the limbic recently spent some time with international multiple myeloma expert Professor Kwee Yong from the University College Hospital London in the UK, talking to her about cure and operational cure in MM, the ground-breaking studies, the challenges in treating patients and her idea of the multiple myeloma ‘holy grail’.
the limbic: What is operational cure?
Professor Yong: Operational cure is a new term in multiple myeloma (MM) and it refers to the fact that we want to achieve durable long term remission for our patients while acknowledging that we can’t get rid of every myeloma cell in a patient’s body. The median age at which people are diagnosed with MM in Australia is 70.91 and so I explain to patients that we can’t get rid of every myeloma cell in their body but if we can keep it under control for long enough they will not die from myeloma.
the limbic: You mention that operational cure is a relatively new term, why has it become part of MM parlance?
Professor Yong: The concept has gradually crept in because outcomes have improved so much for MM patients over the past five, 10, 15 years. The median survival for patients diagnosed 15-20 years ago was 2 years, today the median survival is probably nearer 5 or 6 years and for the younger patients who get to transplant it is probably 6 or 7 or maybe even 8 years.
Because survival is extending, and there are new treatments and new strategies to eradicate disease and control the malignant clones, the concept of patients keeping well long enough has gradually become a little closer to reality. A great deal of it derives from the realisation that we need to keep patients on treatment for longer in order to suppress the malignant clones. So, the concept of keeping patients on treatment has come together with it being an ‘operational’ cure. I guess that’s how [the concept] has evolved and it is becoming, I think, more and more accepted – certainly in the world of specialists who treat myeloma.
the limbic: Does operational cure impact clinical trials and the endpoints that are studied?
Professor Yong: I think it does in an indirect way because the concept of operational cure comes hand in hand with the understanding that we need to achieve a deep response in order to get to this operational cure. Therefore, the way in which we measure this depth of response is critical and has really only become a reality because of new technology around measuring increasingly smaller amounts of residual disease in the bone marrow of patients. We call this Minimal Residual Disease (MRD) – but the concept has been around for a long time and, for instance, has been applied to leukaemia.
The idea in acute leukaemia is that you have to achieve MRD in order to have cure. The same concepts have been applied to myeloma because, essentially these are cancers treated by haematologists. I think the idea of operational cure does affect endpoints for trials in that endpoints are now designed as MRD rather than biochemical measures of disease like complete response, or partial response.
the limbic: Which trials do you think are going to be pivotal in advancing the treatment of MM?
Professor Yong: Some of the trials in newly diagnosed older patients who are not eligible for transplantation are producing some astounding results in terms of progression free survival (PFS) and by implication, overall survival, and alongside that good high rates of MRD negativity. One exciting trial is the ALCYONE trial2 involving the combination of bortezomib, melphalan and prednisone in conjunction with daratumumab. This of course is an unlicensed combination because the phase 3 trial has just reported.
And there’s the front-line trials in transplant eligible patients which randomise patients to have a transplant or not a transplant. Many of these trials have reported – for example a study by the Intergroupe Francophone du Myelome (IFM) group3 – and show, not surprisingly, that transplant is better for all patients.
The transplant arms tend to perform better than the non- transplant arm but actually, if you drill down to the patients who achieved a deep MRD negative response, those patients have equivalent outcomes whether they had a transplant or not. I think that’s beginning to tell us that if patients achieve a deep MRD negative response at first line treatment perhaps they can be spared the intense treatment and morbidity and small mortality of a stem cell transplant.
That brings us into a new era of using depth of response in order to stratify ongoing treatments and we can escalate treatment for patients who haven’t achieved MRD negativity and de-escalate for those who have, saving toxicity and maximising well being.
In the future some of the European groups, and also in the UK, are designing the next front line study for patients with MM and there will be a stratification of patients post-transplant according to whether they are MRD negative or positive.
the limbic: What do you think are the biggest challenges for haematologists treating MM today?
Professor Yong: There are many challenges but one challenge that has emerged today as a consequence of our remarkable advances is managing patients’ expectations. There is so much talk of news drugs and effective treatments, and then there’s the CAR-T cells, and patients begin to expect that they will always have a new treatment around the corner when their disease relapses. Although another treatment is always available it may not be realistically the right thing, or it may not fit the patient’s expectations.
We need to help our patients understand the true reality of what treatments can offer and help them to formulate more realistic goals and priorities for themselves. We need to understand what our patients want – when they say they want to be cured it may not mean that from a practical perspective.
Maybe all they want is to see their grandson graduate. Because the actual truth of the matter is that the biological cure that we see in acute leukaemia or in some the solid tumours is probably not a realistic possibility in myeloma where the malignant clone is so much part of the B-cell make up the patient in that you just can’t eradicate it.
the limbic: what is the ‘holy grail’ for the MM field?
Professor Yong: At the moment we have quite a ‘broad brush’ way of dividing patients up into groups who will do well with minimally intensive treatment, those who will need intensive treatment for a period of time, and those who will need intensive treatment followed by a very long extended treatment in order to continue to suppress the malignant clone.
The holy grail would be to have precision medicine like in other areas of cancer. But to get here we need to do the clinical trials. However, these are being developed. The IFM group in France are stratifying newly diagnosed patients according to their MRD status at the end of a block of treatment. Hopefully these trials will tell us how to stratify patients outside of the clinical setting.
- Australian Institute of Health and Welfare 2017. Cancer in Australia 2017. Cancer series no. 101 CAN 100. Canberra: AIHW.
- Mateos, M. et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528.
- Attal M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320.