J&J gets a smouldering endorsement

An FDA advisory committee on Johnson & Johnson/Genmab’s subcutaneous Darzalex in smouldering multiple myeloma was expected to be contentious, but in the event the drug sailed through, with a 6-2 vote in favour of its benefit-risk profile here.

Ahead of the meeting there had been questions about whether the drug should be given to people with a typically asymptomatic disease precursor, but the anti-CD38 MAb now looks likely to add this use to its already extensive label. One remaining unknown might be which smouldering myeloma patients will actually get the drug, should it be approved.

There are also questions about the sequencing of therapy, specifically whether smouldering myeloma patients who receive Darzalex and then progress to full-blown disease would respond to subsequent Darzalex, a mainstay of first-line multiple myeloma therapy.

Aquila

5,000 people are diagnosed with smouldering multiple myeloma in the US each year, but J&J is aiming at high-risk disease, which only affects around 2,000 people per year – and of these, only around half will progress to full-blown myeloma within two years.

While Aquila, the study that supported the smouldering myeloma submission, purportedly enrolled high-risk patients, less than half were classed as high risk based on current criteria, according to FDA slides presented during the adcom on Tuesday.

This raises questions about the definition of high-risk disease, and how patients might be selected in the real world. The Aquila investigators have noted that criteria for high-risk smouldering multiple myeloma were based on data available at the time the trial started, and that the definition had since evolved. 

Aquila found a 51% reduced risk of progression or death, the primary endpoint, with Darzalex versus the control group, who underwent watchful waiting (p<0.001). The data featured at last year’s ASH meeting.

Still, the FDA noted that, in terms of progression events, the number of deaths between the two arms was similar, with most events being progression in laboratory parameters. 

Aquila also showed a trend towards an overall survival benefit, with a hazard ratio of 0.52, but a broad confidence interval of 0.27-0.98. However, the FDA flagged a “marginal difference” between the arms at five years, as well as “lack of sufficient information” on the cause of deaths, raising doubts about any apparent survival benefit. 

Sequencing?

J&J has also highlighted PFS after first-line multiple myeloma therapy – known as PFS2 – where the hazard ratio between groups was 0.58. However, according to the FDA, PFS2 wasn’t significantly different between arms, and in any case was confounded by the fact that around 20% of patients didn’t receive therapy at the time of their multiple myeloma diagnosis. And less than 20% received Darzalex-containing first-line therapies.

This leads to questions about the sequencing of therapies – particularly as, the FDA noted, it’s unclear how Darzalex therapy for smouldering myeloma might affect the response to subsequent anti-CD38 drugs.

This could soon be something for doctors to unravel, if the FDA follows the advice of its panel. J&J hasn’t disclosed the PDUFA date for Darzalex in smouldering multiple myeloma, but it submitted Aquila to regulators in November, so a decision is expected soon.