Multiple myeloma is a clonal, late B cell malignancy that comprises about 10% of haematological malignancies. Clinically the disease is well-characterized: a premalignant phase is followed by monoclonal gammopathy of uncertain significance, then progression through asymptomatic and symptomatic multiple myeloma, often culminating in an aggressive disseminated form, plasma cell leukaemia. Like all cancers, multiple myeloma is a disease of the genome and at this level it is highly heterogeneous: marked differences are evident between individuals. Crucially, the disease is genetically unstable in a given individual; the rise and fall of clones and subclones within a patient's tumour burden, driven by the selection pressure of sequential therapies, is key to the eventual, inevitable refractory relapse that still characterizes this disease for most. Multiple myeloma, then, is not one disease but many, and must be treated accordingly.
What is precision medicine in multiple myeloma?
Good medicine has always been 'personalized' in the sense of taking a holistic account of the patient and the comorbidities and circumstances of the disease. The evolution of personalized medicine, however, has enabled physicians and patients to make increasingly rational predictions about the behaviour of multiple myeloma in a given individual and choices about therapy. For example, the chromosomal translocation t(4;14) is known to confer an adverse prognosis, but therapy with a bortezomib-containing regimen has been shown to partially abrogate this effect.1
Precision medicine moves this approach on by targeting particular abnormalities, almost independently of the cancer in question. For example, serine/threonine-protein kinase B-Raf (BRAF) inhibitors are an effective therapy for malignant melanoma, 40–60% of which exhibit a BRAF mutation. Whilst this has not historically been considered an important driver mutation in multiple myeloma, whole genome sequencing approaches have found that 5% of multiple myelomas also harbour this abnormality; initial results of targeting the kinase in this subgroup are extremely promising.2 Precision medicine arises from the pairing of next generation diagnostics with an expanding arsenal of targeted therapies.
The key underpinning of a precision medicine approach to treating multiple myeloma is an understanding of the fundamental genetics and molecular biology of the disease. Over the last decade, techniques such as next generation sequencing, genome wide analysis, transcriptomics and proteomics have yielded enormous datasets describing multiple myeloma at both molecular and genetic levels. For example, in a key publication in 2011, Chapman et al.3 reported the massive parallel sequencing of 38 tumour genomes and their comparison with matched germline DNA. Importantly, this study identified a number of new and previously unsuspected oncogenic pathways including protein translation and histone methylation pathways, as well as the BRAF kinase mutations mentioned earlier. Sequencing studies such as these have cast an intense new spotlight on the inner workings of the myeloma genome, though they bring with them the challenges of huge datasets.4
Whilst whole genome and whole exome ...