Multiple Myeloma With Symptomatic Progression: Case 1 - Episode 2
Sagar Lonial, MD: In the current case, what we see is a patient who had a reasonable duration of remission with lenalidomide and dexamethasone. Lenalidomide was increased at the time of biochemical progression, but now he presents with pretty clear symptomatic relapse, and that relapse is associated with hospitalization for pneumonia, as well as the development of progressive renal insufficiency; rising M protein, as well as compression fractures in the spine. So, this is a patient who pretty clearly needs therapy and intervention to reverse some of those new symptoms that were not present during the period of initial remission, and probably needs those responses relatively quickly.
When we’re thinking about how to approach a patient with early relapse, there are a couple of factors that go into play to make that decision. The first is, what was the prior therapy and what was the toxicity associated with that prior therapy? Does that limit subsequent therapies? What was the genetics of that patient? And what is the presentation at the time of relapse? And so, in this specific case, what we know is that the patient was progressing on lenalidomide and dexamethasone, had not been exposed to a proteasome inhibitor to date, and had the development of bone lesions as well as biochemical relapse, that suggested that they needed a more rapid response, suggesting that something like a proteasome inhibitor-based combination may be an optimal salvage therapy.
When we’re thinking about how to approach early relapse, this is an area where there’s a huge amount of confusion, because there are now 7 randomized phase III trials with positive data, suggesting their regimen is superior than doublets across the board. And so, in general, there are a couple of principles that I think of. The first is, have they been exposed or not exposed to a certain class of agents? So, in this specific case, the patient has seen an IMiD. They have not seen a proteasome inhibitor, so that brings us down to the ixazomib-, bortezomib-, or carfilzomib-based approaches. Now, if we think about the carfilzomib data from the ASPIRE trial, that was used in combination with lenalidomide and dexamethasone. And so, this patient has progressed on lenalidomide, so that trial is probably not terribly applicable to the current situation.
If we think about the CASTOR trial, which is bortezomib in combination with daratumumab and dexamethasone, that trial actually is highly relevant to this patient because the patient has not seen a proteasome inhibitor. That’s exactly the patient population that was studied in this trial. And the progression-free survival was clearly one of the longest we’ve seen in relapsed myeloma with a hazard ratio that is among the best we’ve seen in randomized phase III trials in early relapse. So, I think that certainly is a very reasonable opportunity as well.
The third potential option would be the use of ixazomib/lenalidomide/dexamethasone versus lenalidomide/dexamethasone. And, again, the challenge with that study is that the patient has progressed on lenalidomide and dexamethasone, so the data from that randomized phase III trial are not terribly helpful in making a decision for this specific patient. So, I think of the available options, the bortezomib/daratumumab/dexamethasone option would probably be one that we would favor.
The 2 other potential options for this patient, in the context of early relapse, that are provided to us from phase III trials come from the ENDEAVOR trial, as well as the PANORAMA trial. And what the ENDEAVOR trial did was look at a higher dose of carfilzomib at 56 mg/m2given on a twice-a-week schedule versus standard bortezomib and dexamethasone. And, again, from that trial, there’s no question that the higher-dose carfilzomib was associated with a better response rate, as well as a better progression-free survival compared to the use of standard use bortezomib and dexamethasone. However, that trial was associated with a higher incidence of cardiac toxicity, particularly among older, frailer patients. And so, I think for this patient who we know was transplant-ineligible, had baseline renal insufficiency, and now has pretty significant pain issues, I’m not sure that higher-dose carfilzomib might be the optimal answer for him at this time point.
The other potential option to talk about was the use of panobinostat, the HDAC inhibitor, in combination with bortezomib and dexamethasone. And one of the things that we learned from that trial is that the subset that seemed to benefit the most were patients who were resistant to a proteasome inhibitor and resistant to an IMiD. So, this wouldn’t necessarily fall into that patient category, and we do know that panobinostat in combination with bortezomib and dexamethasone, is associated with pretty significant GI toxicity, particularly nausea and diarrhea. And so, given the frailty and renal insufficiency in this patient, I’m not sure that would be a reasonable road for us to go down for him at this time.
Transcript edited for clarity.
Multiple Myeloma in an Older Patient Who Develops Symptomatic Progression