TOURMALINE-MM1: Benefit of IRd Triplet for R/R MM

Ajai Chari, MD, PhD:The TOURMALINE-MM1 study is a randomized phase III study where patients received ixazomib, lenalidomide, and DEX [dexamethasone] in the experimental arm, and the control arm received placebo, lenalidomide, and DEX [dexamethasone]. One of the unique features about the study design in this particular regimen compared with the other randomized phase IIIs is this was double-blinded, and that can be done because there’s no intravenous medication being given so patients were randomized to either get placebo or ixazomib. That’s important because when we think about the progression-free survival [PFS], response rates, and adverse events in particular, there was double blinding so there’s not the bias of over-reporting, under-reporting, and so I think that’s important when we look at the results.

The outcomes of TOURMALINE-1 were favorable for the addition of ixazomib, so there was a 20.6 month median PFS for the addition of ixazomib versus 14.7 months for the Rd [lenalidomide/dexamethasone] arm, which translates into a hazard ratio of 0.74, and that favors the triplet containing regimen.

Importantly, the response rates were comparable but there was really very little difference in the adverse effect profile. Serious adverse events were exactly the same in both arms. The rates of neuropathy were quite low, 2% in both arms. The only added toxicity seen with the triplet was thrombocytopenia and a slight increase in rash. But both of those are typically quite manageable. And so I think this gives yet another option for the management of relapsed myeloma.

Now in terms of why one might switch from bortezomib to ixazomib, it’s important to note that in this study patients who got ixazomib could not have had severe complications with bortezomib. So if somebody had terrible neuropathy, they would not have been eligible. So it’s important to think about that when we look at the [adverse] effect profile, and that may be part of why the neuropathy rates are so low. But it clearly demonstrates that ixazomib given to most patients has very little neuropathy.

But one of the main reasons to switch here is the convenience. Bortezomib on label is given twice weekly, and obviously now we give it subcutaneously as opposed to intravenously. And while that might be important in a newly diagnosed patient where a patient is going to be coming in frequently for [laboratory] testing, in the relapse setting or in somebody who’s out quite a bit from their initial therapy, it’s nice to have an oral regimen so they don’t have to keep coming in for the injections of whichever drug that they’re being given.

So probably convenience is one of the main reasons to switch. And to that point, I think while the use of ixazomib, LEN [lenalidomide]/DEX [dexamethasone] on label is IRd versus Rd, based on the registration study, it’s also something that we can do off label in patients who are say 4;14 [translocation], and we need to continue proteasome inhibition. And I think that’s important to emphasize because we know that from real-world data the duration of drug use in real-world relative to clinical trials is probably only 50%. So we do these great randomized phase III studies saying 3 drugs are better than 2 drugs, and you’re going to get a PFS benefit that can perhaps translate into an OS [overall survival], and then we come to the real world and people aren’t even using the drugs for 50% of the time. So you can’t be sure that you’re going to be getting those PFS and OS benefits that are being seen in the study.

And it’s important to remember that clinical trials are cherry-picked patients. These are healthy patients, motivated to participate in research. They’re being treated and monitored by research teams that are also very driven and interested in keeping people on therapy. And then when we go to the real world, anything we can do to increase the compliance with the prescribed dosing is helpful. And a big point there would be oral therapy. I think there’s going to be much more compliance with an oral regimen rather than a patient coming in twice weekly for parenteral injections for the rest of their life.

I love it when patients say, “I’m going on a trip,” because what’s the point of having your myeloma in remission, but you’re always cooped up at your home tied to the cancer center. So this really liberates patients to travel the world, and I think it’s a great option for them, and that’s one of the benefits of having a completely oral regimen, is being able to adhere to the clinical trial without fatigue of transit.

So IRd is a great regimen for relapsed myeloma, but ixazomib is the only oral proteasome inhibitor [PI]. And for that reason it can be useful in other settings as well. There are studies combining it with cyclophosphamide, pomalidomide. And so in settings where you need a PI, and perhaps especially when you’ve used a very potent triplet regimen and the disease has been debulked but perhaps they have a translocation 4;14 or high-risk feature that makes you want to continue the PI till progression, that’s a great role for ixazomib because it can be helpful in delivering that durable PI exposure.

There has been a randomized study for ixazomib in maintenance, which did show an improvement in PFS posttransplant, approximately 20 months in the control arm to 27 months. So that’s another option for patients perhaps who are intolerant of lenalidomide in the post-transplant setting.

Transcript edited for clarity.

Case: 56-Year-Old Man With Asymptomatic Relapsed Multiple Myeloma

History:

• In 2015, at the age of 53, an African-American man was diagnosed with multiple myeloma; R-ISS stage I
• Patient was treated with bortezomib + lenalidomide + dexamethasone (VRd) for 4 cycles, followed by ASCT
• Patient achieved a VGPR
• Received lenalidomide maintenance for 2 years

September 2018

• On routine follow-up, no clinical symptoms observed
• Imaging: stable disease
• Laboratory results:
  • Hb, 11.3 g/dL
  • Ca²⁺9.2 mg/dL
  • Creatinine, 0.8 mg/dL
  • M-protein:
    • June: 1.2 g/dL
    • July: 1.4 g/dL
    • August: 1.7 g/dL
• Cytogenetics/FISH: no adverse cytogenetics
• ECOG PS: 0
• Patient was started on ixazomib + lenalidomide + dexamethasone (IRd)