Necessity of Transplant Considered in Multiple Myeloma

Sagar Lonial, MD

Sagar Lonial, MD, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine, and the chief medical officer of Winship Cancer Institute of Emory University, explains the need for transplant in patients with multiple myeloma.

Targeted Oncology^TM: Is there a reason to use subcutaneous daratumumab (Darzalex Faspro) instead of intravenous (IV) daratumumab (Darzalex) or vice versa?

LONIAL: The prices are identical [for both]. The observation [after treatment] is only for the first 2 doses [for subcutaneous daratumumab]. Once you get beyond that, the patients stay 10 minutes in the chair after their dose and then leave. It is quick after the first 2 doses. For the first dose, they have to be watched for a couple of hours, which is still shorter than the first dose of IV daratumumab. With the second dose, the patient can come in for an hour, and then you let them go. It is much quicker. Everybody in our practice has switched. We have had [patients] from other practices come to see us because they want to get subcutaneous daratumumab. They don’t want to do the IV anymore.

How does the addition of stem cell transplant (SCT) when patients are under treatment affect response rates?

If you look at patients with newly diagnosed myeloma with SCT as part of the [treatment, there was more] post consolidation very good partial response [VGPR] or better rates in the IFM 2009 trial [NCT01191060] with transplant [78% vs 69% without SCT].¹ The post consolidation VGPR or better rate [also] is higher in the FORTE trial [NCT02203643] with transplant [89% vs 87% without SCT].²

An exception [is] the CASSIOPEIA trial [NCT02541383] data, [which added] daratumumab; it’s in the 80% range [83.4% vs 78%].3 With the GRIFFIN trial [NCT02874742], adding daratumumab to RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] resulted in a 90.9% rate [vs 73.2%].⁴ [SCT made rates] significantly higher across the board. There are patients who get a transplant but also patients who potentially have the addition of daratumumab to either VTd [bortezomib, thalidomide (Thalomid), dexamethasone] or RVd as part of their initial induction therapy.

We will talk specifically about FORTE because I think there’s a weakness there that many physicians don’t necessarily recognize [as worth] discussing.

Before you discuss the FORTE trial, what were the efficacy results of the IFM trial?

If you look at patients in terms of their best response with the IFM study, what you see is a much higher complete response [CR], VGPR, or a better minimal residual disease [MRD] negativity rate for the group that had the transplant than for the group that did not have the transplant.¹

The patients who achieve MRD negativity do better. There’s no question about it. That’s probably prognostic. The question is, if you take somebody who’s MRD positive, can you make them MRD negative by changing therapy? Do you change the progression-free survival [PFS]? Right now, nobody knows the answer to that question. My guess is you may not be able to change their PFS because, prognostically, they are a different group. They [do not have] hyperdiploid disease....[or] low-stage disease. Just because you give them a numeric CR doesn’t mean their PFS is going to necessarily carry in that same vein, but those are the things that are being tested right now in randomized trials.

How was the FORTE trial designed and what did the results show?

It had 3 arms. [The first 2 were KCd [carfilzomib (Kyprolis), cyclophosphamide, dexamethasone] and KRd [carfilzomib, lenalidomide, dexamethasone] times 4; those 2 arms were both followed by a transplant.2 Then you have KRd times 4, KRd times 4 more, KRd times 4 more; a total of KRd12 with no transplant built in at all [in the last arm]. Forget the KCd arm because KCd did terrible in comparison, as VCd [bortezomib, cyclophosphamide, dexamethasone] often does. It was inferior to both of the KRd arms with or without a transplant.

If you look at CRs, VGPRs, and MRD negativity, there is a suggestion that KRd12 is just as good as KRd times 4 followed by transplant [then another KRd times 4]. This was an argument being used by many [physicians], particularly by [those who liked] KRd, that said you don’t need a transplant with KRd because it’s just so good.

If you look at who relapsed earlier, it was [patients] lower in the group [who were given] KRd times 4 and transplant versus the KRd12 group without a transplant; it was twice as high [8% vs 17%, respectively].

The problem was not achieving MRD negativity. The problem with sustained MRD negativity...was that for patients who were in the KRd-only arm and did not have a transplant, the ability to maintain MRD negativity was lower than it was if [they] had the transplant. This is why I think transplants continue to have an important role in consolidation. It speaks to the fact that KRd may be good; it may be just as good as what you see in terms of response rates, but the durability of those responses was not as good if you did not consolidate with the transplant. It was most marked in the high-risk subset. The odds ratio was 4.85, but we saw it in the patients with R-ISS stage II, as well, with an odds ratio of 3.6. So, both high-risk and intermediate-risk disease are worse if you don’t do the transplant.

What were the data from the CASSIOPEIA study for daratumumab?

[These were] phase 3 data of VTd daratumumab versus VTd in transplant-eligible, newly diagnosed myeloma.³ One of the caveats is that a small percentage of patients were high risk. Most of them were at standard risk or an ISS stage I or II.

If you look at the response, stringent CR, and MRD negativity, the caveat here is [that] the MRD negativity was 10⁻⁵, not 10⁻⁶. In my mind, it’s a regulatory end point. It’s not a “Can you stop therapy?” end point. I think 10⁻⁶ is a “Can you stop therapy?” question, whereas 10⁻⁵ is how do you get this drug approved sooner rather than waiting for PFS to be the primary end point. In the patients who received daratumumab with VTd as opposed to VTd [alone], [responses were] higher across the board. There is a big advantage to adding daratumumab early in the treatment.

