Clinical Advances in Myeloma 2019 | Overview Part 1

The annual Clinical Advances in Myeloma 2019 meeting was held at the American Square Conference Centre, London, UK, on 16 January 2019 and the Multiple Myeloma (MM) Hub was delighted to cover the conference for a second year. This small conference of UK-based attendees including clinicians, clinical nurse specialists (CNSs) and company representatives was an invaluable opportunity to learn about advances in myeloma treatment and the implications to the NHS. This is the first of two articles and summaries of the morning sessions on Future Clinical Practice and Current and Emerging Treatments are presented below. The afternoon sessions - Practical Management and Improving Patient Outcomes - are covered in a separate article, available here.

Future Clinical Practice

Professor Kwee Yong, University College London Hospitals NHS Foundation Trust (FT), began the morning by welcoming the delegates to the conference and introducing her talk on how novel therapies can be incorporated into NHS practice. Professor Yong provided an overview of the current NHS treatment pathway for patients with myeloma and highlighted the importance of clinical trials (such as the Myeloma XI [NCT01554852] study) in enabling patients to access novel treatments as well as contributing to the evidence base that ultimately brings these treatments to NHS patients.

Following this, Professor Yong went on to discuss the use of proteasome inhibitors during first relapse. The results with carfilzomib from the ENDEAVOUR (NCT01568866) and MUK5 (ISRCTN17354232) studies were presented as well as a patient case study from her practice which guided the attendees through the clinical decision making process. Moving on to triplet regimens in high-risk disease, Professor Yong discussed the TOURMALINE-MM1 study (NCT01564537) - the only placebo-controlled, phase III study in the relapse setting. Lastly, Professor Yong discussed late relapse in the fourth-line setting and the treatment options currently available in NHS England – daratumumab or pomalidomide.^1,2 At this point, the priority is to balance the efficacy and tolerability of treatment and the patient may want to consider enrolling in a clinical trial. Professor Yong used another case study here in which the patient ultimately received daratumumab.

Professor Yong explained that since NHS practice is constantly changing based on NICE appraisals, it is difficult to describe a ‘regular’ NHS practice. The landscape of treatments for myeloma is rapidly evolving and it is important that clinicians find a way to negotiate treatment decisions. Professor Yong added that this is ‘a good problem’ to be confronted with, as it means novel and effective treatments are being brought into clinical practice, but unfortunately, in many cases there are restrictions on their use in the NHS, outside of a clinical trial setting. Professor Yong ended by highlighting the importance of sharing real-world experiences in order to make informed decisions.

This was followed by a talk on predicting treatment outcomes from Dr Charlotte Pawlyn, Institute of Cancer Research. Dr Pawlyn focussed her talk on the difference between prognostic and predictive biomarkers for outcome, alongside the cytogenetic analysis advances that have been made, and how these are, and can be, utilized. Dr Pawlyn noted that the introduction of fluorescence in situ hybridization (FISH) analysis to NICE guidelines was a step forward.³ Knowing the genetic profile of the disease can greatly assist in predicting patient outcome and personalizing the treatment plan.

Dr Pawlyn discussed the importance of tailoring clinical trials to gain more clinically valuable information on the variable responses of high-risk subgroups to different treatments. Furthermore, chimeric antigen receptor (CAR) T-cell therapies are in early phase trials and could offer a new option for newly diagnosed patients. Dr Pawlyn concluded that the improved availability of genetic techniques within the NHS has assisted in diagnosis and treatment and will hopefully lead to more specific studies to further advances in personalizing MM treatment.

Current and Emerging Treatments

Continuing the morning’s sessions, Dr Fenella Willis, St George’s University Hospitals NHS FT, discussed the current and emerging first-line treatments in MM. Her talk focussed on three different groups: patients with smoldering myeloma, young and fit patients and lastly elderly patients.

Dr Willis began with the smoldering myeloma group, explaining that there is no current standard of care in UK practice to treat high-risk smoldering myeloma. In these patients, active surveillance in clinics is the focus - the frequency of which is based on the patient’s risk status. International clinical trials with curative intent, such as GEM-CESAR (NCT02415413), are investigating both intensive and non-intensive approaches to treating this population. Whilst the data are not yet available from these early stage studies, Dr Willis noted it would be interesting to see if there is a benefit to these patients, which may change current treatment approaches.

