Isatuximab another string in the bow for management of RRMM

This article was originally posted on The Limbic

Addition of isatuximab to carfilzomib–dexamethasone has been hailed “a new standard of care” for patients with relapsed multiple myeloma.

The anti-CD38 monoclonal antibody is already approved in combination with pomalidomide and dexamethasone in many countries for relapsed and refractory multiple myeloma.

The phase 3 IKEMA trial comparing isatuximab plus carfilzomib–dexamethasone versus carfilzomib–dexamethasone found the addition of isatuximab improved progression-free survival and depth of response.

The international study, published in The Lancet, comprised 302 patients from 16 countries including Australia. Patients had previously received one to three previous lines of therapy and had measurable serum or urine M-protein.

“At a median follow-up of 20·7 months (IQR 19·4–22·1), the addition of isatuximab to carfilzomib–dexamethasone showed a significant improvement in progression free survival (IRC assessment) with an HR of 0·53 (99% CI 0·32.”

“At 2 years, estimated progression-free survival was 68·9% (95% CI 60·7–75·8) in the isatuximab group versus 45·7% (35·2–55·6) in the control group.”

The study found the addition of isatuximab to carfilzomib and dexamethasone also lead to an improved depth and quality of response.

More patients in the isatuximab group had very good partial response (73% v 56%), complete response (40% v 28%), minimal residual disease negativity (30% v 13%), and complete response with minimal residual disease negativity (20% v 11%).

Median time to first response was similar in both groups (32 v 33 days) however duration of response was longer in the isatuximab group than the control group (HR of 0·43), as was time to next treatment (HR 0.57).

“Specifically, the rates of MRD negativity and complete response with MRD negativity in the isatuximab group are very high considering these patients had a median of two previous lines of treatment,” the study said.

The investigators, including Professor Ross Baker from the Perth Blood Institute, said a benefit in progression-free survival was seen in almost all subgroups, including patients with high-risk cytogenetics, ISS stage III at study entry, patients aged 65 years or older, patients with renal impairment, and previous exposure to an immunomodulatory drug (including patients refractory to lenalidomide in last previous regimen).

There was a high rate of treatment-related adverse events (TEAEs) in both groups, most commonly infusion-related reactions, hypertension, diarrhoea, and upper respiratory tract infection.

More grade 3 or worse respiratory infections occurred in the isatuximab group than controls but these did not lead to more fatal infections or treatment discontinuations.

Similarly, isatuximab was not associated with more serious TEAEs, fatal TEAEs, or TEAEs leading to definitive treatment discontinuation.

“Taken together, these results show that isatuximab plus carfilzomib–dexamethasone is a new standard of care for patients with relapsed multiple myeloma,” they concluded.

Comment article in the journal agreed that the results support the use of isatuximab with carfilzomib–dexamethasone as a new standard of care in this patient group.

“Although many therapeutic options are available in this setting, treatment algorithms for the growing populations of patients exposed to bortezomib and refractory to lenalidomide upfront, or who are refractory to both these agents (known as double refractory) still need further refinement,” it said.

“The recent introduction of monoclonal antibodies into first-line and subsequent lines of myeloma therapy has been coupled with the challenging management of patients refractory to three classes of drugs. Although drug–conjugate monoclonal antibodies and T-cell redirecting therapies might be the right answer for these patients, the development of novel treatment strategies continues to be a key priority in myeloma research.”

The IKEMA study was funded by Sanofi.

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