Blood cancers

Another CD38 directed therapy shows promise in MM – but will Aussies benefit?

Isatuximab continues to show promise as a standard of care therapy for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitors, according to a two-year, follow-up analysis of the ICARIA-MM study

However the CD38-directed monoclonal antibody may find it difficult to make its mark in the Australian setting any time soon.

The study, published in The Lancet Oncology, compared isatuximab plus pomalidomide and low-dose dexamethasone with pomalidomide-dexamethasone alone.

After a median follow-up duration of 35·3 months, PFS was significantly longer in the isatuximab than the control group (11.1 v 5.9 months; HR 0.60; p <0.0001).

However OS was not significantly different between the two groups given a lower than usual significance level (24.6 v 17.7 months; HR 0.76; p=0.028).

“Because the observed p value of 0·028 did not cross the prespecified stopping boundary of 0·0181, further follow-up for overall survival will continue and a final analysis of overall survival will be done after approximately 220 events,” the study said.

Patients in the control group who moved onto daratumumab therapy had a median OS of 19.9 months.

Fewer patients in the isatuximab group moved on to subsequent therapy after progression (60% v 72%) and median time to next treatment was longer in the isatuximab group (p <0.0001).

“Median progression-free survival on subsequent therapy or death was longer in the isatuximab group (105 [68%] of 154 patients had events) than in the control group (116 [76%] of 153 patients had events; p=0·020).”

Both the overall response and depth of response was higher in the isatuximab than control group.

Overall response rate with daratumumab as subsequent anti-myeloma treatment was lower for patients in the isatuximab group than in the control group.

“However, for patients who received daratumumab as the first line of subsequent therapy (nine patients in the isatuximab group and 46 in the control group), median progression-free survival on the first line of subsequent therapy was lower in the isatuximab group (2·2 months [95% CI 0·1–7·6] in the isatuximab group [six [67%] of nine patients who received subsequent daratumumab] vs 5·1 months [95% CI 3·8–10·5] in the control group [35 [76%] of 46 patients who received subsequent daratumumab],” the study said.

“This discrepancy was not seen when daratumumab was used in combination with a proteasome inhibitor or immunomodulatory agent, raising the question of whether becoming refractory to anti-CD38 therapy can be overcome with additional therapies.”

Professor Miles Prince, one of the study co-authors, told the limbic there was a question of where isatuximab would fit in the Australian armamentarium – if approved – given daratumumab has become front line therapy.

“So this is only going to be useful for patients who have missed that opportunity, who are currently onto their second line treatment and going forward.”

“It would be great to have this drug approved albeit it’s probably only going to be valuable to a limited number of patients who haven’t had daratumumab previously.”

Professor Prince, Director of Molecular Oncology and Cancer Immunology at the Epworth Hospital, said negotiating a cost effective price would be difficult.

“I would be deeply disappointed to see patients miss out but I think that is the likely scenario. I personally believe it is going to be extremely challenging for Sanofi to get isatuximab approved in the current PBAC environment.”

The study found the safety profile of isatuximab in the follow-up period was similar to that observed in the initial analysis with infusion reactions, upper respiratory tract infectious and diarrhea as the most common adverse events.

The most frequent grade 3 or worse TEAEs in the isatuximab versus the control group were neutropenia (50% v 35%), pneumonia (23% v 21%), and thrombocytopenia (13% v 12%).


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