In the young and fit patient population, the standard of care is induction triplet chemotherapy, either NHS funded, or in a clinical trial setting, with the aim of autologous stem cell transplant (ASCT) following a response to induction therapy. Dr Willis compared the UK approach to the European standard, highlighting the main difference is that the European guidelines suggest lenalidomide maintenance following ASCT. Lenalidomide maintenance has proven clinical benefit in progression free survival (PFS), but is not currently available in the UK.⁴ Dr Willis added that in the UK, access to new regimens is restricted if the patient is not enrolled in a clinical trial.

Current UK practice is based on results from the GEM05menos65 (NCT00461747) and IFM 2007-02 (NCT00910897) trials that showed bortezomib provided improved induction response rates.^5–7 Dr Willis noted that whilst treatment decisions in the UK are limited, generally triplet therapies are used. It was then discussed whether ASCT still has a role in treatment today and what the best triplet therapy was for induction. Dr Willis presented the ongoing UK based Cardamon (NCT02315716) study which is looking at the upfront combination of Carfilzomib, cyclophosphamide and dexamethasone triplet therapy. One of the aims of this study is to investigate if patients who respond to this new triplet induction maintain a long remission without having ASCT.⁸ Dr Willis also discussed the TOURMALINE-MM3 study (NCT02181413), which is investigating the novel agent ixazomib versus placebo in the maintenance setting.

Lastly, in elderly, less fit patients, Dr Willis explained that it is important to stage the malignancy and stage the age. The concept of treating based on fit versus unfit versus frail categories and tailoring the treatment accordingly was also discussed.

The VISTA trial (NCT00111319), which established the standard of care in the UK, investigated bortezomib plus melphalan-predisone (VMP) compared to melphalan-predisone (MP). The results demonstrated that VMP was superior MP to in newly diagnosed patients eligible for high-dose therapy. Notably, VMP showed a substantial complete response rate in patients over 65 years old.⁹ The Alycone trial (NCT02195479) which looked at the effect of adding daratumumab to the VMP triplet has shown a 50% lower risk of disease progression or death when compared to VMP alone in patients with newly diagnosed MM who are ineligible for ASCT.¹⁰

Dr Willis concluded that for this population it is important to balance the patient’s quality of life, with the toxicity of treatment and hoped that future trials, tailored to the frail population, will find more appropriate treatment regimens.

The second talk within the session came from Dr Matthew Jenner, University Hospital Southampton NHS FT, who spoke about relapsed/refractory (RR) myeloma and how to select the appropriate treatment for the individual. Dr Jenner identified the three main of objectives in myeloma treatment as efficacy, tolerability and simplicity and explained that, over time, relapse is associated with diminishing duration and depth of response. In the RR setting, new mechanisms of action have been identified that have markedly expanded the treatment options available to these patients.

Explaining the principle of clonal competition, Dr Jenner explained that a patient with high-risk cytogenetics may have multiple subclones, competing for dominance, leading to relapse when only one sensitive clone is suppressed, allowing a refractory clone to become proportionally more dominant. Therefore, combination therapies in high-risk MM patients targeting all coexisting disease subclones are important, as is early effective treatment.¹¹

Dr Jenner explained that triplet regimens, incorporating a novel agent such as ixazomib or elotuzumab, to traditional doublet regimens, such as lenalidomide and dexamethasone, showed improved PFS when compared with doublets in the RRMM setting in the phase III trials: TOURMALINE-MM1 (NCT01564537), ASPIRE (NCT01080391), ELOQUENT-2 (NCT01239797) and POLLUX (NCT02076009), PANORAMA-1 (NCT01023308) and CASTOR (NCT02136134).^12–17 It was noted that these triplet therapies must have minimal cumulative toxicity so that patients can tolerate the treatment long-term. Dr Jenner discussed the factors that affect a patient’s decision to take a certain treatment within the RR setting, which included the severe side effects, method of administration, average survival time, and frequency of administration.

Dr Jenner emphasized the difficulties faced by treating physicians in the UK when selecting treatments due to the numerous authorizing bodies and concluded by stating there should be a balance between tolerability and efficacy when treating RRMM patients.

The afternoon sessions from Dr Simon Stern, Dr Olwen Westerland, Dr Jenny Bird, Ms Julie Watson and Professor Sam Salek, are covered in a separate article published here on the topics of Practical Management and Improving Patient Outcomes.