Precision or personalised medicine entails managing an individual patient according to their own tumour biology and/or risk profile. The aforementioned section on MRD provided examples of MRD directed therapeutic approaches, however, this can be taken further with therapies selected based on the presence of specific tumour mutations, GEPs, proteins etc. Since the MAPK pathway can be dysregulated due to activating mutations in NRAS, KRAS or BRAF in 40–50% of MM patients, the BRAF inhibitor vemurafenib has been investigated in BRAF V600E-positive RRMM patients, with durable responses reported120. Similarly, over half of the patients with RAS-mutated MM treated with the MEK inhibitor trametinib experienced at least a 25% reduction in paraprotein although many responses were short lived, especially when the drugs were used as single agents121. FGFR3, together with MMSET/WHSC1, is overexpressed in 10–15% of MM patients due to the t(4;14) translocation, however first generation FGFR inhibitors have demonstrated limited efficacy122. The recent discovery of activating FGFR3 mutations in a third of t(4;14) cases has, however, renewed interest in novel FGFR inhibitors targeting FGFR3-mutated MM123,124. Similarly, the identification of activating alterations in IDH1/2 and NTRK1/2/3 makes them interesting as potential candidates for precision medicine trials in MM125,126.
Clinical trials with novel therapies have in some cases revealed molecular sub-groups of patients highly sensitive to specific drugs. For example, single agent and combination trials with venetoclax (ABT-199), a small molecule inhibitor of Bcl-2, have consistently demonstrated superior PFS in patients with RRMM harbouring t(11;14) and related increased expression of Bcl-2 gene and protein127. AMG-177 and AZD5991 inhibitors against anti-apoptotic molecule Mcl-1, the most frequently expressed Bcl-2 family member, are also undergoing clinical evaluation. Given Mcl-1 resides on chromosome 1q, which is frequently amplified in MM, it will be interesting to see whether the new Mcl-1 inhibitors achieve responses in this and other molecular sub-groups of MM patients. Finally, translocations resulting in MYC overexpression have been detected in approximately 15% of MM cases and novel approaches aimed at targeting this transcription factor are being tested clinically128.
Traditional clinical trials are not optimal for the rapid evaluation of precision medicine approaches. Recently, integrated platform trials known as master protocols have been developed to facilitate the simultaneous and rapid testing of multiple treatments in the same trial129. An example is the MMRF Myeloma-Developing Regimens Using Genomics (MyDRUG) study (NCT03732703). This is a Phase I/II trial master protocol designed to develop novel precision medicine combinations for patients with high risk MM whose disease has rapidly progressed in spite of standard-of-care therapies. Genomic alterations that can be therapeutically targeted are being identified with study arms for individuals with RAS/RAF mutations, CDK activating alterations, FGFR3 and IDH2 mutations, as well as t(11;14) translocations. Patients without these genetic aberrations receive an immunotherapy (daratumumab) and all patients receive a backbone of ixazomib, pomalidomide and dexamethasone (IPd). However, a major problem for precision medicine approaches is that of tumour clonal heterogeneity69. Specifically, therapy targeting molecular aberrations present in only a subset of MM cells might not achieve clinical benefit and may result in the rapid growth of sub-clones. With regard to the MyDRUG trial, the genetic lesion being targeted must be present in a relatively large proportion of the MM cells, having an allelic fraction > 0.3.
Despite these advances, a number of obstacles remain. Precision medicine MM drugs will require appropriate companion diagnostic tests to detect the targetable lesions, however, assay availability and cost remain barriers. The FDA recently approved the MSK-IMPACT™ and FoundationOne CDx™ panels which will hopefully help to accelerate reimbursement for clinical sequencing. Moreover, assays need to be developed to detect functional changes such as signalling pathway activation rather than only the presence or absence of a genetic or protein lesion. Additionally, bone marrow biopsies in MM are limited in their ability to fully represent the genetic heterogeneity of the disease. As discussed previously, liquid biopsies are emerging as promising tools in MM to satisfy the requirements of precision medicine approaches, however, much work is needed to optimise this methodology for use clinically91. Finally, in recent years new immunological treatments including anti-CD38 and anti-SLAMF7 monoclonal antibodies have become available4,130. B-cell maturation antigen is currently being investigated clinically through a variety of Chimeric Antigen Receptors (CARs), T-cell engagers and monoclonal antibody therapeutics, however, reliable methods to evaluate a patient’s immune system are not available, which is frequently deranged in MM patients, particularly those heavily pre-treated. Immune profiling will therefore be essential to match patients with the appropriate combinations of targeted and/or immune-based therapies.