Multiple Myeloma: Emerging Concepts in Management - Episode 12
A. Keith Stewart, MB, ChB: Let’s move on and talk about some of the really exciting new drugs. We’re blessed by having lots of new therapies available in myeloma. Maybe we’ll just start with small molecules. We have a number to talk about, but let’s start with venetoclax. And maybe Noopur, you could explain to the audience what venetoclax is, what the data are in multiple myeloma, and what has been presented at this meeting.
Noopur Suresh Raje, MD: Sure. So, venetoclax is a BCL2 inhibitor, and we actually borrowed this from the lymphoma and the CLL world. It has been used quite nicely in lymphoma patients and chronic lymphocytic leukemia with very high response rates, wherein it’s so active that you actually even see tumor lysis in those patients with CLL. In multiple myeloma, what has been seen very nicely in this data that were presented—I believe, a year back now—by Shaji Kumar, he saw single-agent venetoclax has, in a patient population who is 11;14-positive, a response rate of about 40% or so. And in addition to the myeloma subset, which is 11;14-positive, there is a plasma-cell leukemia population also that harbors the 11;14 translocation, and they, in fact, may be BCL2 dependent. There are data that are going to be presented at this meeting combining venetoclax with dexamethasone in just 11;14-translocated patients. It’s one of the first studies where we’re doing a genetically enriched patient population, and there, I think Jonathan Kaufman is seeing a response rate in excess of 60% in that patient population. So, I think it’s a great niche drug. It’s not for everybody.
A. Keith Stewart, MB, ChB: Let me push back. So, we have 11;14 translocation, 20% of myeloma patients somewhere in the 40% to 60% response rate with a single agent or a single agent plus dexamethasone. It has been studied with bortezomib in combination. Hari, are you familiar with that?
Parameswaran Hari, MD, MRCP, MS: Right. Actually, we have the paper that just came out on that. So, again, people who are on bortezomib, exposed or even refractory, could reestablish responses with venetoclax in that setting.
A. Keith Stewart, MB, ChB: Venetoclax in combination?
Parameswaran Hari, MD, MRCP, MS: In combination, yes.
A. Keith Stewart, MB, ChB: What kind of response rate were they seeing?
Parameswaran Hari, MD, MRCP, MS: I don’t know the exact number right now, but I think it’s about 50% still.
A. Keith Stewart, MB, ChB: No, no, way higher. So 90% response rate with bortezomib, right?
Robert Orlowski, MD, PhD: Yes, it was in the 80% range and certainly looked very encouraging. And because BCL2 is anti-apoptotic, there’s a rationale for why it shouldn’t be something we could block and enhance a number of different chemotherapeutic regimen activities.
A. Keith Stewart, MB, ChB: Talk about your personal experience with venetoclax. Have you used it, Christina, in patients?
Cristina Gasparetto, MD: Yes. In fact, I’m on the venetoclax/dexamethasone combination. I have very good experience with the specific patients with 11;14 translocation. It’s very well tolerated. We were concerned about tumor lysis because of the CLL data where we really have seen it, but not seen it in myeloma. We were doing a leading week, increasing the dose, and now we established the dose of 800 mg and we can go out of the gate in combination with Velcade. I do have several patients maintaining their response for many months.
A. Keith Stewart, MB, ChB: So, you’ve been quite pleased with it. Bob, have you had a chance to use venetoclax and how did that go?
Robert Orlowski, MD, PhD: We have. It is very active in 11;14. At MD Anderson, we’ve not tried it outside of that subgroup. As long as we’re on BCL2 family targets, although we don’t have any data yet, there are now ongoing beginning trials with an MCL-1 inhibitor from a number of different companies and that should be much more broadly applicable to all subtypes of myeloma.
A. Keith Stewart, MB, ChB: Noopur, have you had success with venetoclax and have you had any toxicity from it?
Noopur Suresh Raje, MD: So, most of the toxicity is GI related, but it’s not significant though, and patients have been able to tolerate it quite all right.
A. Keith Stewart, MB, ChB: Talk about selinexor. This is another novel drug with a novel mechanism of action. It targets a protein called exportin. What’s your knowledge base of that one, Hari?
Parameswaran Hari, MD, MRCP, MS: So, that’s another agent that’s being investigated for the p53-mutated myeloma where it keeps the p53 protein in this nucleus and prevents this nucleus export by blocking XPO1. Again, it’s being investigated in penta-refractory and quad-refractory myeloma, with exciting response rates at this point, although the durability of response is something we have yet to see.
A. Keith Stewart, MB, ChB: Noopur, you told me earlier you tried it out in some patients.
Noopur Suresh Raje, MD: It’s a tough drug. It’s an oral drug, and there’s a lot of GI-related toxicity and a lot of fatigue associated with it. They are coming up with a better formulation, so I do think that will help.
A. Keith Stewart, MB, ChB: Anybody else have experience with selinexor and how has that gone?
Cristina Gasparetto, MD: Yes, I’m actually part of the STORM trial where the selinexor is combined with different backbone therapy: selinexor with bortezomib/dexamethasone, selinexor with Revlimid/dexamethasone, and selinexor with pomalidomide/dexamethasone. And we’re presenting an abstract with Darzalex (daratumumab), actually, on Sunday.
A. Keith Stewart, MB, ChB: What are you going to tell us?
Cristina Gasparetto, MD: I think, first of all, the response rate is impressive. We have a limited number of patients, first of all. We’re talking about less than 10, but we see a rapid response within the first month, a relatively high response. We were comparing selinexor doses of the biweekly with the weekly, and we think we have to go with a weekly.
A. Keith Stewart, MB, ChB: For tolerability?
Cristina Gasparetto, MD: Particularly because of the highest adverse events in the myelosuppression with thrombocytopenia, the neutropenia, and some of GI nature as well. But I think it’s a promising combination.
Transcript Edited for Clarity