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In early July 2017, Merck announced that the US Food and Drug Administration (FDA) has put a complete clinical hold on two multiple myeloma trials testing its drug Keytruda (pembrolizumab) in combination with established therapies pomalidomide or lenalidomide. The decision comes after a review of the data by independent safety monitors found more deaths in the pembrolizumab groups than the controls. A third myeloma trial, in which one treatment arm received pembrolizumab plus lenalidomide, has been placed on partial hold.
It is unclear at the moment why these particular drug combinations appear to be unsafe. But this approach — combining new agents with established therapies to treat multiple myeloma — has had unprecedented success over the past decade.
Pembrolizumab is an immuno-oncology drug targeting the PD-1 protein on the surface of T cells. It was approved in September 2014 for the treatment of melanoma and has since been approved for use in a number of other cancers. Merck is still testing pembrolizumab in other cancer populations.
Multiple myeloma is a relatively rare cancer affecting bone marrow cells. It is diagnosed in about 4,900 people in the UK each year
[1]
. Myeloma cells rapidly divide and mutate, and there are often several subclones present at any time, which makes combination treatments particularly effective.
Findings from a retrospective study conducted by researchers at the Mayo Clinic showed that median overall survival improved by almost one-third for patients diagnosed between 2006 and 2010 compared with those diagnosed between 2001 and 2005. The researchers attributed the increased survival rate, at least in part, to the introduction of two new drugs, lenalidomide and bortezomib.
Because the current clinical approach is to try patients on new drug combinations when their disease progresses, it is hard to evaluate overall survival under any particular drug regimen. But the trend in increased survival has almost certainly continued, with new combinations regularly increasing progression-free survival in trials.
For example, panobinostat, the first histone deacetylase inhibitor to be approved for the treatment of multiple myeloma, was shown in a phase III trial to increase progression-free survival by almost four months when combined with the established treatment regimen of bortezomib and dexamethasone[2]
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This survival increase may seem small. And, when weighed up against the cost of the entire drug regimen, as evaluated by the UK drug and technology appraiser National Institute for Health and Care Excellence (NICE), many of these drugs struggle to get approval in the UK. But for patients, cumulative benefits from different therapies add up.
The reasons behind the increased mortality seen in the halted pembrolizumab trials should be investigated, and lessons learnt. However, this should not deter pharmaceutical companies or researchers from pursuing further combination therapies to treat multiple myeloma. For many patients, this approach remains their best hope.
References
[1] Kumar SK, Dispenzieri A, Lacy MQ et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014;28;1122–1128. doi: 10.1038/leu.2013.313
[2] San-Miguel JF, Hungria VT, Yoon SS et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014 Oct;15(11):1195–206. doi: 10.1016/S1470-2045(14)70440-1
