Entering a 4-Drug Regimen for Multiple Myeloma Treatment

Ola Landgren, MD, PhD: Let’s spend a little of time, as an end to this conversation, talking about the 4-drug combinations. You already brought it up. You mentioned the GRIFFIN study, which is RVd [lenalidomide, bortezomib, dexamethasone] with daratumumab versus RVd. That was the first presentation at ASH [American Society of Hematology Annual Meeting & Exposition] last year, in 2018. Based on very small numbers, it was shown that there was superiority, and I think it’s been updated for ASCO [American Society of Clinical Oncology Annual Meeting] this year. Then there was a press release just a few weeks ago showing that the primary endpoint, a little unusual, was that stringent CR [complete response] was reported to be superior. It met the endpoint, and it was reported to be 42% in the 4-drug combination versus the 3-drug combination.

We also know there are multiple other studies going on with 4 drugs, which is modern combinations. There is the KRd [carfilzomib, lenalidomide, dexamethasone]—dara [daratumumab] study. We have that open at our institution. We also showed up at Paris last year, and it’s about to be presented at this coming ASH. Then there is isatuximab, the other monoclonal antibody for CD38 in combination also with these backbones. Four drugs—is that going to be the new future?

Sundar Jagannath, MD: Well, I believe that the additional monoclonal antibody on top of what has been the standard, the triple regimen, is likely to become standard simply because their cancer center showed more patients respond. Overall response rate is now closer, consistently over 90%. The depth of response when you look at MRD [minimal residual disease] is consistently better when you added the 4 drugs versus 3 drugs.

Ola Landgren, MD, PhD: Right.

Sundar Jagannath, MD: From that point of view, if you’re going to cure patients with myeloma, it should be done up front. My feeling is, yes, the 4-drug would become the standard of care. Then, as you pointed out, whether it’s this 4-drug versus that 4-drug, 1 of the proteasome inhibitors may be too expensive, or 1 of the other drugs like IMiD [immunomodulatory drug] could be too. You can always worry about how the exact cocktail is and which is a better financial toxicity, etc. But I think 4 drugs will be important.

Ola Landgren, MD, PhD: If we look at the current duration of the response with the current 3-drug combinations, and then we think of adding a 4-drug, we’re talking many years. To prove that the addition of a fourth drug really translates into a clinically meaningful difference—that’s going to take many years to prove.

Then we are back to the MRD, where we can’t say that with the 3 drugs you have, say, 25% MRD, and with 4 drugs maybe 35%. You say 25% and 35%—how many months of longer PFS [progression-free survival] is that? We don’t know at this point. Let’s say it’s another year of PFS. That sounds pretty good to me.

Sundar Jagannath, MD: Yeah.

Ola Landgren, MD, PhD: Well, if you are that patient who has 2 more months, you would say yes. But the payer may have other opinions about this. So what do you think?

John Fox, MD, MHA: I think it depends on what the strength of the correlation between MRD, PFS, and OS [overall survival] is. If you look at breast cancer, there’s a very poor correlation between overall response rate, progression-free survival, and ultimately overall survival. Using ORR [objective response rate], or even PFS as a proxy, is not evidence based. If you can show evidence in multiple myeloma that there’s a strong correlation between MRD negativity and overall survival, then I think that’s a reasonable proxy to use if you have evidence for that.

Ola Landgren, MD, PhD: We did the first meta-analysis in collaboration with the National Library of Medicine in 2015. We pooled all the studies that have been done for MRD testing, and also captured overall and progression-free survival. The studies showed that the correlation translates into a hazard ratio of about 0.5. Therefore, you reduce the risk of progression by 50% if you’re MRD negative. There’s a second study that was initiated by Celgene Corp and Dana-Farber Cancer Institute. They expanded the 2 slightly larger study-based trials, and they showed very similar results.

John Fox, MD, MHA: Sure.

Ola Landgren, MD, PhD: We have 2 meta-analyses showing that MRD is highly significantly associated with both progression-free survival and, in this setting, overall survival.

John Fox, MD, MHA: Yeah. Does the medical community accept that that’s a good proxy, and that you don’t need PFS or OS?

Sundar Jagannath, MD: That’s a big question. In this regard we were talking about phase III trials. We talked earlier about KCd [carfilzomib, cyclophosphamide, dexamethasone], KRd. The trials looked at relapse, and so surprisingly for patients who got the transplant, those who achieved MRD when they looked at the relapse or in follow-up, there were fewer patients relapsed. The continuous MRD was more in the transplant arm versus on the KRd arm alone. There were a greater number of patients who were relapsing on the KRd arm, even though they were MRD negative. People are now using MRD at multiple treatment points, and in 70% of the cases they were able to detect by MRD ahead of the time that the patient was going to relapse. The MRD positivity was also able to tell them when they’re going to relapse.

I understand your question, and I see your rebuttal for Ola’s statement. But the data are now coming because all the clinical trials are monitoring MRD much more sequentially. The precise question of the relationship of MRD to PFS, and when the MRD becomes positive, that they are coming out of remission rather than staying in a smoldering field, will be answered within the next few years. But the answers are coming.

Ola Landgren, MD, PhD: But I think also, and I’m sure you would agree, that if you look across the board for all the different malignancies, both hematologic and solid tumors, overall survival becomes less possible to use as an endpoint because there are more drugs available.

John Fox, MD, MHA: Sure, I agree.

Ola Landgren, MD, PhD: This is because you can always treat recurrence. Eventually, if you think about it like the alphabet—if you’re going to go through the entire alphabet, and it’s just a matter which drugs or which letter you start with—then that’s the drug, of course. That would probably be diluted by adding all the other letters subsequently. So overall survival will probably go away, right?

John Fox, MD, MHA: I agree. Especially now, as you point out, we have 4 lines of treatment in multiple myeloma and maybe 5.

Ola Landgren, MD, PhD: So MRD and PFS most likely will be the new regulatory endpoints. That’s what the FDA also has declared in its guidance document of where we’re headed. We are not yet there, but we are heading there.