What The Princess Bride Teaches Us About Outcomes in Multiple Myeloma
Mené sur 360 et 362 patients atteints d'un myélome multiple réfractaire ou récidivant, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout du ixazomib à un traitement combinant lénalidomide et dexaméthasone (durée médiane de suivi : 85 mois)
In the article that accompanies this editorial, Richardson et al1 present long-term follow-up on the phase III TOURMALINE-MM1 trial and report no improvement in overall survival (OS) for the three-drug combination, ixazomib-lenalidomide/dexamethasone (I-Rd), over the two-drug combination, placebo-Rd. On the surface, this looks like a negative finding, a failure, and that we have gone backward in our rush toward novel combinations of drugs with our goals of gaining synergy and improving outcomes. But this is where Vizzini and his famous exchange with Inigo Montoya in the 1987 classic film The Princess Bride2 come to play. “It's inconceivable,” says Vizzini. Having heard this claim three times only to be confronted by alternate realities, “I don't think that word means what you think it means,” responds Inigo. So how, you may ask, does this relate to multiple myeloma (MM)?
Twenty years ago, it was inconceivable that the median OS for a patient with myeloma would be in excess of 10 years, yet that is where we are in the field using modern myeloma therapy.3 Twenty years ago, it was inconceivable to consider alkylator-free induction regimens for fit or frail patients, yet it has become all but routine to use induction therapy regimens that do not use this class of agents. Twenty years ago, it was inconceivable that postrelapse outcomes could be nearly as long as initial responses and that the results of phase III trials could be confounded by postsalvage therapies including new agents such as daratumumab and carfilzomib and even access to B-cell maturation antigen–directed treatments. Yet this is what we see in the phase III TOURMALINE-MM1 trial.
In the article that accompanies this editorial, Richardson et al1 report that with a median follow-up of over 7 years, the median OS was not different by treatment arm, 53.6 months for I-Rd versus 51.6 months for placebo-Rd (hazard ratio [HR], 0.939; 95% CI, 0.784 to 1.125; P = .495). No difference in OS by treatment arm was seen in prespecified subgroups including patients with del(17p), high-risk cytogenetics, expanded high-risk cytogenetics, standard-risk cytogenetics, receipt of two to three prior therapies, refractoriness to prior line of therapy, or International Staging System stage III at study entry. Importantly, no difference in treatment exposure, safety, or quality-of-life improvements or side effects to treatment was noted. Exploratory ad hoc analysis of OS according to subsequent therapy on the basis of next line of treatment including receiving subsequent daratumumab or not also did not show difference by treatment group.
Journal of Clinical Oncology , éditorial en libre accès, 2020