Triplet Regimens Show Positive Efficacy for Transplant- Ineligible Multiple Myeloma

During a Targeted Oncology Case-Based Roundtable event, Rafael Fonseca, MD, director chair, Department of Internal Medicine, and professor of Medicine at the Mayo Clinic Cancer Center n Phoenix, Arizona, discussed the case of a 72-year-old patient with multiple myeloma.

Targeted Oncology^TM: What factors make a patient with multiple myeloma eligible for stem cell transplant?

FONSECA: It’s more functional age [than chronological age], and it’s fitness. Anyone under 65 years old has to have a significant comorbidity to not move to transplant. The way we look at it at our centers, [for those] 65 to 75 years old, it depends. Even between 70 and 75 years, people that are “very healthy,” “very athletic” can still get quite a bit of toxicity from transplant. It takes some time to recover. One has to be careful with that. Organ function [is another factor], and one of the key aspects is amyloidosis.

Which trials have looked at VRd (bortezomib [Velcade], lenalidomide [Revlimid], dexamethasone) in the multiple myeloma space?

The SWOG S0777 trial [NCT00644228] fulfills all the basic tenets of evidence-based medicine. [It was] randomized, phase 3, and a total of 525 patients [receiving] VRd versus Rd [lenalidomide, dexamethasone]. Both [groups went] onto maintenance, and the idea was that these were patients without intention for immediate transplant. There was median follow-up [of]…55 months, and about 43% of patients were 65 years or older.¹

The results for median progression-free survival [PFS] were in favor of the triplet versus the doublet, 41 versus 29 months [HR, 0.742; 95% CI, 0.594-0.928; P = .003].² When you look at overall survival [OS], it was not reached [with VRd vs 69 months with Rd]….We’re talking about 10 years almost. It’s getting to be what we’re seeing across the board for multiple myeloma—that most patients should have a half-life greater than 10 years. It has a ratio of 0.7 between the 2 treatments [95% CI, 0.543-0.926; P = .0114].

[The toxicity profile was] expected to have more neurologic adverse events [AEs], grade 3 or higher. Neurologic AEs were 33% [in these] patients; 12% of patients had grade 3 or more pain, and 23% had sensory AEs and [22% had] gastrointestinal toxicities. This was a very good regimen but still with some toxicities to deal with.

The other approach would be VRd-lite, which is a reduction in dosing. Now, [in some data], investigators used bortezomib 1.3 mg/m², lenalidomide 25 mg, and dexamethasone 40 mg, but you can still go significantly further down from that to 15 mg [lenalidomide] and then dexamethasone to 20 mg.³ So dose adjustment is important.

How has daratumumab been used in triplet regimens?

The MAIA study [NCT02252172] is a randomized, phase 3 of 737 patients.⁴ It was with a triplet, but instead of bortezomib, now it was daratumumab [Darzalex; DRd] versus the doublet Rd. In this case, it was continued until progressive disease. The primary end point was PFS.

If you look at the efficacy, the medium PFS has not been reached with the triplet versus 31.9 months [with Rd]. Remember, in SWOG S0777, it was 29 months [with Rd]; these are pretty consistent, 29 versus 31.9 months. At 30 months, the PFS rate was 71% for the triplet and 56% for those in the Rd arm, and the OS has not been reached. Stringent complete response was 30% versus 12% [for DRd and Rd, respectively].

These are pretty interesting data. The group that did the best are the patients who got the triplet and achieved minimal residual disease [MRD] negativity, who seemed to do just as well as the ones who got the doublet and achieved MRD negativity. Both groups did better than those given the triplet or the doublet and remained MRD positive, even though in this patient category, the triplet is still better than the doublet.

It just means that some patients can get to MRD [negativity] and that’s why they’re doing so well. While in my mind there’s no question there’s a bit of biology [to this], I think the key is

a better treatment. Because what [these data tell] me is that [a patient is] 3 times more likely to become MRD negative if they get the triplet than if they get the doublet. We’ve never had MRD ranges like this with…some of the older regimens. That is an issue, and I think it really supports that even in this patient population, arguably, getting the treatments that cause deeper response—of course, that’s good.

The safety profile: I’ll point out [there was] a bit more neutropenia with the triplet, so grade 3/4 neutropenia was 50% versus 35%. That would be another good takehome message, because I don’t think this should be a showstopper. It’s just something we need to be aware of. In general, for the rest of the toxicities, they seem pretty similar [between DRd and Rd], perhaps a bit greater [with DRd]. I tell my patients always that I think daratumumab doesn’t add much to the toxicity of the regimens.

Can you discuss trials that compared triplet regimens?

ENDURANCE [NCT01863550] is the ECOG study that Shaji Kumar, MD, presented as a plenary session at the American Society of Clinical Oncology Annual Meeting.⁵ This was a very interesting study. First of all, it had over 1000 patients and…the idea was to provide treatment for patients who [did not have] intent to move to stem cell transplants. Patients with high risk were excluded. They randomized patients between VRd and KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone].

Keep in mind that in the study, the primary end point was to test the hypothesis whether KRd was superior to VRd. It is not an equivalency study. It’s not meant to say they’re identical. The reason that was important is because a lot of phase 2 studies had shown great results with KRd, so will that translate into ultimate benefit [over VRd] for patients?

The clinical trial was negative. The PFS and the OS were identical and if you look at the toxicity, essentially what you’re doing is a trade-off for toxicity. If you bring together cardiopulmonary and renal AEs, they are more common with the carfilzomib treatment. If you look at peripheral neuropathy, they are more common with the VRd. The cardiopulmonary, in unique circumstances, would be graver or more serious than neuropathy, but the cardiopulmonary tends to be reversible, whereas the neuropathy tends to be enduring.

When Kumar presented the study, he concluded that VRd should remain the standard of care for patients with multiple myeloma. I would say that could be open to interpretation. I think what you are dealing with is trade-offs between the various toxicities and the various treatments, but in my mind, both in clinical practice as well as for clinical trials, I think KRd is still an acceptable and a good option for the front-line treatment of multiple myeloma.

How do you usually treat patients after they receive a transplant?

There are a number of trials that are asking what we [should] do for treatment post transplant. More treatment of the good kind is better. I think maintenance was the first way to do it. The STaMINA trial [NCT02322320] tried to address this, and it had shown that continuation of therapy seems to be better. The same was true with the FIRST trial [NCT00689936]. Until we get to the point that our treatments are curative—and there might be a future for that—longer therapy also seems to be better for most of our patients.

_References:

_{1. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X}

_{2. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase 3 trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8}

_{3. Rodriguez C, Lantz J, Akbar F, Lantz L, Dressler E. Assessing efficacy and tolerability of a modified lenalidomide/bortezomib/dexamethasone (VRd- 28) regimen using weekly bortezomib in multiple myeloma. Presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract SP-036.}

_{4. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249}

_{5. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6}