Role of immunotherapy and precision medicines in multiple myeloma and key new guidelines

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Published: 3 Mar 2017
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Prof Sagar Lonial - Emory University, Atlanta, USA

Professor Sagar Lonial (Emory University School of Medicine, Atlanta, USA) discusses key advances from IMW 2017, such as the emerging role of new immunotherapies where standard cytotoxic therapies have not been successful. 

Looking at genetics and genomics, Prof Lonial notes how precision medicine has been very successful in solid tumours but has not previously shown a similar impact for the haem malignancies.

He suggests that if we are to cure myeloma it won’t come through one approach but will instead be by utilising all three of immunotherapy, precision medicines and “biology-based” approaches. 

Touching on MRD, Prof Lonial notes how there is controversy around whether to use flow or next-generation sequencing to measure MRD, suggesting that the latter will be the modality of the future.

Whilst MRD is useful as an investigational tool, Prof Lonial suggests that it is not ready for “prime time”.

Finally, Prof Lonial discusses the three new treatment guidelines coming from the chairs of IMW 2017.

This includes definitions of smoldering myeloma and risk stratification, guidelines for how clinicians could assess risk and suggested treatment approaches, and a consensus statement around vaccination and infection prophylaxis in patients with myeloma.

Summarising the recent advances and what this means for patients, Prof Lonial said the overriding message is one of hope for the treatment of myeloma, as well as strong global alignment in the myeloma community due to meetings such as IMW. 

The role of MRD negativity is discussed further by Prof San Miguel, here.

Smoldering myeloma is discussed by Prof Mateos and Prof Richardson here.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceuticals (A Johnson & Johnson Company).

There has been a lot of interest, obviously, in cancer in general for trying to use immunotherapy where standard cytotoxic therapies have not been successful. Because of some of the tools that we have, such as PD-1 inhibitors, CTLA4, all those other targets, we’ve been finally successful after decades of lack of success with immunotherapy. In the hematologic malignancies we think about things like CAR T-cells, monoclonal antibodies in myeloma specifically targeting two known important targets, we’ve heard some data on BCMA, all of this will roll up into really exciting new therapeutic options. But we know that even those approaches are not fool-proof and so you go to the other potential reason why cancer occurs and that’s genetics and genomics.

Now precision medicine is something that has been really successful in the solid tumours but has not been quite as successful in the haem malignancies and particularly in myeloma, mostly because many of the mutations that we see are not single drivers. Removing that blockade, like in CML, doesn’t result in long-term remissions. So part of an approach that I’ve thought about is using standard therapy with IMiDs and proteasome inhibitors, immunotherapy to try and get you down to low level disease and at that point you may have one or two clones that remain and you target that with a mutation driven therapy. So ultimately if we’re going to cure patients with myeloma it won’t be just immunotherapy, it won’t just be precision medicine and it won’t just be what I call biology-based approaches, it will be putting all three together to really get rid of the disease.

What is the role of MRD negativity in the frontline and relapsed setting?

MRD has really been developed because we’ve been a victim of our own success. When you’re starting to get CRs reliably now, both in the induction and in the relapsed setting, then all CRs are not the same and you use MRD as a way to separate out really, really deep responses versus less deep responses. There is a lot of controversy in the community right now about using flow or using NGS, next generation sequencing, to measure MRD. My personal bias is that next generation sequencing is going to end up being the modality we use because it’s easily reproducible and it gets you a log better depth of response, 10-6, than you get with average flow cytometry. Now, flow cytometry may have other advantages in that it can give you immune profiling and other things that are useful but MRD is here as an investigational tool but it’s not quite ready for prime time and certainly not ready for making therapeutic decisions.

What are the new consensus guidelines coming out in multiple myeloma?

There are three different consensus guidelines that are coming out from each of the chairs of the meeting. The first consensus guideline is from Shaji Kumar and what he’s really talking about is MGUS and smouldering, giving guidelines on definitions, giving some level of risk stratification for both MGUS and smouldering, and then talking about standard ways to monitor these patients based on where they fit into the risk stratification guidelines. That’s really important because there’s a lot of heterogeneity in terms of practice out there. I may see a high risk smouldering every month, others may seem them every three months and there is some data to talk about how often you should see them, what imaging you should do, what are the standard tests you need to do to appropriately risk stratify them. So that will be a nice and welcome consensus document.

The second is the one I’m leading which is based on high risk and special populations. Our goal is not to redefine high risk but to give clinicians guidelines on what to use to assess risk. So you can do things like FISH and cytogenetic testing, they should be done in certain methodologies, you can use gene expression profiling, you can use NGS, but we also created a category of clinical high risk – patients with plasma cell leukaemia, extramedullary disease, things that we all sort of know or feel but they’ve never been codified in any document. I think that’s really another strength of the manuscript as well. Then we go into recommended treatment approaches for patients, whether they’re older or younger and then focus on four special populations – patients who may be eligible for allotransplant, patients with frailty, patients with renal failure and then emerging targets in high risk disease.

The third consensus statement is coming from Dr Noopar Raje and what she’s going to talk about is vaccination and infection prophylaxis in patients with myeloma which is an area that everybody has very strong opinions on but there’s very little data out there. So what Noopar and her group tried to do was come up with some consensus agreement on areas where we need clinical trials to answer questions but what best available data is to be able to do that. So those three guidelines will be very practical clinical things that will hopefully be available for practitioners in the near future.

What does this mean for myeloma patients?

The take home message for patients is really twofold. One is one of hope – there are lots of new drugs and new targets that are coming out that will be very useful for them in the near future and hopefully approvable in the near future as well. The second is that one of the things I often hear from patients is, ‘Do you all talk to each other? I can see a doctor in California, I can see a doctor in Texas, I can see a doctor here but how do I know that you guys are all communicating and are working together?’ What this meeting really shows is that there is that communication, not just in the US but globally. Particularly in the myeloma community we’re a very close-knit group and we do share our information, we do share our ideas. We may have opinions about who is right and who is wrong but that sharing occurs really frequently and that ultimately is better for patients.