Trials in Multiple Myeloma Show Improved Efficacy With Transplant and/or Daratumumab

Joseph Mikhael, MD

Joseph Mikhael, MD, professor of Applied Cancer Research and Drug Discovery Division Translational Genomics Research Institute (TGen), an affiliate of the City of Hope Cancer Center, discussed the case of a 51-year-old patients with multiple myeloma.

Targeted Oncology^TM: What are the primary therapies that are available for a patient like this who is transplant eligible?

MIKHAEL: From an NCCN [National Comprehensive Cancer Network] standpoint, we have a pretty big laundry list available to us.1 The regimens that have the category 1 designation are the preferred regimens. We have RVd [lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone], CyBorD [cyclophosphamide, bortezomib, and dexamethasone], and now DRd [daratumumab (Darzalex), lenalidomide, and dexamethasone]. We also have other combinations that maybe we don’t use quite as much that are still available such as melphalan [Alkeran].

What data backs up current treatment regimens that are available and how they are evolving?

The IFM 2009 study [NCT01191060], was one of the most influential studies for transplant that we’ve seen in the last 10 years, which was giving people RVd plus or minus transplant.^2,3

The second study that I’ll describe is the FORTE study [NCT02203643].^4,5 Similar design, although [in this study they gave] KRd [carfilzomib (Kyprolis), lenalidomide, and dexamethasone] for up to a year without transplant or 8 months with transplant. Then the next step forward was adding daratumumab to the induction regimen. The European-based study was the CASSIOPEIA study [NCT02541383], where they added daratumumab to VTd [bortezomib, thalidomide, and dexamethasone], though we don’t use a whole lot of thalidomide here.6 So, the American equivalent to that was the GRIFFIN study [NCT02874742], albeit a randomized phase 2 study, which was daratumumab plus RVd vs RVd alone.^7-9

There are lots of different ways to compare these and all the caveats about cross-trial comparisons. But there are a couple of things that I’ll highlight that helps us to appreciate that the depth of response matters in multiple myeloma. First, the post-consolidation, VGPR [very good partial response]—what’s the deepest response in these studies? In IFM 2009, with transplants and RVd it’s 78%, vs 69% with just RVd.^2,3 In FORTE, they used a more intense KRd for longer, and both of those numbers go up and are almost even [KRd and transplant had a post-consolidation, VGPR of 89% and KRd alone was 87%].^4,5 With CASSIOPEIA, by adding daratumumab to VTd, we deepen that response [to 83.4% vs 78% with VTd].6 Similarly in GRIFFIN, we do the same with a postconsolidation VGPR of 90.9% when daratumumab was added to RVd vs 73.2% with RVd alone.^7-9

If you come down to the MRD [minimal residual disease] negativity, IFM 2009 was 79% with transplant and RVd vs 65% with RVd alone; FORTE was 65% with KRd and transplant vs 66% with KRd, which seems quite equivalent.^2-5 Again, quite a difference in the daratumumab plus VTd group 64% vs 44% with VTd alone and quite a difference in the daratumumab plus RVd arm at 62.5% vs 27.2% with RVd alone.^6-9 Of course, these are cross-trial comparisons. I’m looking more so within each study than across the board, but there is an increasing benefit by adding more intense therapies early on.

What were the design and details of the IFM 2009 trial? Patients got either RVd with or without transplant.^2,3 Those that did have the transplant got 3 cycles and then had a transplant and then a couple of more cycles as consolidation. In those who were not getting a transplant, they got 3 cycles, had their cells collected, and then had another 5 cycles of RVd. Everybody was placed on lenalidomide maintenance thereafter.

In terms of PFS [progression-free survival], we see over a year benefit in those who had a transplant over not having a transplant.

Although, in the 8-year OS [overall survival] rate at the 90 months follow-up was essentially the same between groups; 62% in the transplant arm, 60.2% in the nontransplant arm. I will say that, of course, 80% of the non-transplant arm got a transplant at first relapse. We see quite a significant difference in PFS, but not necessarily in OS when patients are given the option to have a transplant later. Both the high-risk vs standard-risk groups favor the transplant. [It was less overt] in the high-risk group, but those numbers [were] pretty small, less than 50 patients. One of the things that really came through in the IFM study was the power of the depth of response.³ So MRD status was particularly prognostic in these patients. Such that even if you didn’t get the transplant, having achieved MRD negativity was much more likely and gave you a better outcome. That being said, having had a transplant gives you a much better likelihood of getting into MRD negativity.

How did the FORTE trial play a role in this setting? The FORTE study built on this.^4,5 So this had a 3-arm study design. [The first arm was 4 cycles of KCd (carfilzomib, cyclophosphamide, and dexamethasone), then transplant, then 4 more cycles of KCd. The second arm was 4 cycles of KRd, then transplant, then 4 more cycles of KRd. The third arm was KRd over 12 months.] I won’t go into a lot of detail about the KCd arm.

Let’s focus in on the KRd arms, either for 12 months, or KRd with a transplant and then 4 cycles of consolidation. Again, very similar to the IFM design but for a longer period of time. There’s a second randomization to either just go onto lenalidomide maintenance or onto carfilzomib plus lenalidomide maintenance.

