Clinical Data and Toxicity Profiles for Multiple Myeloma Therapies

Paul G. Richardson, MD:So, as we think about this whole rationale of combining a next-generation IMiD, like pomalidomide, with a proteasome inhibitor, it’s important to go further into that. As I’ve mentioned, for just biochemical progression, you can think about a relatively limited exposure, such as bortezomib, every 2 weeks or ixazomib weekly, or something along those lines. Having said that, if you wanted to be more aggressive and the relapse was more worrisome, I think it’s very appropriate to consider carfilzomib.

The carfilzomib/pomalidomide combination is highly active, generally, very well tolerated, but it does require the day 1, 2, 8, 9, 15, 16 administration of carfilzomib every month. And that, obviously, is an investment for the patient. Having said that, the potency and activity of this combination is, in my experience, particularly encouraging, particularly promising. And so it’s a very rational thing to do. It’s also generally very well tolerated. However, just as one worries about neurotoxicity with bortezomib, we always have the concern with carfilzomib of the uncommon, but real, vascular toxicity that can be seen. We had hypertension, thromboembolic disease, pulmonary hypertension, renal dysfunction, and sometimes cardiac issues, as well. Fortunately, these side effects are not common, so that’s the good news. And the really good news, as well, is that, of course, carfilzomib is not neurotoxic. But it’s important to bear that in mind when making these choices.

What is very fair to say is that pomalidomide, as an IMiD, that’s the most potent that we have to date; it has a side effect profile that’s generally very well tolerated. In my experience, my patients have found that after prior lenalidomide exposure, some of them actually find pomalidomide even easier than they did when they were on actually lenalidomide, by comparison. Having said that, what I have seen with pomalidomide is you have to be aware that there is some neurotoxicity associated with its use, and sometimes fatigue, as well as cytopenias (such as thrombocytopenia). So, one has to be aware of that. But generally speaking, in my experience, pomalidomide has been an extremely good partner with proteasome inhibitors in this setting.

As we think about carfilzomib and pomalidomide in the more aggressive relapse, say this lady had a more rapid progression, what would we expect? I think what’s very encouraging is data published by colleagues such as Dr. Jatin Shah, from MD Anderson, showing that the combination carfilzomib and pomalidomide is a very high quality and rate of response approaching 75% to 80%. It’s also worth mentioning that with the combination of pomalidomide and bortezomib, we also see very encouraging results with very similar high rates of response, not only with the twice weekly schedule of bortezomib, but also with the weekly schedule, as well. So, a variety of studies have shown the potency of this combination platform.

   I should mention that with the use of ixazomib and pomalidomide, my colleague, Dr. Peter Voorhees, has presented data on that and shown that to be reactive, as well. But I think, certainly, the most mature information comes from the carfilzomib/pomalidomide experience from Dr. Shah, and I think it’s very encouraging. I think, also, we now have phase III trials ongoing with pomalidomide/bortezomib and dexamethasone that will also give us further information about the use of this platform in early relapse.

   My own impression from my own use of carfilzomib and pomalidomide together is it’s generally well tolerated, excellent neurotoxicity profile, and, again, fatigue can be a challenge, as can sometimes cytopenias. But generally speaking, it’s a well-tolerated regimen.

   As I mentioned before, there is obviously always the concern about vascular toxicity with carfilzomib. So, I’m careful in selecting patients because patients who have hypertension or cardiac history, I’m particularly cautious with regarding carfilzomib use. Similarly, patients with significant renal dysfunction I’m careful with because pomalidomide in patients with renal dysfunction is quite safe. Carfilzomib certainly can be used, but, again, one has to be careful because the data suggest, and my own clinical experience has been, that there can sometimes be a renal signal with carfilzomib use that one has to be aware of.

   As we think about toxicities for this patient, she’s very ambulatory, she’s fit, she’s well, she’s working full time. So, anything we want to use is designed to minimize that. So, I would suggest that pomalidomide as an oral regimen, that could be used in her case, it’s very reasonable substituting it for lenalidomide. There’s a very reasonable chance she will respond nicely to it. And then there’s the platform for adding additional agents to it if needed, if her response to pomalidomide use is, in any way, suboptimal.

Case Scenario 1:

July 2011

• The patient is a 61-year-old Caucasian female who was diagnosed with stage II MM. Genetic testing showed her to have t(4:16). At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation.
• She achieved a partial response with RVD and remained in remission. Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy.

August 2016

• Routine follow up shows that her M-protein levels have now risen to 1.4 g/dL and her light chain levels continue to rise.
• Although she has developed mild anemia and her creatinine level is slightly elevated to 1.3 mg/dL, she continues to work full-time, has no bone pain, and a has a normal calcium level.