VIDEO: Incorporating important multiple myeloma trial results into practice

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Yes, so again, as much excitement as we have in later lines of therapy in refractory disease, I'm actually also very excited about two front-line studies that were recently presented. The way we are approaching newly diagnosed myeloma is also changing. [Lenalidomide, bortezomib and dexamethasone (RVd)] followed by transplant for eligible patients, followed by maintenance, has been our standard of care for so long. Since the GRIFFIN study evaluating the addition of daratumumab to standard dara-RVd induction came out — and it's a phase 2 study, but the results were very promising — so many myeloma doctors started incorporating daratumumab [Darzalex, Janssen] into front-line therapy, and I, personally, have been treating the majority of my patients with dara-RVd in the past couple of years.

But now, we have data presented from the PERSEUS study, which is a phase 3 randomized study evaluating this novel induction regimen of dara-RVd compared to RVd standard. Over 700 of patients who were transplant eligible were randomized to dara-RVd versus RVd induction, followed by transplant, followed by dara-RVd versus RVd consolidation, and then daratumumab-lenalidomide versus standard lenalidomide maintenance. We have PFS data now presented, and it is very, very impressive. So, 48 months, 4 years PFS rate was significantly higher at 84% for dara-RVd versus 67% for RVd. So, we have 17% increase at 4 years PFS in the front-line therapy, and I think this is really clinically meaningful. Now, [minimal residual disease (MRD)], of course, was another endpoint in this study, and we really want to interpret MRD assessments in clinical practice as well, not just on the studies level. And so, 10 to the power of negative six MRD, which is really our benchmark now, was double, 65% in the dara-RVd group compared to 32% in the RVd group. And we know that deep MRD negativity does translate to longer and better outcomes. So, I think with these results, it's really practice changing and I think dara-RVd should be our new standard for newly diagnosed myeloma. And the benefit was maintained across all subgroups, too.

Now another study that is also looking at even more intensified front-line therapy of newly diagnosed myeloma is the IsKia study. It was presented at a plenary session at ASH. And this is a study of isatuximab [Sarclisa, Sanofi], which is another CD38 antibody just like daratumumab, in combination with carfilzomib [Krypolis, Amgen], lenalidomide and dex. This control arm of carfilzomib and dex.

So, it's [unintelligible] intensification, so quadruple therapy, including carfilzomib.

And the treatment consisted of four cycles of induction, followed by transplant, followed by four cycles of consolidation, and followed by what they called light consolidation, which was basically a maintenance with multidrug regimen. So, this study was presented with a primary endpoint of MRD negativity, and, again, it achieved very high rates of MRD negativity after consolidation of 67% in the treatment arm, compared to 48% in as a control arm. So here we so far only have the surrogate endpoint, and longer follow up of course will be very important, but I think it's a very important study also in the context of other studies that are investigating quadruple combinations including carfilzomib.

And particularly, I would like to mention GMMG-CONCEPT study. It was a European study, a single-arm phase 2 study of isatuximab-KRd, specifically in high-risk patients. So, the high-risk population, including patients with at least one high risk cytogenetic abnormality. And approximately 30% of patients had two cytogenetic abnormalities, which we know already that those patients have really dismal prognosis in terms of PFS. And all these patients received very intense therapy, and then response rates in terms of MRD negativity were very impressive. And even more so, progression-free survival, again, for this very high-risk population, was 77% at 2 years and 68 at 3 years, which we know, without comparing it to control arm, but we know from historical controls that those patients usually don't do well. And so, I think we should really be very cognizant of intensification of front-line therapy for patients who are at high risk, such as patients with those high risk cytogenetic abnormalities, patients with plasma cell leukemia, as well as patients with [unintelligible] very poorly. So, in my practice, I am using upfront quadruple carfilzomib-containing regimens for patients who are very high risk.