The key point here was that if you had had the transplant, the PFS was improved.⁵ [In those who had a transplant and KRd in the FORTE trial the PFS was 78% vs 66% in those who received KRd for 12 months with no transplant (HR, 0.64; 95% CI, 0.44-0.94; P = .023)]. There is benefit in getting a transplant and we see it both in standard and in high-risk patients. What’s interesting is that in that second randomization [to maintenance therapy] there also seems to be a benefit in giving more than just lenalidomide. Lenalidomide maintenance is pretty much the standard of care across the board.

One could argue in high-risk patients they need more. But at least in the preliminary results it looks like adding something more to lenalidomide can improve PFS. The interesting thing about this FORTE study was that the depth of response that people achieved after their consolidation, whether they had a transplant or not, was essentially the same, even the MRD negativity. But the PFS was influenced. So, I think it still makes the argument that even in that deep response, it doesn’t capture everything. This is a way in which the field is moving a little bit [to understand] that a single MRD negativity doesn’t tell you everything. As we say in the transplant world, transplant contributes to both the depth and the duration of response.

But if someone had already achieved that depth, there’s not much further to go, though it did seem to be more durable. So, even if patients between the KRd without transplant and the KRd with transplant [arms] seem to be the same at the end of their induction or their consolidation, there was a difference. Transplant kept you in remission for longer.

Please discuss the CASSIOPEIA trial that added daratumumab to their regimen for patients with multiple myeloma.

So the natural question is, can we do better than a triplet by adding a doublet? The CASSIOPEIA study was a large, randomized trial [that addressed this question].⁶ I’m not going to spend a lot of time on it, because we really don’t use a lot of thalidomide here in the US. But the patients received VTd or daratumumab plus VTd for 4 cycles, had their stem cells collected, had a few more cycles collected in transplant, and then received 2 more cycles of VTd or VTd plus daratumumab. After that, there was a further randomization, which I’m not going to get into. The primary end point of the study was sCR [stringent complete response], which was kind of an unusual but an important end point by the depth of response that they observed. It met its end points. So if you had had daratumumab plus VTd, your sCR rate was 29% vs 20% in the VTd arm [odds ratio (OR), 1.60; 95% CI, 1.212.12, P = .0010].

When we start to look at the PFS, this favored daratumumab plus VTd across the board, except those with the highest-risk disease where that [was not] as impressive [HR, 0.47, 95% CI, 0.33-0.67, P < .0001].⁶ The MRD negativity rates, whether they were done by next generation flow or next generation sequencing, [showed] about a 20% improvement by adding the daratumumab to the triplet of VTd.

What did the GRIFFIN trial demonstrate when using daratumumab plus RVd? The GRIFFIN study was similar to the CASSIOPEIA, albeit a randomized phase 2 trial.^7,9 In GRIFFIN, daratumumab was added at each step along the way, in the daratumumab plus RVd arm in induction, and then after a patient had a transplant, they were given 2 more cycles of consolidation, either with daratumumab plus RVd or just RVd. Then lastly, without a randomization, if a patient were getting daratumumab all along, then they continued daratumumab with the lenalidomide for 2 years. After that, the daratumumab is dropped and the lenalidomide continued. In the control arm lenalidomide was continued indefinitely.

So, GRIFFIN was trying to determine if adding daratumumab improves response after induction, after transplant, after consolidation, and even in maintenance therapy.^7,9 The bottom line is, even if you just focus on the RVd group, those patients benefitted by deepening their response after each step—after induction, after transplant, and interestingly after consolidation.⁹

Consolidation with chemotherapy after a transplant is not the standard of care in this country. It is in a couple of other countries. But it’s interesting that the response deepened after further consolidation. This may speak to the sensitivity of patients and a patient’s disease after having had a transplant. That being said, when you compare the RVd with the daratumumab plus RVd, you can see a deeper response in those patients that had the daratumumab added to their regimen and literally at each cut-off—after induction, after transplant, and after consolidation.

Then at the end of 12 months of maintenance, 63% of people in the daratumumab plus RVd arm achieved that deepest response of sCR [OR, 1.98; 95% CI, 1.123.49; P = .0177).7 The rate of CR was 81.8% or greater in the daratumumab plus RVd arm compared with 60.8% in the RVd arm [OR, 2.53; 95% CI, 1.33-4.81; P = .0045]. So, you see an additional 20% depth of that response. This was seen, whether it was looking at sCR or MRD, across the board.

Again, they did not see a clear benefit it in those highest-risk patients [eg, ISS stage III disease or high-risk cytogenetic abnormalities] because the numbers were small. There were only 15% of patients that were high-risk. But [there was a] consistency of benefit [in subgroups] across the board based on age and prior therapy and cytogenetic risk. It’s too early to make any definitive comments about both PFS and OS. But [there appears to be an] early trend. in that direction.

What adverse events are most concerning with the combination of daratumumab plus RVd?

In terms of AEs [adverse events] when patients were treated with daratumumab plus RVd there was a higher percentage of certain cytopenias observed at grade 3 or 4 [ie, neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia].^7-9 In particular, whenever we add a CD-38 antibody to an immunomodulatory drug, we definitely see more neutropenia and a degree of thrombocytopenia and anemia. So those have to be considered as we use these treatments. Then we look at those AEs that were non-hematological, as we [would] expect when we have a CD-38 antibody plus a immunomodulatory drug, we tend to see more upper respiratory tract infections. Of course, there was also the presence of infusion reactions that you wouldn’t get with RVd alone.