatment indication that patients must not have had prior exposure to bortezomib. Does this mean that with the current indication, carfilzomib will rarely be used in practice?

CB: It may do, but I think NICE is not a perfect system. I think NICE makes decisions for financial reasons. If we are reactive to NICE, rather than proactive in terms of what we think is best for patients, then we will always be playing catch-up. So I don’t think it is right to base what we do at first line on what is available second-line because the system for what’s available second-line via NICE is not free from financial bias. In reality, carfilzomib should be available for all patients, not just for patients that haven’t had prior exposure to bortezomib. *There is compelling evidence that maximizing the PFS progression-free survival) from the first treatment is the best way to improve patient outcome in the long term, which means that we should always use the most clinically effective available regimens.

FC: It was commented at the meeting that one option is to use CTD front-line so that carfilzomib can then be used second-line, what do you think?

CB: The rationale is that if CTD is used first-line, then the patients are naive to bortezomib and therefore carfilzomib is an option at second-line. However, in 2018, regimens such as CTD (cyclophosphamide, thalidomide and dexamethasone) should not be the best we can offer. My feeling is that using CTD first line is doing people a disservice as it risks giving patients an inferior regimen upfront to save something for a rainy day. The first response is almost always the longest, therefore we need to be optimistic and effective with our treatment upfront.

FC: It’s interesting that doctors may be using CTD upfront instead of bortezomib-dexamethasone, yet there is no trial comparing CTD with bortezomib.

CB: Using CTD upfront is a reactive move, which is not my philosophy. There has been no direct comparison of CTD with bortezomib-dexamethasone as a frontline regimen, but data for bortezomib upfront is overall more convincing. Unfortunately, often people don’t do the studies we need them to do. For example, there hasn’t been a head to head study of bortezomib versus lenalidomide, yet now in Wales, we have the option in the non-transplant setting to use either. In these circumstances, the decision on which regimen to choose comes down to a combination of patient and clinical factors. It’s hard to be prescriptive or change your practice without evidence to show that what you do differently is actually better.

FC: The MM Hub has previously written about how many of the preliminary dosing studies are carried out with only a small number of patients (sometimes less than 20), then larger trials are often developed on the back of these with dose levels that may not be the most effective. So there is a necessity for non-profit organizations to repeat these dosing studies and to carry out clinical trials that many of the drug companies won’t. Do you think there are funding and resources in the UK to do this?

CB: We have benefited in the UK from establishing a track record of conducting very large multi-center phase III trials, in an iterative process. For example, the most recent trial is Myeloma XI, in which thousands of patients were involved and cutting-edge questions, such as the role if IMiD based maintenance, were posed. These kinds of studies provide answers that are statistically more robust than smaller studies. The problem is that this process takes such a long time and often by the time the trial reports, the data isn’t necessarily out of date, but there are already several new options that weren’t considered in the trial question. In an ideal world our UK trial portfolio will always include a mix of complex phase II/III studies, but with additional shorter, more defined phase I/II studies where evidence can be generated more quickly. A good example of the latter is the  MUK CTN programme which has now been running for 10 years and has produced some really good data in a rapid fashion. The programme has also recently opened the first dedicated study for High-Risk cytogenetic myeloma (MUK9) which is recruiting very well.

FC: One of the comments regarding the caveats associated with individual drug indications was: “We don’t know what the rules will be next year”. How much of a challenge is it to try to think ahead with a treatment plan to account for these caveats and to leave viable options down the line?

CB: In reality, we aren’t entirely blind to what is on the horizon, we know what’s on the NICE work program a long time in advance of a final HTA decision. We know when things are and aren’t going to be considered and through our patient advocacy work and particularly organizations such as UKMF, UKMRA, and Myeloma UK, we do have some ability to influence the NICE work programme.

FC: It was commented that there is potentially a grey area for patients undergoing clinical trials, as when they emerge from the trial it is unclear whether clinicians should count this [as a line of treatment] therapy. What are your thoughts on this?

CB: I think this attitude does not support patients, it would be better if clinicians were allowed to make purely evidence-based decisions on best treatment rather than needing to look for loopholes in funding systems, which shouldn’t be what we are paid to do.

FC: Are there any regulations surrounding this?

CB: Not that I am aware of, but we have a different system in Wales being relatively free from commissioning, but I have heard many difficult stories of pressure in this area from colleagues in England.

FC: You mentioned using the frailty index in your talk, which is not part of the NICE guidelines. How can doctors that don’t attend conferences keep up and how easy is it to incorporate such ideas into clinical practice?

