All I want for Christmas is ethical, informative trials

Why the AQUILA trial is disappointing for patients and their loved ones

Recently, at the American Society of Hematology and concurrently published in the New England Journal was a randomized controlled trial of treating smoldering myeloma. The investigators congratulated themselves and said there's a new standard of care. But the reality is the trial has fatal flaws, and reflects the failures of our field.

Smoldering myeloma is an interesting disease. People who have it don't have any symptoms. They don't have any organ damage. In fact, the only way they know they have it is that the doctor drew blood, or did a bone marrow biopsy, or often both. It’s a classic example of the patient didn’t know he was sick, until the doctor said he was.

Most people with smoldering myeloma eventually developed multiple myeloma, but the time course can vary. Some people can smolder for years or decades. Although there've been lots of attempts to figure out who's at high risk, all these risk scores are imperfect. There are high-risk people who never progress— or don’t progress for decades.

Over the years, there have been many attempts to see if treating smoldering myeloma is better than waiting until myeloma develops and treating it then. In the 1990s, the studies failed to find and improvement in overall survival, and experts advocated against treatment.

In the last 10 years, there have been three studies. A Spanish study, which was severely underpowered, found a survival benefit to treating patients with smoldering. But when the control arm progressed, they did not get the best available care. They got old, antiquated, barbaric care. As such, the study only proves it's better to get modern therapy early rather than outdated therapy later, but that's not a question that faces doctors or patients.

Then there was an Eastern Cooperative Oncology Group study. It did test the right question of early treatment versus delayed treatment, but the problem was when the investigators saw that early treatment delayed progression, they crossed over the control arm.

In other words, people in both arms were exposed to treatment before they developed myeloma, so the study was uninformative. It was disappointing to see investigators make this protocol change, because the original secondary endpoint was overall survival and it would have answered the question.

Notably, many of these investigators consult for the pharmaceutical firms that benefit from treating early. Why does the industry benefit from early treatment? Well, it expands the patient population, and it expands the amount of time a person spends on therapy in their life. This grows the market share.

Enter the recent study. It's called AQUILA. It did one thing smart. The treatment that was tried for smoldering myeloma was one of the most tolerable treatments we have. A drug called Dara. Unlike the other studies in recent years, this is not a teratogen.

The study also looked at overall survival as a secondary endpoint. In the clinical trial publication, the paper is careful to present confidence intervals, but it does not actually provide a p-value and does not say that the survival was statistically significant. Yet some online claimed it was significant.

Note: for a clinical trial to report that survival is statistically significant it has to pre-specify at what point it's going to look in the data, and provide statistical test at that moment. This is different than just reporting the confidence interval around a point estimate.

The control arm of the study was careful observation, which is good. But the key question is if you developed multiple myeloma in the control arm, did you get the best available therapy? And the answer is no.

The treatments given in the control arm included some of the most barbaric and outdated treatments such as len-dex (alone), boretezomib-melfalan-pred, bortezomib-dex. These have not been standards for many years.

Worse, the study was funded by Jansen, the maker of Dara. If the academics who ran the study had courage, they could have negotiated that the company provided the study drug free of charge to all people in the control arm when they progress. This is the ethical and scientific thing to do. But they didn't do that. It looks like only 17% of people in the control arm ever got Dara.

Some argue that Dara was not a standard of care in frontline myeloma at the time this study ran. That's true, but Dara was a proven therapy that should be given to patients sometime in their disease course. And that didn't happen here. Worse, the authors don't report the data in a granular fashion that allows us to judge it perfectly.

The investigators designed the study in such a way that progressing to myeloma included criteria that patients don’t feel (so called SLIM criteria). Then progressing again included PET positive disease— again asymptomatic. In other words, you could “progress” twice in this study and still never feel a thing. Thirty years ago, you wouldn’t even have myeloma!

Here's the question: why do investigators agree to participate in studies that are not informative or ethical or both? Why didn't the authors of the study demand that Jansen provided dara to the control arm or they would not enter the trial?

Part of what makes a good doctor is advocating for patients who no one advocates for. In this case investigators faced a choice: they could either encourage the sponsor to pay for appropriate therapy for the control arm when they progressed, or not. By not doing so, they were much more likely to get a favorable overall survival estimate. By not doing so, they were more likely to earn the good graces of the sponsor and be more likely to be invited again to be the nominal pi of a study. By not doing so, they got another NEJM paper.

I think history will be unkind to these researchers. The arc of medicine always bends towards more informative trials. The investigators were aware of these criticism, and chose to ignore them. History is usually unforgiving to that error.

All I want for Christmas is ethical, informative cancer trials. Maybe some day, but not today.

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