Stringent CR, using a flow cytometry or next-generation sequencing at 10⁻⁵, after transplant was much higher in the group that received daratumumab compared with the group that did not receive daratumumab. This translated into a better response up front in the first 4 cycles and resulted in a better posttransplant consolidation number, as well.

The PFS data are being touted as the evidence that supports the use of daratumumab VTd as part of the induction regimen, because the PFS was much longer [HR, 0.47; 95% CI, 0.33- 0.67; P < .0001].

Everybody [underwent] a transplant, but the challenge here—and I’m going to tell you my interpretation—is when do the [Kaplan- Meier] curves start to separate? It was right around 9 months. What happened at 9 months? They were randomized to maintenance daratumumab versus observation. There was no lenalidomide maintenance arm in this trial. Everybody [was given] daratumumab VTd. They [underwent] a transplant, and then they were randomized to daratumumab versus observation for maintenance therapy. I’m not convinced that this is going to hold up because I think a lot of it has to do with the second randomization, which was the daratumumab versus observation. I could be wrong. It just looks too close to be more than a randomization at maintenance question.

How does the GRIFFIN trial play a role in this setting?

This is far more relevant for us. The study was daratumumab RVd versus RVd in patients with newly diagnosed myeloma. [Patients either received] daratumumab RVd, then [underwent] a transplant, then daratumumab RVd consolidation, then maintenance with daratumumab and lenalidomide; or RVd, transplant, RVd consolidation, and then single-agent lenalidomide as the maintenance.⁴

In terms of response rates, CR, stringent CR, and VGPR were superior for the group that received daratumumab RVd compared with the group that just received RVd. MRD negativity was at least double, if not 2.5 times higher, for the group that received daratumumab RVd compared with the group that received just RVd initially.

This trial was too small to be able to see anything in terms of who has the greatest benefit [in the subgroups]. One of the points I’ll make is patients with ISS stage I [favored the daratumumab arm], whereas in the high-risk group, it was in the middle or was neutral in terms of the benefit of the addition of daratumumab. That’s part of the rationale for our group [regarding] how we decide whether a patient gets daratumumab RVd or KRd as part of their initial induction based on risk.

The median PFS with 2-year follow-up was similar [in both arms]. It’s starting to separate at 95.8% median PFS for the group that [was given] daratumumab RVd compared with 89.8% for the RVd-alone group....This 89.8% is not that far off from what we’d expect in terms of PFS for a group of patients getting RVd transplant and maintenance.

With the most common hematologic toxicities, there was a slightly higher rate of neutropenia and thrombocytopenia in the group that received daratumumab. That’s not a surprise. If you’ve used lenalidomide and daratumumab or pomalidomide [Pomalyst] and daratumumab in the relapse setting, you know that neutropenia numbers are higher. The lymphopenia is not a surprise, either, but in general, this was pretty good for what one would expect. There were only 100 patients in each arm, so this is not a randomized phase 3 trial; it’s a randomized phase 2 trial. There is a European randomized phase 3 trial that is doing exactly the same thing with 1000 patients. We will have much more information from that trial.

Why isn’t overall survival a primary end point for these trials?

I think that the challenge with overall survival in a newly diagnosed myeloma trial is that it will take 10 years. You are not going to know the answer any time soon. The flipside of that is you are arguing the mSMART [Mayo Stratification of Myeloma and Risk-Adapted Therapy] guidelines, which are added to the high-risk group. I don’t [believe] there is any evidence to say it makes high-risk [disease] any better.

If you look at the first analysis of the CASSIOPEIA trial, the only group that did not benefit from the addition of daratumumab was genetic high risk. It was the same for the ALCYONE [NCT02195479] and MAIA [NCT02252172] trials. There is now a meta-analysis published by the group at The University of Alabama at Birmingham that looked at later analyses of those trials and says high risk does better with daratumumab than it does without.⁵ But they are not taking that first analysis into account. They are only looking at the later analysis, and all the high-risk patients [have died in] the first analysis. By the time you get to the second analysis, they’re not the same high-risk patients as they were with the first. So, I’m skeptical that it makes a difference in high-risk patients.

Do you use daratumumab as consolidation and maintenance or only as induction therapy?

That’s in the trial. But I’m not sure that you should adopt what they did in the GRIFFIN trial as the standard of care. I’m only taking the GRIFFIN outcomes with the short-term outcomes and not giving any consolidation or maintenance because I don’t think we’re there yet. [We only use daratumumab for induction.]

_REFERENCES:

_{1. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bort- ezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{2. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexametha- sone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(suppl 15):8002. doi:10.1200/JCO.2019.37.15_suppl.8002}

_{3. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1}

_{4. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bort- ezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}

_{5. Giri S, Grimshaw A, Bal S, et al. Efficacy of daratumumab in the treatment of multiple myeloma with high-risk cytogenetics: meta-analysis of randomized phase III trials. J Clin Oncol. 2020;38(suppl 15):8540. doi:10.1200/JCO.2020.38.15_suppl.8540}