CB: This comes down to departments encouraging staff to attend educational meetings and conferences in order to keep up to date. It’s entirely possible that something like that will be included in the next revision and would then move into national recommended practice. However, often guidelines can take many years to change and complete, and keeping up to date allows us to adjust our practice in a more dynamic fashion.

FC: How easy is it for someone like yourself to find time to keep up with changes to guidelines and is there adequate funding for clinicians to attend international conferences?

CB: Again this comes back to attending meetings and talking to colleagues, and yes, there is funding available for conference travel, although it would be very hard for me to attend such meetings without sponsorship from pharmaceutical companies. I like attending ASH, and there are also many excellent European congresses every year as well as the bi-annual IMWG.

FC: In your role, will you come back and disseminate information and set up meetings with local colleagues?

CB: Yes, I presented highlights of the ASH meeting this year in Bristol, which was attended by colleagues in South Wales and the South West. I also run the South Wales Myeloma Regional MDT which meets once a month and I am always willing to see patients from across the region for a second opinion or offer email advice to my colleagues.

FC: You mentioned the importance of managing infections in MM. Do you have any thoughts on the data presented by Andrew Branagan at ASH showing that two flu vaccines are better than one? How quickly could such findings be incorporated into practice?

CB: I believe that practice changes should be guided by evidence. Whilst I have not read the manuscript in this case I expect it is linked to the observation that patients with myeloma are immunosuppressed, and so the way they respond to vaccines is not as effective as in people with a normal immune system. This is the case not just for flu, but for every other vaccine we provide at diagnosis or after a transplant. Infection is the leading cause of death in our patients so it’s vital that more studies like this are carried out to assess baseline morbidity and mortality from infection in the population, and then design interventional studies to tackle the areas of need identified.

FC: Denosumab was recently approved by the FDA. How would this impact clinical practice if it was approved for use in the UK? Do you think it could replace zoledronic acid (ZA)?

CB: Again, we would like to carry out a head to head study of anti-resorptive versus anabolic agents in the UK, and talks with pharma are in progress. FDA licensing almost always precedes that of the EMA, but it would be nice to see a European license this year and more mature data from comparative studies between the two classes of agents, and also in combination. Bone disease is a major cause of morbidity for many of our patients and again an evidence-based change in practice could have a big influence on patient outcomes. This was the case in the clodronate versus ZA question in myeloma IX, where an overall survival advantage was seen for ZA. 

FC: Presumably this will mean that the EMA can follow real-life data because once its approved, then practice in the USA can serve as further evidence for decisions by the EMA?

CB: Perhaps, I suppose it depends whether you think myeloma care in the US reflects Real Life! I think the best approach is to strengthen our data capture capabilities in the UK so that we can continuously monitor the impact of treatment clinically and also in terms of patient quality of life. If we can demonstrate advantages in both of these areas, it will be easier to justify the high cost of treatment.

FC: Daratumumab is currently approved in the UK as a fourth-line therapy. What are your thoughts on this and do you think it will be long before it’s moved closer to frontline therapy?

CB: Some access is better than none. But it would be more attractive if it was approved in combination and could be used earlier. Daratumumab is on the NICE work stream and there should be a decision before the end of the year on the DVd (daratumumab, bortezomib, and dexamethasone) combination. Sadly, but not surprisingly patients in the UK are unlikely to ever be able to access DRd (daratumumab, lenalidomide, and dexamethasone) which has shown better efficacy in trials, due to its astronomical cost.

FC: I’d like to touch on the topic of ‘Women in MM’, as there seems to be a level of male dominance. Would you consider hematology a challenging discipline in terms of finding a work-life balance?

CB: I have always found myeloma and hematology a very rewarding discipline to work in and I hope that no women are put off, I don’t think being female should be a barrier. In my early career I had 21 months maternity leave and worked part time and yet was still able to complete my training and obtain a research degree. Now I have two children and two step-children, I travel a lot and am fortunate enough to lead a great service, and yet I always feel I have as many pressures as any other women, it’s just about adapting and knowing what you want. There are a lot of great role models for me in research and clinical work in myeloma, so I have never felt limited by my gender. Perhaps teaching hospitals and research groups still carry more of a male bias, particularly towards the top and this is something we need to work on. In 2018 I would encourage all my female colleagues to strive for their best possible outcome in all aspects of their work, and in fact in all aspects of their lives!

FC: Thank you so much for talking to the MM Hub!