DR LOVE: Let’s move on now and talk about new agents in the management of myeloma. And I want to start out with something that’s really been exciting in hematologic cancers, particularly CLL, which is the Bcl-2 inhibitor venetoclax. And we’re just talking about that all the time. There’s some really interesting issues about it. And all of a sudden I see it popping up in myeloma. Can you talk a little bit about the biologic background of why people even thought about venetoclax in myeloma?

DR FONSECA: Venetoclax is this new oral agent that’s been approved for CLL. But there’s been interest in myeloma because obviously it’s a late B-cell malignancy. And there’s emerging data that suggests that certain subsets of myeloma are particularly sensitive to venetoclax. Short of that, it’s not fully understood, but we know there’s a very strong association with lymphoid-like myeloma. And that is mainly those myeloma patients that have the 11;14 translocation.

DR LOVE: Lymphoid-like?

DR FONSECA: Lymphoid. Sometimes in myeloma cells are a little bit smaller, scant cytoplasm, not as mature, plump plasma cells. So they look more like lymphoplasmacytes or lymphocytes than they look actually like plasma cells.

DR LOVE: And what’s the biologic or clinical phenotype of these?

DR FONSECA: Well, most of those patients have had the 11;14 translocation, perhaps 6;14, which is almost identical to the 11;14. But some groups — again, including the group from Emory — have figured out that most of myeloma cells depend on signaling through Mcl-1 for apoptosis. But there’s a subset of them that shift to Bcl-2. And it is then in those that shift to Bcl-2 that you have this particular sensitivity to venetoclax.

So we’re following this with great excitement because if the data holds as it’s coming through, that there are a subset of myeloma patients that depend on this Bcl-2 pathway and you have the inhibitors to that, you might be able to make a substantial difference for that subgroup of patients.

DR LOVE: Now, is the thinking in this subset monotherapy or combination?

DR FONSECA: It’s been used as monotherapy. And some of my colleagues who have used it in that way have reported excellent responses, including complete responses. But most of what we’re seeing now is in combination, particularly with bortezomib.

DR LOVE: So, Noopur, you know I’m not a real good pathway person. Maybe you can take another shot at talking about the biology that Rafael’s referring to. I haven’t even heard of the lymphoid thing. That’s really interesting.

DR RAJE: Typically, the way we thought about lymphomas and myelomas is lymphomas are very Bcl-2 dependent. Bcl-2 is a proapoptotic factor. And that’s what predisposes those lymphoid cells to die. In myeloma, we’ve always said that Bcl-2/Bcl-XL, that group of genes is not that important. It’s the MCL one, which is, again, a downstream pro-apoptotic factor in the majority of myeloma. And that’s true even now, Rafael, where the majority of myeloma does rely on Mcl-1. So there’s great interest in Mcl-1 inhibitors as well, which are being studied in clinical trials as we speak. The data is very, very early.

But as Rafael is pointing out, there’s a subset of myeloma patients who are Bcl-2 dependent. So they’re behaving more like the lymphomas. And in those folks, a drug like venetoclax has seen single-agent activity.

But what’s exciting to me is actually seeing it when combined with a proteasome inhibitor. In this case, it’s bortezomib. And a correlative of that on FISH is we’ve seen that these folks tend to have the 11;14 translocation. This is part of our FISH testing, routinely, on our myeloma patients.

So those patients who have the 11;14 translocation — because we are still not able to, at a biomarker level, say who are Bcl-1 dependent versus Mcl-1, but we’re using 11;14 as a biomarker in considering treatment with venetoclax in this subset of patients — it’s about 15% of patients who would fit that category, I would say. And it’s totally worth trying this drug there.

DR FONSECA: And, Neil, if I could add to that, many years back the 11;14 was thought to be a good prognostic marker in myeloma, and it was. But what has happened over the last several years, the progress that we have seen for myeloma has not translated into progress for the 11;14. And this goes back to the yang. The 11;14, they have less cytoplasm, they have less proteins, so the cells are less challenged when it comes down to protein metabolism. So it’s kind of stayed stagnant over the years. And the prognosis of the 11;14 is potentially even considered bad nowadays. That’s why this is so exciting, that 11;14-specific agent.

And there’re a couple of other things that are very, very interesting. Our patients who present with primary plasma cell leukemia, half of them have the 11;14 translocation. And also patients who have primary amyloidosis that we call now light chain amyloidosis, half of them have the 11;14 translocation. So you can see where a targeted approach for those subgroups is going to make a big difference.

DR LOVE: That’s fascinating. Any other novel agents, for example, that have been looked at in these 11;14s that you’re normally used to thinking about in B-cell malignancies — PI3 kinase inhibitors, Bruton tyrosine kinase inhibitors, any of those?

DR FONSECA: Well, there’s some work going on with ibrutinib for those patients, although it really hasn’t been segmented into that population. The French did a trial now many years ago looking at rituximab because those are lymphoid. They express the CD20.

DR LOVE: Right.

DR FONSECA: And it was negative. But I think we need to continue to explore the difference in the various pathways. What we’re telling people is that for an 11;14, given that we don’t have the certainty of the effect — or as much certainty of the effect of IMiDs and proteasome inhibitors — alkylators are important, so stem cell transplant becomes particularly important for that population.

DR LOVE: Any situations where you could envision attempting to utilize venetoclax off label right now in myeloma?

DR FONSECA: All the time. And patients are asking that question.

DR LOVE: Really?

DR FONSECA: Yes. Patients are asking the question.

DR RAJE: I will give you an example right now, Neil. We have a young, young gentleman — he’s in his thirties — who has plasma cell leukemia. Initially, we used carfilzomib/lenalidomide/dex as induction treatment. Got transplanted, did well for, I want to say, about 18 months, which is why it’s interesting that Rafael has brought this up. He has the 11;14 translocation, and he’s the one we are going to get off-label venetoclax for.

So patients are also seeing this data. We are using it because plasma cell leukemia patients do not traditionally get included in some of our clinical trials. So he would be a classic patient where I would absolutely get this off label.

DR LOVE: As monotherapy?

DR RAJE: No. We would use it in combination with bortezomib in his case because he’s got very aggressive disease.

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Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM