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Improving Outcomes in Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Wednesday, Mar 14, 2018



Transcript: 

A. Keith Stewart, MB, ChB: One thing that I wanted to spend a couple minutes on is supportive care aspects. In our own practice, we’re using daratumumab, we’re using carfilzomib, and we’re probably going to start using some kind of anti-BCMA therapy. We find hypogammaglobulinemia is becoming increasingly common. Has that been an experience you’ve had, Bob? And how do you treat that?

Robert Orlowski, MD, PhD: Yes, definitely. Even without CAR T cells, which of course will take care of myeloma, normal plasma cells are also BCMA-positive. Even without that, you have lots of people who are hypogammaglobulinemic, and there are some older studies that were done in a nice randomized fashion that showed that repleting gammaglobulin does help reduce the risk of infections. And some of them showed an improvement in overall survival as well. But, unfortunately, it’s not something that’s approved, so it can be challenging to give. But we definitely try to replete gammaglobulin in people who have a low IgG (immunoglobulin G) and if they have documented bacterial infections.

A. Keith Stewart, MB, ChB: We seem to have a staple of these people now. I used to use it once a year. Now it seems I have 4 or 5 at any one time on immunoglobulin. Christina, what about you? Are you finding that as well?

Cristina Gasparetto, MD: Yes, occasionally I do use it. I recall the old study actually showing positive outcomes with the use of routine infusion. But it’s not easy. Lots of patients may have reaction, fluid. It’s expensive. But in patients with recurrent infection, yes.

A. Keith Stewart, MB, ChB: Anybody using routine antibiotics, either an induction or end-stage disease, or is that still something that causes you to worry about resistance?

Parameswaran Hari, MD, MRCP, MS: There are some exciting data, as you know, from this meeting where the use of Levaquin (levofloxacin) for 12 weeks in induction was associated with lower risk of infection without an increase in resistance of C. diff (Clostridium difficile) rates. I’ve been always worried about inducing resistance for later when the patients do get neutropenic.

A. Keith Stewart, MB, ChB: That study was with Levaquin or ciprofloxacin?

Parameswaran Hari, MD, MRCP, MS: Levaquin. Levaquin and sulfamethoxazole, or Bactrim. So, that’s very interesting in that it did not actually lead to any adverse effect except reducing the infection. But there are some caveats with that study. I have not used it. I need to see the study in print before I would actually change practice.

A. Keith Stewart, MB, ChB: Yes, I’m quite fascinated by that one. We used to use a lot of Levaquin in induction but got a bit worried about tendonitis and other things. But we lose a lot of patients to pneumonia and infection. And if you look at all the clinical trials, that is one of the major toxicities of a lot of our therapies.

Noopur Suresh Raje, MD: I think what was interesting in the study, which you both are alluding to, was—again, this is a UK-based study—a lot of Cytoxan and therefore Levaquin; they actually showed a survival advantage also early on. But that survival advantage was lost by the end of a year, so it’s hard to kind of use that in what we do out here. So, I typically don’t, but it’s interesting to think about.

A. Keith Stewart, MB, ChB: I’m going to pick on you again because the last topic we’re going to cover today is bone disease. We haven’t talked about that. You ran a very large and, I think, very important study. I’d like you to describe it to the audience comparing denosumab with zoledronic acid.

Noopur Suresh Raje, MD: Sure. So, we did a very large multi-center, multi-national efforts trial with 1700-plus patients where we compared the standard of care, which is zoledronic acid, in the treatment of myeloma-related bone disease to denosumab. And the primary endpoint here was first-on-study skeletal-related events. And the way the study was designed was to show equivalence, which we were able to show.

A. Keith Stewart, MB, ChB: Equivalence for skeletal events, right?

Noopur Suresh Raje, MD: Equivalence for skeletal-related events (SREs). When we did a landmark analysis, we did see an improvement in SREs in the denosumab arm. And, very interestingly, what we found in the study was a pretty significant PFS benefit in this patient population in excess of 10-1/2 months. And these were patients wherein we had stratified for the kind of induction treatment. They were mostly newly diagnosed, so the only real difference was denosumab versus zoledronic acid. I thought that was quite striking. And the last point there was this was very well tolerated from a renal standpoint. We did not see a lot of renal toxicity in the denosumab arm compared with zoledronic acid.

A. Keith Stewart, MB, ChB: So, I loved your study. I think it was a very surprising 10-month improved progression-free survival. That is longer than with carfilzomib, elotuzumab, ixazomib, and yet there hasn’t been a fantastic upswell of excitement about that. What’s going on there, Hari? Why aren’t people more excited about that result?

Parameswaran Hari, MD, MRCP, MS: It’s intriguing.

A. Keith Stewart, MB, ChB: Why don’t you say this is fantastic and we should be doing this?

Parameswaran Hari, MD, MRCP, MS: It was not something that you had planned for, obviously. Again, you worry if there is some unknown difference that’s bringing it out. Zoledronic acid, as we all know, does have an overall survival advantage that was shown in the large UK study irrespective of your induction, if you got zoledronic acid versus an older bone agent.

A. Keith Stewart, MB, ChB: It was fairly modest.

Parameswaran Hari, MD, MRCP, MS: But it is the only one. And for denosumab in the original denosumab study of skeletal events, the myeloma subset actually did not show a PFS advantage. But this myeloma specific study does show a PFS advantage. So, I’m intrigued, but I clearly don’t think I’d change my practice just yet.

A. Keith Stewart, MB, ChB: I still don’t understand why not. Bob, explain to me why we’re not all using denosumab apart from the fact that it’s not paid for yet, which is trivial.

Robert Orlowski, MD, PhD: You took my answer.

Cristina Gasparetto, MD: Yes, that was my answer, too.

Robert Orlowski, MD, PhD: But I do think once it’s FDA approved that it should be something we think about for all patients and definitely for people with renal insufficiency, as Noopur mentioned. With the zoledronic acid, sometimes the guidelines say maybe reduce the dose or maybe not give it at all to some people.

A. Keith Stewart, MB, ChB: Are you using denosumab at all, Christina?

Cristina Gasparetto, MD: So, I tried. I was at ASCO listening to Noopur, and she did a great presentation, but I couldn’t and didn’t get insurance approval. Particularly with renal disease, I thought it was a no-brainer to go there immediately, but I didn’t.

A. Keith Stewart, MB, ChB: It’s a lot more expensive, that’s for sure. So, do we need another trial to convince you for PFS? They already have a 1700-patient study. Noopur, do we need another trial?

Noopur Suresh Raje, MD: I don’t think so. I think everybody is waiting for the FDA approval. And when you look at cost, I know most people will say, “If SREs are equal, I’m going to go by cost.” We have actually done a cost analysis also, and we’ve looked at value-added with denosumab versus zoledronic acid. And you have to remember sticker prices are a very arbitrary way of looking at costing. When you look at infusion costs, when you look at this benefit in terms of disease control, I think denosumab and zoledronic acid are not that different. So, I’m hoping that once we get the label, there’s going to be more people using it.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: One thing that I wanted to spend a couple minutes on is supportive care aspects. In our own practice, we’re using daratumumab, we’re using carfilzomib, and we’re probably going to start using some kind of anti-BCMA therapy. We find hypogammaglobulinemia is becoming increasingly common. Has that been an experience you’ve had, Bob? And how do you treat that?

Robert Orlowski, MD, PhD: Yes, definitely. Even without CAR T cells, which of course will take care of myeloma, normal plasma cells are also BCMA-positive. Even without that, you have lots of people who are hypogammaglobulinemic, and there are some older studies that were done in a nice randomized fashion that showed that repleting gammaglobulin does help reduce the risk of infections. And some of them showed an improvement in overall survival as well. But, unfortunately, it’s not something that’s approved, so it can be challenging to give. But we definitely try to replete gammaglobulin in people who have a low IgG (immunoglobulin G) and if they have documented bacterial infections.

A. Keith Stewart, MB, ChB: We seem to have a staple of these people now. I used to use it once a year. Now it seems I have 4 or 5 at any one time on immunoglobulin. Christina, what about you? Are you finding that as well?

Cristina Gasparetto, MD: Yes, occasionally I do use it. I recall the old study actually showing positive outcomes with the use of routine infusion. But it’s not easy. Lots of patients may have reaction, fluid. It’s expensive. But in patients with recurrent infection, yes.

A. Keith Stewart, MB, ChB: Anybody using routine antibiotics, either an induction or end-stage disease, or is that still something that causes you to worry about resistance?

Parameswaran Hari, MD, MRCP, MS: There are some exciting data, as you know, from this meeting where the use of Levaquin (levofloxacin) for 12 weeks in induction was associated with lower risk of infection without an increase in resistance of C. diff (Clostridium difficile) rates. I’ve been always worried about inducing resistance for later when the patients do get neutropenic.

A. Keith Stewart, MB, ChB: That study was with Levaquin or ciprofloxacin?

Parameswaran Hari, MD, MRCP, MS: Levaquin. Levaquin and sulfamethoxazole, or Bactrim. So, that’s very interesting in that it did not actually lead to any adverse effect except reducing the infection. But there are some caveats with that study. I have not used it. I need to see the study in print before I would actually change practice.

