EHA 2016: Preventing clonal evolution in multiple myeloma – evidence from clinical trials. Professor Roman Hájek from the Czech Republic discussed the clinical implications of clonal evolution in multiple myeloma (MM) and summarised the latest clinical data.

Preventing clonal evolution in multiple myeloma – evidence from clinical trials

by Maria Dalby

Professor Roman Hájek from the Czech Republic discussed the clinical implications of clonal evolution in multiple myeloma (MM) and summarised the latest clinical data. Professor Hájek reminded the audience that MM is a complex disease that as it progresses from monoclonal gammopathy of unknown significance (MGUS) via smouldering myeloma to active MM requiring treatment, the disease shows increasing genetic instability in the form of copy abnormalities, DNA hypomethylation and acquired mutations.^{1, 2} Several genetically distinct subclones are present at diagnosis;^3-6 factors, such as treatment, cause these subclones to evolve over time and this clonal evolution can lead to disease progression and treatment resistance.^{3, 6, 7} Not only does clonal heterogeneity in MM look different at different stages of the disease,⁷ but it will also vary depending what site the bone marrow is collected from.⁸

 

The main clinical implications of clonal evolution in MM are that treatment should be initiated at an early stage of the disease where there is less genetic instability and fewer clones, and that both newly-diagnosed and relapsed MM should be treated with combination therapy with agents with different mechanisms of action.^{4, 6, 9} The place for targeted/personalised therapy and monotherapy should be eradicating residual disease, not the start of treatment.⁹ The results of randomised controlled trials (RCTs) show consistently that triplet therapy prolongs progression-free survival (PFS) compared with doublet therapy in patients with up to three prior lines of therapy^10-16 and in newly-diagnosed patients.^17-20 In particular the monoclonal antibodies elotuzumab and daratumumab have demonstrated impressive PFS benefits when added to lenalidomide plus dexamethasone^{13, 15} and bortezomib and dexamethasone,^{14, 21} respectively. A meta-analysis of five RCTs comparing triplet with doublet therapy that was presented at this year’s American Society Of Clinical Oncology (ASCO) annual meeting showed that the pooled odds ratios (OR) for triplets versus doublets were 2.325 for complete response (CR) or better (p<0.000); 1.962 for very good partial response (VGPR) or better (p<0.001); and 1.811 for the overall response rate (ORR; p<0.000). A pooled hazard ratio for PFS of 0.674 was found in favour of triplet therapy (95% CI 0.613, 0.741; p=0.000).²² As expected the risk ratio of overall and selected grade ≥3 adverse events was higher in the triplet arm.

 

Sequencing or alternating agents with different mechanisms of action may be an alternative to combination therapy in frail patients. A recently published phase 2 study in 233 patients aged over 65 years compared 9 cycles of of bortezomib, melphalan and prednisone (VMP) followed by 9 cycles of lenalidomide and dexamethasone (Rd; sequential use) with alternating administration of 1 cycle of VMP followed by 1 cycle of Rd for up to 18 cycles (alternating use). No significant differences were seen between the two arms in complete response rate (42% and 40%), median PFS rate (32 months vs 34 months), and 3-year overall survival (72% vs 74%), with similar haematological and non-haematological toxicity profiles.²³ Another potential strategy is continuous therapy which has been shown to prolong the time to both first and second progression and overall survival in patients with newly-diagnosed MM.²⁴ Professor Hájek concluded by stressing that understanding clonal evolution in MM is essential for selecting treatment strategies that can target coexisting subclones in a synergistic way and thus achieve a deeper response.

 

References

 

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