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An important part of the immune system is its ability to tell between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells while leaving the normal cells alone. To do this, it uses “checkpoints” – molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints hold a lot of promise as cancer treatments.

Checkpoint inhibition is emerging as an important immunotherapeutic approach in myeloma. Many inhibitors are monoclonal antibodies which target normal proteins on tumour cells or the proteins on the T cells that respond to them (receptors). These checkpoint proteins or their receptors normally act as a brake on the immune response and can keep T cells from recognising myeloma cells: blocking checkpoint proteins such as PD-L1 or their receptors such as PD-1, allows T cells to recognise and destroy myeloma cells.

Figure 2 provides a simplified schematic overview of how checkpoint inhibitors enhance the capacity of the immune system to recognise and combat myeloma cells.

Figure 2A schematic overview of how checkpoint inhibitors enhance the immune response

Pembrolizumab (Keytruda®)

Pembrolizumab is a checkpoint inhibitor immunotherapy and specifically an anti-PD-1 monoclonal antibody. Early data shows that as a monotherapy, pembrolizumab has little impact but when combined with other anti-myeloma treatments such as IMiDs or other monoclonal antibodies (daratumumab, elotuzumab), it produces good responses even in multiply relapsed patients.

Several trials of pembrolizumab in various combinations are investigating its use in the newly diagnosed and relapsed and/or refractory settings. It is also being investigated in smouldering myeloma patients. However recently, the FDA has placed on hold the KEYNOTE clinical trials using pembrolizumab in combination with IMiDs (KEYNOTE-183, KEYNOTE-185 and KEYNOTE-023), due to reports of deaths within the trial groups. Other trials using pembrolizumab are not affected.

Further reading

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