Impact case study database

Worldwide incidence of MM is currently 160,000, and mortality is 106,000. In the UK, there are around 5,800 new myeloma cases every year, with incidence rates projected to rise by 11% between 2014 and 2035, to 12 cases per 100,000 people. The introduction of ASCT to support high-dose melphalan in patients with MM in the 1980s represented a step change in the management of this disease, with randomised trials confirming its clinical use to be better than conventional chemotherapy in terms of progression-free and overall survival. Consequently, the procedure is regarded as standard care for the treatment of patients with newly diagnosed MM up to the age of 65–70 years without significant comorbidities. The incorporation of novel drugs (thalidomide, bortezomib, and lenalidomide) into the first-line management strategy during induction, consolidation, or maintenance in the past 15 years has further contributed to improving patient outcomes. However, for the vast majority of patients, cure remains elusive and the disease will eventually relapse.

The NCRI-badged UK Myeloma Forum Myeloma X trial, designed and delivered by Leeds researchers (Cook, Brown and Cairns) is the only global, prospective interventional study in this setting, and demonstrated a superior durability of response (time to progression and progression-free survival) when sASCT is used compared to non-transplant consolidation [ 2, 3].

Furthermore, Myeloma X showed the durability of response is maintained in the subsequent line of therapy (time to second objective disease progression), and demonstrated a superior survivorship advantage [ 3]. This provides the first, and only, randomised evidence to suggest a survivorship benefit for sASCT [ A], with no significant influence being inferred by β2-microglobulin at relapse and age, though adverse molecular markers continue to show poorer response [ 4]. Myeloma X demonstrated that this survivorship advantage is not at the expense of quality of life measurements [ 6].

Inclusion in national guidelines increases uptake and improves patient outcomes

The trial output has delivered the necessary prospective evidence in an up-to-date clinical treatment scenario to demonstrate the clinical effectiveness of sASCT in first relapsed MM. Consequentially, the study has informed the recommendations of national guidelines in the UK. A sASCT is considered ‘standard’ by the British Society of Blood and Marrow Transplantation (BSBMTCT) Indications Committee [ B], and has been approved and recommended by the National Institute for Health and Care Excellence [ C].

Updates to the UK Myeloma Forum guidelines on the diagnosis and management of multiple myeloma, produced on behalf of the British Committee for Standards in Haematology in 2014, reflected our trial outcomes on the clinical utility of sASCT, with Cook a contributing author for both the original guideline and amendment [ D].

This has resulted in MM being the first disease group to have the baseline commissioning policy approval for sASCT in first relapse by NHS England (and devolved governments). This, in turn, has led to a change in clinical practice, with recorded increase in the number of patients undergoing sASCT in the UK (from 160 per annum in 2012 to 293 per annum in 2019) [ E].

The MM care pathway is multi-faceted, and continually evolving, but sASCT is a recognised clinical utility. The survivorship of patients is the culmination of all treatment lines but Myeloma X has shown that use of sASCT has a positive impact on survivorship. Real-world outcomes in 50-69 year olds eligible for sASCT, show a 2.3% point improvement in the 50-59 age group at 5 years from diagnosis, and a 4% improvement in the 60-69 age group [ F]. This is the effect of several evolutions in clinical care but includes the impact of sASCT, and is not related to the impact of the (very) recently adopted monoclonal antibody therapy (daratumumab).

Sole global data on sASCT for relapse MM leads to adoption in international guidelines

The Myeloma X trial results have been pivotal to formulating the recommendations for international guidelines. The International Myeloma Working Group (IMWG) emerged through the International Myeloma Foundation in order to promote collaborative research, and reach consensus for guidelines. Together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation (ESBMT), IMWG produced guidelines that included our recommendations [ G].

The Deputy Division Head of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, who co-led the guidelines, said:

*“Dr Cook and his colleagues from Leeds University have been instrumental not only in filling the knowledge gap, but in encouraging others to study this important and potentially more cost-effective strategy for remission consolidation in patients with myeloma failing primary therapy [ H].”*

These guidelines have led to increased uptake of sASCT into routine clinical practice as a standard of care in the United States since 2015, with the Leeds research having a:

“direct impact on the improved survival of multiple myeloma patients” [ I].

It is estimated that 100 patients a year in the US have benefitted from this treatment [ H]. Similar benefits have been reported in France and other European countries [ J].

Our trial results have also been adopted in the American Society of Clinical Oncology and Cancer Care Ontario joint clinical practice guideline on the treatment of MM [ K], and incorporated into a ESBMT report addressing the issue of myeloma treatment relapse options following a previous autologous transplantation, where it recognised the Leeds research as:

*“offering a dataset on which to base clinical decision making [ L].”*

The consequence of this research is shown through real-world evidence demonstrating increased uptake of sASCT into routine practice as a standard of care as a consequence of presenting and publishing the results (BSBMT and ESBMT registries). Taken together, the results of this study are already having an impact on the clinical management pathway in myeloma and helping the decision-making process for both physicians and myeloma patients.