DR EVENS: It’s a 1-to-2-to-2 randomization. So the standard arm is the Rummel BR for 6 cycles followed by GELA-like 2 years of rituximab. In other words, every 2 months for 2 years.

DR EVENS: There’s an induction component and, obviously, the maintenance. And we couldn’t frankly decide which is more important to tweak and improve, so we tried to do both. And at least at the time, again, 2008 — and maybe it’s not different now — at the time, what were the 2 — we surveyed all the available drugs in follicular lymphoma. And at the time it was really bortezomib and lenalidomide. And Jonathan has actually presented and published data adding, albeit in the relapsed setting, bortezomib to bendamustine/rituximab. So we actually used his dosing regimen, adding bortezomib, which started out IV. I should mention that halfway through, about a year ago, we changed it to subQ dosing and definitely have seen marked reduction in neurotoxicity, neuropathy. It’s given biweekly, 1.3 mg/m². We perseverated on that. Do we give weekly, biweekly? So 1.3 mg/m² on days 1, 4, 8 and 11 for the 6 cycles. And that primary objective is CR rate.

And then the second experimental arm, we intuitively called it continuation, not maintenance, partly because we’re using a pretty healthy dose of lenalidomide. So for the first year of the 2 years of rituximab, it’s 20 mg of lenalidomide for 3 weeks on a 4-week schedule. And so we’ll see. That second primary endpoint is 18-month disease-free survival. So we’re obviously excited and somewhat biased about the study.

DR LOVE: Julie, what about bortezomib in FL? It’s always been kind of hard for me to sort out exactly what the activity of it is.

DR VOSE: I think the studies now are kind of vetting out what we’ve all thought, that it does have some activity, but it’s not overwhelming activity, certainly as a single agent. And when combined with other agents, it appears that it does enhance it to some degree. But I wouldn’t say it’s the most active drug. And we definitely have the neuropathy issue. Subcutaneous administration really helps out. And most people are going to once-weekly subcutaneous administration now, which I think helps that quite a bit. But it’s still perhaps not the most active drug. Anxious to see what other people think.

DR LOVE: Jonathan?

DR FRIEDBERG: Yes. I think one of the most disappointing relatively recent studies that was presented and published was a large international trial that randomized patients to rituximab alone versus rituximab plus bortezomib in the relapsed setting. This was hundreds of patient with follicular lymphoma. And the bortezomib added about 4 or 5 weeks to the progression-free survival with a significant increase in toxicity, obviously, over rituximab alone. And I think that study, probably more than any other, suggests that at least the single-agent activity of bortezomib in the relapsed follicular lymphoma setting is really quite limited.

We’re interested in combining it with chemotherapy due to some laboratory studies, wherein cell lines — which, of course, are not follicular lymphoma cell lines — you do see some evidence of synergy. And depending on the mechanism of action that you choose to think about for bortezomib with NF-kappa-B and so forth, there is certainly rationale in diseases like mantle-cell lymphoma and large-cell lymphoma, even, to have those combinations.

So I’m eager to see what these results are. I would have predicted there would be a clear winner out of these 3 arms. So we’ll have to see if I’m right. But if I had to put a wager down, I would think that the lenalidomide arm is likely to do the best.

DR LOVE: How about the bortezomib?

DR FRIEDBERG: I don't know. I think that the response rate of BR in follicular lymphoma is quite high. And you might be able to convert some patients with the addition of bortezomib to MRD, but in a study where there’s already planned maintenance, the question is, are you making up for that small difference with a maintenance component? I think the bar is going to be higher to show benefit of bortezomib based on that trial design.

DR EVENS: In terms of other proteasomes, there’s second generation — I don't know if they call it officially a second generation. I don’t remember the name, either. I just know it has “9” — MLN9708.

DR LOVE: Right.

DR EVENS: That’s been studied mainly in myeloma, although there is going to be a follicular lymphoma study that’s opening soon, relapsed/refractory. It’s an oral proteasome inhibitor. And the key difference is the proteasome disassociation rate. Part of the problem is bortezomib impacts the proteasome in red blood cells but doesn’t let off. Its effect stays on normal proteasome too long. This oral proteasome inhibitor has a much shorter disassociation rate. In other words, it has much less impact, longevity in terms of the effect on normal proteasomes. And that’s the problem, is you have off-target effects. There are proteasomes in cancer cells. There are proteasomes in normal cells. And so by that, they’re able to achieve 20 times higher dosing relative to bortezomib with this. And so I think Julie’s exactly right. It could just be that the target is right, maybe just the drug or drug formulation wasn’t precise enough.

DR LOVE: That’s fascinating about the MLN compound, because up to now, I’d heard in the myeloma sector, more that it’s a boron-based proteasome inhibitor. It’s kind of like oral bortezomib. But you’re saying there’s a qualitative difference.

DR EVENS: There really is. There’s a really nice Clinical Cancer Research paper. It was done in diffuse large B-cell lymphoma xenograft studies, a couple of years ago now, where they really, I thought, elegant experiments, teasing out that difference. Really marked improved pharmacokinetic and pharmacodynamic to this MLN9708 drug.