Treatment Advances in Myeloma Necessitate More Sensitive Techniques
All stakeholders in medicine – patients and their physicians, the companies that make drugs, regulators – must contend with the tension between wanting to have new therapies available as quickly as possible, while at the same time requiring that proper investigations be done to ensure that the new therapies are safe and effective.
One way new medicines are sped to the clinic is the FDA’s accelerated approval pathway, which allows for the approval of a medicine based on a surrogate endpoint (sometimes referred to as a surrogate marker) that is a likely predictor of clinical benefit. In myeloma, one of the surrogate endpoints used for accelerated approval has been response rate – the percentage of patients experiencing a complete or partial reduction in tumor burden. But with each new approval, the response rate gets pushed higher and higher, especially when combinations of drugs are used. The time has come for us to change our definition of response, so that we can continue to evaluate ever-more powerful regimens and get patients to the lowest levels of disease possible, which we know will translate into better outcomes.
The FDA and numerous pharmaceutical and biotech companies have set their sights on minimal residual disease (MRD) evaluation as a new method for measuring deeper response rates. MRD is the small number of cancer cells that may remain in a patient’s body after treatment and can eventually cause the cancer to return. As therapies have become increasingly effective, MRD testing – which can detect disease at levels much lower than possible with conventional assessment methods and has been shown to predict both progression-free survival (PFS) and overall survival (OS) in multiple clinical contexts – can differentiate between medicines with similar response rates, potentially distinguishing whether one treatment is more effective than another.
The difference between complete response (CR) as traditionally defined and what I’ll call “MRD-response” has been shown in multiple studies. Patients who are in CR but are MRD-positive have worse outcomes than patients who are also in CR but are MRD-negative. And within the category of “MRD-negative”, it’s been shown that how low you go matters. Most studies to-date have set the threshold for MRD-positivity at 10-4 (1 myeloma cell per 10,000 white blood) cells due to the technical limitations of the most often used techniques, flow cytometry and allele-specific oligonucleotide PCR (ASO-PCR). However, we’ve shown using our next-generation sequencing-based MRD test that patients with MRD levels between 10-4 and 10-6 (1 myeloma cell per one million white blood cells, the limit of the MRD test) have worse prognosis than those with MRD less than 10-6.1-11
It’s an exciting time to be part of the myeloma field. Things are moving quickly and in the right direction. But I know that for the patients that have this serious disease, and the people who care about them, new developments cannot come quickly enough. For us here at Adaptive, it’s gratifying to know that our immunosequencing technology and its application to MRD testing for myeloma and other lymphoid malignancies may help speed things along.
Adaptive Biotechnologies and its collaborators will share data from the IFM/DFCI 2009 trial, in an oral presentation at the ASH Annual Meeting, demonstrating NGS-based MRD prediction of outcomes supports its potential as a surrogate endpoint in clinical trials.
1Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079.
2 Ferrero S, Ladetto M, Drandi D, et al. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015;29(3):689-695.
3Landgren O, Owen RG. Better therapy requires better response evaluation: Paving the way for minimal residual disease testing for every myeloma patient. Cytometry. Part B, Clinical cytometry. 2015.
4Mailankody S, Korde N, Lesokhin AM, et al. Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nature reviews. Clinical oncology. 2015;12(5):286-295.
5Paiva B, Puig N, Garcia-Sanz R, San Miguel JF. Is This the Time to Introduce Minimal Residual Disease in Multiple Myeloma Clinical Practice? Clinical cancer research: an official journal of the American Association for Cancer Research. 2015;21(9):2001-2008.
6Paiva B, van Dongen JJ, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2015;125(20):3059-3068.
7Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023.
8Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia. 2014;28(2):391-397.
9Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013;31(20):2540-2547.
10Rawstron AC, Davies FE, DasGupta R, et al. Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood. 2002;100(9):3095-3100.
11Putkonen M, Kairisto V, Juvonen V, et al. Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. European journal of haematology. 2010;85(5):416-423.