Frontline Therapy Options for Multiple Myeloma

Amrita Krishnan, MD, FACP: There are now many therapeutic options for transplant-eligible patients, which is great for them. Some of it reflects, obviously, geographic challenges in Europe in terms of what drugs are approved in the frontline setting versus in the United States. In the United States, we do have a little bit more leeway. Look at some of the randomized trials, for example, the StaMINA trial, which was a large transplant trial that I was fortunate to be part of. Looking at the induction therapy that patients got prior to the transplant, a little over 50% got RVd, or lenalidomide (Revlimid)/bortezomib (Velcade)/dexamethasone, and that really reflects United States practice. Another about 20% got CyBorD, or Cytoxan (cyclophosphamide)/bortezomib/dexamethasone. But I would say that CyBorD is tending to be less commonly used. It’s used more in patients who have renal failure, where one doesn’t want to necessarily use lenalidomide initially because of the dose adjustments required. But, generally, most patients are switched to RVd fairly quickly.

The other regimen in the frontline setting that’s starting to gain a foothold is a regimen of carfilzomib (Kyprolis)/lenalidomide/dexamethasone—so, KRd. That’s a regimen that has shown very deep and quick responses, different toxicity profile, so perhaps a little bit more challenging to give. And certainly, the administration, IV twice a week, has other constraints to it, and that’s a discussion we have with patients. It’s a regimen that many of us are using, though, in younger patients, in patients who have more aggressive, advanced disease.

And most recently, the regimen daratumumab, the anti-CD38 monoclonal antibody, plus bortezomib/melphalan/prednisone was approved—so, daratumumab/VMP. And that was also a big step forward, because that was in a transplant-ineligible population. Granted, most of us in the United States don’t use VMP, but what it showed us is that you can use daratumumab in the frontline setting—you can use daratumumab in combination with other drugs in an older population, and that by using it, you can get patients to become MRD-negative who are not transplant eligible, so that, hopefully, you can get the same benefits in terms of sustained responses.

Carfilzomib has unique sets of toxicities, so certainly less neuropathy, but the toxicities we see tend to do more with endothelial damage, which can lead to pulmonary hypertension and also cardiac dysfunction in about 6% of patients. What we’ve learned as we’ve used carfilzomib more and more over the years is that it can be given safely to older patients, but you have to mitigate your risks up front. And by that, I mean first of all controlling hypertension, which is a key element to this. So, before you even start the carfilzomib, you really want to make sure that blood pressure is very well controlled. When you start it, you want to also be equally fastidious about that and monitor those patients very closely. So, I often have patients check their blood pressure at home, certainly, while they’re started on that regimen.

I mentioned earlier, in regard to older patients, we tend to abrogate the dexamethasone dose, as well, to minimize toxicity—very careful fluid management, as well, in older patients—because we used to give a lot of fluids pre- and post-carfilzomib, every dose. Now we’ve also learned that you may not need as much fluid, so we’ve tended to back off after the first couple of doses if patients don’t have tumor lysis and their renal function is stable. So, careful fluid management can also help.

The addition of antibodies to our frontline combination therapy is going to be landscape changing. We’ve seen it already with the combination of daratumumab/bortezomib/melphalan/prednisone, or daratumumab/VMP. Now, that’s a regimen that you don’t use in a transplant population because of, obviously, the stem-cell effects of melphalan. It’s not a commonly used regimen in the United States, but it showed us that 4 drugs in an elderly, nontransplant-eligible population can be done, be well tolerated, and with deep responses including MRD negativity. In the transplant-eligible population, obviously, we would look at a regimen such as RVd, our commonly used regimen, and if you can add daratumumab. And there is a phase II randomized trial that completed accrual, the GRIFFIN trial, looking at RVd plus or minus daratumumab. And we participated in that trial, and certainly that combination has been well tolerated, with deep and rapid responses. So, I think it clearly shows us that you can add antibodies to our commonly used induction regimens prior to transplant and collect stem cells adequately, as well, which has also been reported on and proceed to transplant.

Daratumumab plus KRd, or carfilzomib/lenalidomide/dexamethasone, has also been studied in a smaller number of patients, and it also shows deep responses and favorable toxicity profiles. Some of that, I think ,is a little bit more challenging. The infusion schedule of daratumumab plus carfilzomib is a little less user-friendly. I think in the future, as we’ve heard a lot at this ASCO, weekly carfilzomib will abrogate some of that issue. And in the future, obviously, we’re looking for subcutaneous daratumumab, so both those things, I think, will also be landscape changing. And we may see a further shift toward more of the daratumumab/KRd for young patients with high-risk disease.
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