Biochemical Relapse of Multiple Myeloma

Ajai Chari, MD:In trying to decide how to treat a patient with relapse, the first question is, where is this patient on that continuum of purely biochemical relapse to fulminant disease? Not everybody with mild biochemical relapse, which isn’t even fully detectable or fully measurable by IMWG (International Myeloma Working Group) response criteria, needs immediate therapy. That type of patient could potentially be watched for a few months longer until we do have symptoms. Conversely, if the patient has symptomatic disease, we need to obviously start therapy immediately, regardless of whether or not it’s measurable.

It’s important to know that for some patients who have a heavy chain component (an IgG [immunoglobulin G] kappa M-spike of 1.3 at the time of initial diagnosis), by the time they relapse, they may have that concept or free light chain escape. They only have kappa light chain disease. So, it’s important that community doctors check all of those myeloma labs in patients on maintenance therapy, so that we’re not missing that type of relapse.

If somebody had this symptomatic relapse, as our patient has, then I think the first question is, what kind of regimen do we use? Fortunately, in myeloma, we’ve had a plethora of relapse studies. In fact, we’ve had 7 phase III studies and 1 randomized phase II study. It’s unprecedented, I think, in oncology to have so many studies to choose from—phase III, randomized, high-quality studies that have all led to the approval of these agents.

The first thing I think that we need to do is break these studies down into either a lenalidomide-based backbone or a bortezomib-based backbone. And that’s important because this patient, for example, is on lenalidomide maintenance therapy. By definition, her progression on lenalidomide maintenance would make her ineligible for all 4 studies that required lenalidomide sensitivity. There was a control arm in those 4 studies where half the patients were only going to get lenalidomide and dexamethasone, and that might not be appropriate if somebody is clinically relapsing (to just give them a little bit more lenalidomide and dexamethasone). We do that, sometimes, outside of studies because if it’s a biochemical relapse, perhaps we can milk some more mileage. But, in a prospective clinical trial, that would not be appropriate, especially when you have a randomization regimen there that we need, depending on the outcomes, both arms to be as good as possible.

For this patient, if we were practicing evidence-based medicine, we couldn’t use those 4 studies. So, we would then go to the PI (proteasome inhibitor) backbone studies. For pretty much all of these studies, we have a daratumumab-containing regimen, a carfilzomib-containing regimen, and an elotuzumab-containing regimen. In the PI studies, there’s also panobinostat. So, to summarize, we have daratumumab/VD (bortezomib and dexamethasone) versus VD; KD (carfilzomib and dexamethasone), which is high-dose carfilzomib at 56 mg/m²versus VD; and elotuzumab/VD versus VD, although this is a randomized phase II trial but also sizable—150 patients or so. And then, lastly, we have panobinostat/VD versus VD.

So, we have 4 studies, and it’s important to remember that, as we were taught in medical school, it’s always tempting to compare cross studies. Let’s just take the one with the best response rate, with the best PFS [progression-free survival] and the best OS [overall survival], and then, boom, apply that to everybody. The problem with that is these studies are not balanced, and there’s always going to be differences between the eligibility criteria. Were they relapsed at the time of entry? Were they actually refractory? How old were these patients? What is their risk status, both international stage and molecular risk? How many lines of prior therapy did they have? Were they being enrolled in ex-United States or United States trials, where the initial therapies may have been very different?

I bring up all of those factors because we really can’t compare directly to median PFS, for example, across all of these studies. And although it’s intellectually the easiest to do, it’s also intellectually the laziest to do. What we really need to do is look at hazard ratios, which at least gives you the relative value added within each study for the novel agent versus conventional option. And what’s interesting is, when you look at these hazard ratios for all of these studies, they pretty much all line up in this 0.6 to 0.7 range with 1 exception—that’s daratumumab. There is daratumumab/RD (lenalidomide and dexamethasone) or daratumumab/VD. In this case, reflecting on the CASTOR study that compared daratumumab/VD versus VD, the hazard ratio was quite impressive—0.39 (or, the other way of saying that is 61% reduction in the risk of progression or death).

That’s quite impressive and, admittedly, the follow-up is not going to be as long as those other studies. So, we don’t yet see OS benefit. That’s going to require longer follow up. But, I think that’s why, for that reason, people are so interested in daratumumab-containing regimens. These hazard ratios are quite impressive. Again, it’s not to say that those other regimens may not be appropriate, and they’re all excellent regimens. They all will work very well. But, if you had to pick what would be the best option in terms of evidence-based, that’s probably one of the most compelling. And so, that would be the approach for this patient, given that she was in lenalidomide maintenance failure.

Now, it’s also important to talk about the other options. There was another group of 4 studies, that are equally compelling, that have the lenalidomide-based backbone. Again, we have daratumumab/RD versus RD—this was demonstrated by the POLLUX study. We have carfilzomib/RD versus RD, which was demonstrated the ASPIRE study. We have elotuzumab /RD versus RD, demonstrated in ELOQUENT. The last study is ixazomib/RD versus RD. So, we now have 4 more regimens that are lenalidomide-containing. How do we pick? Again, the same caveats apply. There’s differences in patient populations, and it’s easy to just say, “I’m going to take the one with the highest PFS.” But that’s, again, not the right way to do it. And if we look at the hazard ratios, yet again, they kind of stack up in this 0.5 to 0.7 range with the notable exception of the POLLUX study, where daratumumab/RD versus RD gives you a hazard ratio, again, in the 0.3 range. This, again, shows a much better reduction in the risk of progression or death. It’s a very good regimen to consider for patients who are progressing.

This is where that generalizability of a study to the patient is so important. The hazard ratios that we just talked about for the lenalidomide-containing regimen may not be applicable to this patient because she’s had lenalidomide maintenance failure. So, if we were to try to add the third drug to her lenalidomide/dexamethasone regimen, we may not be able to guarantee that the benefit for her would be as good as it was for the other patients in that study who, by definition, could not be lenalidomide-refractory (including those not refractory to lenalidomide maintenance). It’s nice that daratumumab and carfilzomib are both regimens containing a PI backbone as well as an IMiD (immunomodulatory drug) backbone. It’s nice to have all these options. And, at the end of the day, the choice of a regimen is really going to be patient specific, as well.

We need to think about this patient’s age, frailty, comorbidities, neuropathy rates, and renal function—and those are host factors. The second thing to consider is the disease factors, which are not only related to the burden of the disease and symptoms, but also biology. Is there a molecular risk? And lastly, we need to think about therapies, including what they had been treated with before. How well did they respond? What toxicities did they have? Is this therapy going to be parenteral or oral? Is it going to be a combination or single-agent regimen? What is the cost of this drug, both to the healthcare system and also to the patient (in terms of out-of-pocket costs)? I think we have a lot of factors to consider, and, at the end of the day, this is why we say medicine is an art and not a science. You can have these evidence-based studies with hazard ratios, but maybe you have to throw all that out the door when you see this patient in front of you (where things don’t apply). I think it’s nice to have evidence, though, to have so many choices so that you can pick the right combination for the right patient.

Transcript edited for clarity.

Biochemical Progression of Stage II Myeloma

July 2011

• A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma
• Genetic testing showed t(14:16)
• At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation
• She achieved a near complete remission with RVD and transplant
• Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy

August 2016

• On routine follow up, the patient reports having mild fatigue but continues to work full-time; she has grade 1 neuropathy
  • M-protein, 1.3 g/dL
  • SFLC, kappa, 150 mg/L
  • Hb, 10.3 g/dL
  • Creatinine, 1.3 mg/dL