Rafael Fonseca, MD: A common question that will arise is, should we save some of these great drugs for down the line? I explain this with an analogy. Do we use a strategy like we use in soccer, or do we play like you would play in baseball? In soccer, you put your best players in the first game. If you’re playing Messi, you don’t put him on the bench hoping your team will get to the World Cup finals. In fact, he’s going to be playing in game number 1. Whereas in baseball, you can save some great players for those late innings. As we have gone through the process of clinical research in myeloma, more and more we think for the frontline diagnosis, and perhaps even for the first relapse, that it has to be like soccer. And I know this is different for different diseases. Sometimes, I will hear people say, “Well, in breast cancer, we do sequencing. We save some of these drugs for down the line.”

The reality is that in multiple myeloma, putting your best foot forward pays off. Now, one must recognize—and this is very, very important—if you have a patient who gets optimal therapy, it doesn’t necessarily ensure that they’re going to get to the next line of therapy. Likewise, if someone gets suboptimal therapy, they’re not necessarily going to get to that second line of therapy. So, there’s an attrition process, all the more reason to try to keep those patients under optimal control until the time comes that they might need second-line therapy.

Now, the baseball approach may be fine for further down the line, maybe for third- and fourth-line. In fact, this analogy was given to me by a patient of mine who was an avid baseball fan. And he said, “For me, at this stage, it’s not about winning. It’s just about not losing. So, with every new line of treatment you give me, I actually have a new option, so I have another inning.”

Gareth Morgan, MD, PhD: There’s a need for treatment planning throughout the entire disease course. It is entirely clear that you want a doctor who designs a therapeutic strategy for the duration of your disease and your life, and not just a strategy for getting you to a remission. That’s very important. And part of the way you implement that strategy is to monitor the response to the drugs that you’re using. If you see a good response, you’re making progress. I believe aiming to get first to a PR, then to a complete response, then to an MRD-negative complete response, is becoming the first part of the strategy for myeloma. The more people you get to deep response, the better the long-term outcomes.

It’s very important to use the most effective combinations up front. That’s the time when the disease is at its most sensitive, and you can get the best long-term outcomes for patients. So, I would very much design a triplet or a quadruplet for up-front patients.

You should think of different stages when you treat. It’s not analogous to some of the solid tumor, so there’s an induction phase where you maximize your response. For younger patients who can tolerate it, you should consider stem cell transplant. And after the stem cell transplant, there’s a consolidation phase where you can deepen response even further. And then there’s the long-term setting, where there are good data now. Maintenance seems to be able to control the disease for a prolonged period of time.

Thomas G. Martin, MD: In myeloma, the up-front and subsequent therapies are really a planned pathway from when patient first comes in at diagnosis. I try to use the medications that are the most potent right up front. And I think that strategy is most important for the transplant-eligible patient population, where we might potentially have the ability to cure some of those patients. And then, for the elderly and frail patients, we should really try to make their medications as least toxic and as effective as possible.

When I start somebody on an initial therapy, say I start them on RVD or RVD lite, I’m already thinking about what’s going to be the next therapy and the next therapy. The second-line therapy for me is often a carfilzomib-based regimen or potentially a monoclonal antibody-based regimen. We have 2 new antibodies, daratumumab and elotuzumab. And we often think, “OK, that’s the second regimen, but what’s our third regimen going to be?” And in myeloma, we call this a ping-pong approach, where we give maybe an IMiD [immunomodulator] backbone first and then a PI [proteasome inhibitor] backbone next, and then go back to a second-generation IMiD and maybe then a second-generation PI. We’re already thinking multiple regimens ahead when we’re defining a treatment path for an individual patient.

Transcript Edited for Clarity