Costa Reviews Regimens for Patients With Transplant-Eligible and Transplant-Ineligible NDMM

Luciano J. Costa, MD, PhD

Associate Director for Clinical Research

O’Neal Comprehensive Cancer Center

University of Alabama at Birmingham

Birmingham, AL

Targeted Oncology^TM: What are the options for primary therapy in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM)? What is the role of transplant in these patients?

COSTA: Transplant-eligible patients with NDMM were in the IFM 2009 study [NCT01191060], which was designed 12 years ago, when people were very impressed by the efficacy of RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone].^1,2 So they said, “Well, now that we have this great regimen, let’s see if we can postpone transplant without prejudice.”

They got transplant-eligible patients up to the age of 65, and everybody got 3 cycles of RVd, and [collection of] autologous stem cell transplant [ASCT] cells. Half the patients got ASCT followed by 2 cycles of RVd and the other half got RVd for 5 more cycles, making it 8 cycles. Beyond that, everybody received fixed-duration maintenance for 12 months with lenalidomide as a single agent. Upon progression, the patients on deferred transplant in the RVd alone arm, were to get an ASCT and indeed, 77% of them did. The primary end point was progression-free survival [PFS]. It was a positive trial, which showed that up-front transplant is superior to the deferred transplant and this was more prominent in the standard-risk patients.^1,2

The IFM 2009 [PFS by MRD (minimal residual disease) status] study results were updated at the ASH [American Society of Hematology] 2020 annual meeting by Dr Perrot. The MRD was 10^-6, the deepest level of MRD, and importantly, only about 30% of the patients on the transplant arm had MRD negativity, and only 20% in the RVd alone arm. Nevertheless, the group that achieved MRD negativity had outstanding results. Just keep in mind: These patients only got 1 year of maintenance, but if you look at patients 7 years after discontinued maintenance, you still have many alive without progression. But interestingly, even among MRD-negative patients, the ones who got there with transplant still do better. That’s also certainly true for the patients who were MRD positive with transplant.²

How has transplant been investigated in more recent studies?

The FORTE trial [NCT02203643] still informs the current role of transplant and takes it up a notch [by using] carfilzomib [Kyprolis], which is seen as perhaps a better proteasome inhibitor than bortezomib. This 3-arm study tried to answer 3 questions.³

First, what was the best partner for carfilzomib for these patients? Was it cyclophosphamide [Cytoxan] or lenalidomide? When a triplet is used with carfilzomib, does one still need transplant? So the options are KCd [carfilzomib, cyclophosphamide, dexamethasone], ASCT, KCd; KRd [carfilzomib, lenalidomide, dexamethasone], ASCT, KRd; or 12 cycles of KRd , essentially replacing transplant with 4 cycles of KRd. There was a second randomization between lenalidomide or carfilzomib [KR] plus lenalidomide alone [R] maintenance until progression or intolerance.³

I think this is the second or third study that confirmed that the best partner for proteasome inhibitors is an IMiD [immunomodulatory imide drug]. So the KRd plus ASCT arm did far better than the KCd plus ASCT arm. But also, and very importantly, KRd plus ASCT did far better than the [12 cycles of] KRd. So even when using 12 cycles of a triplet with carfilzomib, ASCT still outperformed conventional therapy, and that seems to be the case irrespective of staging or cytogenetic risk or LDH level at the time of presentation.³

The most intriguing part of this study is the second randomization [for maintenance therapy]. So those are people who made it to the end of those 12 cycles, or 4 cycles plus ASCT plus 4 more cycles. They got randomized again for R, very much like it is done in the United States, or KR maintenance. There was still a positive comparison that showed an improving PFS for patients who got doublet maintenance therapy, and the benefit, again, seems to go for different profiles of risk and not limited to particular patient groups.^3,4

What if monoclonal antibody therapy is incorporated?

The largest study done to date, [which is the phase 3 CASSIOPEIA study (NCT02541383)], used daratumumab [Darzalex], an anti-CD38 monoclonal antibody. It used a European paradigm where arm A had 4 cycles of VTd [bortezomib, thalidomide [Thalomid], and dexamethasone], transplant, and then 2 more cycles of VTd and compared that to arm B, which had the addition of daratumumab [D-VTd]. There was a second randomization for the maintenance phase that compared observation vs single-agent daratumumab every 8 weeks, which is very infrequent dosing, for 2 years [followed by observation until progression of disease].⁵

It was a huge study with over 1000 patients. As they evolved to different phases of treatment, the responses got deeper, but certainly more in the D-VTd arm, which outperformed both arms in terms of the primary end point that was stringent CR [(complete response) at 29% for D-VTd vs 20% for VTd (P = .001)], but also in MRD-negative rates, and median PFS, which was [51.5 months for VTd and was not reached for D-VTd (HR, 0.58; 95% CI, 0.47-0.72; P < .0001)]. The overall survival [OS] hasn’t been reached on the interim analysis but it looks like it’s going to favor D-VTd.⁵

The data presented at the annual American Society of Clinical Oncology meeting in June 2021 generated a lot of discussion because of the maintenance phase of observation vs daratumumab for 2 years.⁶ It was a positive comparison. The arm that got daratumumab maintenance had almost a 50% reduction in the risk of progression or death.

Looking at the subsets, all the impact from daratumumab maintenance was for patients who had not received daratumumab during induction or consolidation. For that group, the reduction of risk [of progression] was gigantic at 68%, with a hazard ratio of 0.32 [95% CI, 0.23-0.46; P < .0001]. For patients who had already received daratumumab for induction and consolidation, continuing with it for maintenance did not seem to make any difference. The same was true for MRD negativity. There was a bit more MRD negativity with D-VTd plus daratumumab maintenance than D-VTd plus observation, but that was not sufficient to better PFS.⁶

Which regimen with daratumumab was investigated in the United States?

The best data we have so far with our standard regimen in the United States, which is VRd, was from the GRIFFIN study [NCT02874742]. It had a very similar eligibility criteria and study design. There were 4 cycles of RVd, ASCT, and 2 more cycles of RVd vs the same combination but with additional daratumumab. It also had 2 years of maintenance, but the difference is there was no second randomization. The RVd arm got R for maintenance and the D-RVd arm got D-R maintenance. It was a much smaller randomized phase 2 study with over 200 patients.⁷

Like in the CASSIOPEIA study, as you go through the phases of therapy, the responses become deeper and more frequent on both arms, but certainly more on the daratumumab-containing arm.

The subset analysis that was presented at the ASH 2020 annual meeting showed no clear tendency, although the high-risk subset seems to benefit less from the addition of daratumumab, but that’s a difficult group that tends to benefit less from just about any therapy introduced.⁸

The PFS and OS were both secondary end points. This study, it is important to remember, is not powered and mature to show differences in these outcomes. But interestingly, both PFS and OS remain extremely high for both arms.⁸ A more definitive trial is the randomized phase 3 PERSEUS trial [NCT03710603], with subcutaneous daratumumab plus VRd vs VRd alone.

So it is a very similar design to the GRIFFIN trial: 4 cycles, ASCT, 2 more cycles, then the patients who got the VRd continue R maintenance until progression. The groups that get D-VRd go with D-R for 24 months and are then assessed for MRD. If the MRD is negative they discontinue D and continue R; otherwise, they continue both agents.⁹

Every time an agent is added, there is an increase in toxicity. In the GRIFFIN study there was an increase in grade 3 and 4 neutropenia and an increase in thrombocytopenia. There has been a signaling in other trials of a little bit more infection, particularly upper respiratory infection.^7,8

What are the options for primary therapy in transplant-ineligible patients with NDMM?

A trial that really informed our current choices include the SWOG-0777 trial [NCT00644228] that had patients with NDMM. It’s a little bit tricky because traditionally we look at trials in myeloma as being transplant eligible vs transplant ineligible, but this trial was a different population, because in the United States, we have patients with no immediate intent for transplant. So it captures patients who are transplant ineligible, but also some younger patients that, based on practice pattern, were not going to proceed with transplant. So it ended up being a much younger population than we see in the European transplant-ineligible trials.¹⁰

Patients were randomized to the Rd arm for six 28-day cycles and the VRd arm for eight 21-day cycles. So the duration of therapy was 24 weeks for both arms. Both arms got maintenance with Rd at a dose of 25 mg and 40 mg, respectively. The patients continued to progression, unacceptable toxicity, or patient withdrawal. Less than half the patients were over the age of 65, which is quite interesting, but it was not truly a transplant-ineligible population.¹⁰

This study is significant, with improvement in PFS of 41 months for VRd vs 29 months for Rd [HR, 0.74; 95% CI, 0.59-0.92; P = .003]. Patients older than 65 did not seem to benefit.¹¹

The OS in this study is the reason why we are so attached to VRd in the United States, although I would argue we were already attached to it before this study. There was an improvement in [median OS, which was not reached for VRd vs 69 months for Rd (HR, 0.709; 95% CI, 0.543-0.926; P = .0114)]. Looking at age groups, the difference is mostly due to younger patients, but there’s not a discernible difference between Rd and VRd in patients 65 years and older.¹¹ For the toxicity profile there is more neurological toxicity, pain, sensory neuropathy, and gastrointestinal toxicity with VRd.¹⁰

We love a regimen until there’s something better, then we start hating it. We have a little bit of a mixed relationship with bortezomib. It once was the savior of myeloma, but now it is the drug that everybody loves to hate, but I think the OS argument, which I think is a very strong one, needs to be taken with a big grain of salt among the older patients because the advantage is not so clear, and they have more toxicity.

How have other regimens been investigated in the transplant-ineligible space?

RVD Lite [NCT01782963], a published phase 2 study, had patients who were over 65 [or ineligible to transplant]. It was a relatively small study with 50 patients. I think every center has their own version of RVD Lite and ours is slightly different from this study, which used 15 mg of lenalidomide from day 1 to day 21; bortezomib, once weekly; and dexamethasone 40 mg twice weekly for patients younger than 75, and once weekly for patients older than 75. This was done for nine 35-day cycles followed by consolidation with less frequent dosing of both, and an optional maintenance phase [with lenalidomide until progression or unacceptable toxicity]. The median PFS was 41.9 months, which is pretty good.¹²

The results of the ENDURANCE study [NCT01863550] were published in 2020. The trial sought to see if outcomes of patients with NDMM without immediate intent for transplant [could be improved] by upgrading the proteasome inhibitor from bortezomib to carfilzomib. So the Rd arm is the same, but the proteasome inhibitor was either bortezomib at the traditional dosing, or carfilzomib 36 mg/m² twice weekly, for 3 weeks out of 4 for a total of 9 cycles. There was a second randomization trying to answer the optimal duration of maintenance, 2 years of lenalidomide vs indefinite lenalidomide, but we have no results yet.¹³

With bortezomib there is more neuropathy, but with carfilzomib, there is more cardiovascular and renal toxicity. The overall response rates [ORR] were very similar at 84% for VRd vs 87% for KRd. The MRD negativity was a little bit higher in KRd, but to great disappointment, the PFS didn’t seem to change, and was about 34.5 months in both arms.¹³

What were the results of adding daratumumab to treatment for these patients?

Another important study is the MAIA trial [NCT02252172] built on the prior standard, at least in most of the world, for transplant-ineligible patients with NDMM, which was lenalidomide and dexamethasone until progression.

This study asks whether adding daratumumab to the regimen until progression or intolerance improves outcomes. So this population was truly transplant ineligible, as defined in Europe. The patients were either older than 70 or younger than 70 with a contraindication for transplant. The median age was 73, almost a decade older than in the SWOG-0777 trial.¹⁴

The outcomes were improved with the addition of daratumumab: 5-year PFS rate was 53% for D-Rd vs 29% for Rd, and the median PFS was not reached for D-Rd vs 34 months for Rd, with a hazard ratio of 0.53 [95% CI, 0.43-0.66; P < .0001].¹⁴ The biggest update, a late-breaking abstract, came from the European Hematology Association in 2021 and showed, for the first time, a statistically significant improvement in OS. The 5-year OS rate went from 53% in Rd to 66% in D-Rd [HR, 0.68; 95% CI, 0.53-0.86; P = .0013] but the median OS has not been reached in both arms. Not surprising, there’s more frequent and deeper responses on the D-Rd arm with a higher proportion of patients with MRD negativity.¹⁵

From the population level data, the median OS for patients with myeloma in the United States is about 6 years. Now, you have a population that’s older, transplant ineligible, with a 5-year PFS rate of 53% and a 5-year OS rate of 66%, which is quite impressive.

Of course, the common theme is adding a drug adds toxicity. For D-Rd, there is more neutropenia, particularly grade 3 and 4 going from 35% to 50%, but thrombocytopenia was about the same, and lymphopenia was a little bit more. Of course, you get infusion-related reactions from daratumumab of about 41% for any grade, but rarely grade 3 or 4. There is more pneumonia of any grade in the daratumumab arm, at 23% vs 13%, and grade 3 and 4 at 14% vs 8%. Certainly, there is a penalty to improving PFS and OS, in terms of a little bit more cytopenia and infections.¹⁵

In summary, I find it very intriguing that even though the SWOG-0777 trial had a younger and healthier population, the PFS of the control arm, which was Rd, was comparable if not even inferior to VRd, which was 41 months. All these studies have different populations; they are hard to compare and they are about 1 decade apart. But I think when you look at the control arm of both studies, it shows that it is not too far fetched to compare the impact of adding a proteasome inhibitor vs the impact of adding an anti-CD38 [monoclonal antibody].

The RVd-Lite study is right there in the middle; it doesn’t seem to have performed as well as the VRd, but it’s close at 35.1 months. The OS advantage for VRd from the SWOG 0777 trial showed a hazard ratio of 0.71 [95% CI, 0.54- 0.93], and DRd, from the MAIA study had a hazard ratio of 0.68 [95% CI, 0.53-0.86].

_REFERENCES

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