A. Keith Stewart, MB, ChB: Yes, I’m quite fascinated by that one. We used to use a lot of Levaquin in induction but got a bit worried about tendonitis and other things. But we lose a lot of patients to pneumonia and infection. And if you look at all the clinical trials, that is one of the major toxicities of a lot of our therapies.

Noopur Suresh Raje, MD: I think what was interesting in the study, which you both are alluding to, was—again, this is a UK-based study—a lot of Cytoxan and therefore Levaquin; they actually showed a survival advantage also early on. But that survival advantage was lost by the end of a year, so it’s hard to kind of use that in what we do out here. So, I typically don’t, but it’s interesting to think about.

A. Keith Stewart, MB, ChB: I’m going to pick on you again because the last topic we’re going to cover today is bone disease. We haven’t talked about that. You ran a very large and, I think, very important study. I’d like you to describe it to the audience comparing denosumab with zoledronic acid.

Noopur Suresh Raje, MD: Sure. So, we did a very large multi-center, multi-national efforts trial with 1700-plus patients where we compared the standard of care, which is zoledronic acid, in the treatment of myeloma-related bone disease to denosumab. And the primary endpoint here was first-on-study skeletal-related events. And the way the study was designed was to show equivalence, which we were able to show.

A. Keith Stewart, MB, ChB: Equivalence for skeletal events, right?

Noopur Suresh Raje, MD: Equivalence for skeletal-related events (SREs). When we did a landmark analysis, we did see an improvement in SREs in the denosumab arm. And, very interestingly, what we found in the study was a pretty significant PFS benefit in this patient population in excess of 10-1/2 months. And these were patients wherein we had stratified for the kind of induction treatment. They were mostly newly diagnosed, so the only real difference was denosumab versus zoledronic acid. I thought that was quite striking. And the last point there was this was very well tolerated from a renal standpoint. We did not see a lot of renal toxicity in the denosumab arm compared with zoledronic acid.

A. Keith Stewart, MB, ChB: So, I loved your study. I think it was a very surprising 10-month improved progression-free survival. That is longer than with carfilzomib, elotuzumab, ixazomib, and yet there hasn’t been a fantastic upswell of excitement about that. What’s going on there, Hari? Why aren’t people more excited about that result?

Parameswaran Hari, MD, MRCP, MS: It’s intriguing.

A. Keith Stewart, MB, ChB: Why don’t you say this is fantastic and we should be doing this?

Parameswaran Hari, MD, MRCP, MS: It was not something that you had planned for, obviously. Again, you worry if there is some unknown difference that’s bringing it out. Zoledronic acid, as we all know, does have an overall survival advantage that was shown in the large UK study irrespective of your induction, if you got zoledronic acid versus an older bone agent.

A. Keith Stewart, MB, ChB: It was fairly modest.

Parameswaran Hari, MD, MRCP, MS: But it is the only one. And for denosumab in the original denosumab study of skeletal events, the myeloma subset actually did not show a PFS advantage. But this myeloma specific study does show a PFS advantage. So, I’m intrigued, but I clearly don’t think I’d change my practice just yet.

A. Keith Stewart, MB, ChB: I still don’t understand why not. Bob, explain to me why we’re not all using denosumab apart from the fact that it’s not paid for yet, which is trivial.

Robert Orlowski, MD, PhD: You took my answer.

Cristina Gasparetto, MD: Yes, that was my answer, too.

Robert Orlowski, MD, PhD: But I do think once it’s FDA approved that it should be something we think about for all patients and definitely for people with renal insufficiency, as Noopur mentioned. With the zoledronic acid, sometimes the guidelines say maybe reduce the dose or maybe not give it at all to some people.

A. Keith Stewart, MB, ChB: Are you using denosumab at all, Christina?

Cristina Gasparetto, MD: So, I tried. I was at ASCO listening to Noopur, and she did a great presentation, but I couldn’t and didn’t get insurance approval. Particularly with renal disease, I thought it was a no-brainer to go there immediately, but I didn’t.

A. Keith Stewart, MB, ChB: It’s a lot more expensive, that’s for sure. So, do we need another trial to convince you for PFS? They already have a 1700-patient study. Noopur, do we need another trial?

Noopur Suresh Raje, MD: I don’t think so. I think everybody is waiting for the FDA approval. And when you look at cost, I know most people will say, “If SREs are equal, I’m going to go by cost.” We have actually done a cost analysis also, and we’ve looked at value-added with denosumab versus zoledronic acid. And you have to remember sticker prices are a very arbitrary way of looking at costing. When you look at infusion costs, when you look at this benefit in terms of disease control, I think denosumab and zoledronic acid are not that different. So, I’m hoping that once we get the label, there’s going to be more people using it.

Transcript Edited for Clarity 
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