Therapeutics: isatuximab for multiple myeloma

Despite the advances in treatment that have been made in recent years, multiple myeloma blood cancer remains incurable

Patients who initially have a response all too frequently relapse, with disease that is refractory to current therapies.

Sanofi has developed a monoclonal antibody, isatuximab, which has the potential to improve the prospects of multiple myeloma patients. It binds to the CD38 receptor, which is highly expressed on multiple myeloma cells, inducing apoptosis.

In an open label, dose escalation Phase Ib trial, 57 patients with relapsed or refractory multiple myeloma were given weekly doses (10 or 20 mg/kg) or 3, 5 or 10 mg every other week, in combination with lenalidomide (25 mg) for days 1–21 and weekly doses of dexamethasone.1

The median duration of dosing was 36 weeks. It was generally well tolerated and the maximum tolerated dose was not reached.

The most common antibody related adverse events were infusion-associated reactions. In the evaluable population, the overall response rate was 56% and 52% in lenalidomide-refractory patients. The overall median progression-free survival was 8.5 months.

A randomised, multicentre, open label Phase III study has also been done in 307 patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor, but had not previously been found to be refractory to an anti-CD38 monoclonal antibody.2

Subjects were given either weekly isatuximab (10 mg/kg) for the first 4 weeks then 2-weekly, plus 4 mg of pomalidomide biweekly and 40 mg of dexamethasone weekly (20 mg if they were older than 75), or just the pomalidomide/dexamethasone combination.

The median progression-free survival with the antibody was 11.5 months and 6.5 months without. The most frequent treatment-emergent adverse events were infusion reactions, upper respiratory tract infections and diarrhoea.

Another Phase III trial is under way with the antibody being dosed alongside carfilzomib and dexamethasone in more than 300 patients.3

It is also being investigated as a monotherapy, showing promise in a Phase I dose escalation and expansion trial in 84 patients with relapsed or refractory multiple myeloma.4

There was an overall response rate of 24% in patients given at least 10 mg/kg, including one complete response. The median duration of response was 25 weeks for high risk patients and 36 weeks for others.

References

  1. T. Martin, et al., Blood 129, 3294 (2017).
  2. M. Attal, et al., Lancet 394, 2096 (2019).
  3. P. Moreau, et al., Future Oncol. 16, 4347 (2020).
  4. T. Martin, et al., Blood Cancer J. 9, 41 (2019).

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