Triplets Target Lenalidomide-Refractory Myeloma Subgroup

Faith E. Davies, MD

Treatment for patients with relapsed/refractory multiple myeloma is becoming more personalized, including for those who are refractory to lenalidomide (Revlimid), with a number of triplet regimens that have demonstrated clinical benefit, explained Faith E. Davies, MD.

“Times have changed dramatically. There are now over 30 different options if you look at the National Comprehensive Cancer Network guidelines for relapsed/refractory myeloma,” said Davies. “The important thing is trying to choose the best option for a particular patient.”

For example, in the phase III ICARIA-MM trial, the addition of isatuximab-irfc(Sarclisa) to pomalidomide (Pomalyst) and low-dose dexamethasone led to a greater than 40% reduction in the risk of disease progression or death versus pomalidomide and dexamethasone alone in patients with relapsed/refractory disease.¹ These results led to the March 2020 FDA approval of isatuximab plus pomalidomide/low-dose dexamethasone for the treatment of adult patients with myeloma who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor.

Similarly, the OPTIMISMM trial looked at adding pomalidomide to bortezomib (Velcade) and dexamethasone versus bortezomib/dexamethasone alone. Patients on the study had relapsed/refractory myeloma and had received 1 to 3 prior lines of therapy, including ≥1 lenalidomide-containing regimen. The overall response rates were 82.2% in the triplet arm versus 50.0% in the doublet arm, and the median PFS was 11.20 months and 7.10 months, respectively (HR, 0.61; 95% CI, 0.49-0.77; P <.0001).²

Lastly, results from the phase III CANDOR trial showed that adding daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone reduced the risk of disease progression or death by 37% versus carfilzomib/dexamethasone alone in patients with relapsed/refractory myeloma. The median PFS was not reached in the triplet arm versus 15.8 months in the doublet arm (HR, 0.63; 95% CI, 0.46-0.85; P = .0014). Furthermore, the median overall survival had not been reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08).³ Based on these data, a supplemental biologics license application was submitted to the FDA for daratumumab for use in combination with carfilzomib and dexamethasone for the treatment of patients with relapsed/refractory disease.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Davies, a professor in the Department of Medicine and director of the Clinical Myeloma Program, NYU Langone Health’s Perlmutter Cancer Center, discussed pivotal research in relapsed/refractory myeloma and precision medicine efforts in the field.

OncLive: How do you currently determine treatment for patients with relapsed/refractory multiple myeloma?

Davies: When patients move from newly diagnosed to first relapse to second relapse, there is a drop off of patients.

Although we sit there and think, "I can save that treatment for later," we shouldn't be doing that because many patients don't make it to third- or fourth-line treatment. We should be using our best treatment as soon as we can, and we should try to individualize that treatment to the patient. When looking at a patient, consider their prior treatments, their clinical responses, tolerability, and current challenges, and use that information to decide upon a combination.

What recent studies have had an impact on relapsed/refractory disease?

One of the difficult areas is what to do with lenalidomide-refractory patients. Relapsed/refractory patients will usually receive maintenance lenalidomide, and many of the options that we have available at first relapse contain lenalidomide.

One option would be to increase the dose of lenalidomide from 10 mg to 25 mg. There have been 3 recent studies that have taken a slightly different approach. One study is using an antibody, isatuximab, with pomalidomide and dexamethasone. This trial particularly looked at patients who were lenalidomide-refractory. In that study, the 3-drug regimen was compared with pomalidomide and dexamethasone alone; results showed that the 3-drug regimen was much better.

The second study comprised that same group of patients, but utilized pomalidomide with bortezomib/dexamethasone. Patients who received the 3-drug regimen had better outcomes than those patients who received bortezomib/dexamethasone alone.

A study that was presented at the 2019 ASH Annual Meeting used a slightly different 3-drug regimen: daratumumab with carfilzomib and dexamethasone. They compared that regimen with the 2-drug regimen of carfilzomib/dexamethasone. Patients on the 3-drug regimen performed better. Additionally, adding the third drug didn't particularly affect the safety profile, but it did make a big difference to the response profile and progression-free survival.

Now, there are a number of combinations we can use for that difficult-to-treat group of lenalidomide-refractory patients.

Carfilzomib has also been evaluated in a number of settings, including the ARROW trial. Could you discuss that trial and its findings?

Carfilzomib is an excellent proteasome inhibitor. One of the issues, as a prescribing physician, is that a number of the different phase III clinical trials [investigating carfilzomib] use different dosing. The original studies use twice weekly dosing at 27 mg/m². Other studies have used a 36 mg, a 56 mg, and then more recently, a 70 mg/m² dose.

The ARROW study showed that if we use once-weekly dosing at 70 mg/m², compared with twice-weekly dosing at 27 mg/m², those patients on the once-weekly dosing with the higher dose had a longer PFS, better response rate, and better tolerability. This suggests we can use once-weekly dosing, which is more convenient for patients, but also it seems to be more tolerable.

Carfilzomib has a specific safety profile. Unlike bortezomib, there is not a peripheral neuropathy issue. We need to be careful when measuring blood pressure, as well as potential shortness of breath—which, if it's going to be an issue, tends to be an issue on that first dose. The data are very promising for moving that once-weekly dosing forward.

One issue is whether we can take the ARROW study data forward to some of the combinations, and we’re unsure at the moment. Many of the combination studies that have been performed have been using the twice-weekly dosing. I think that it is OK to go forward with the once-weekly dosing, but we don't have the clinical data to support that approach.

What precision medicine efforts are being used in relapsed/refractory multiple myeloma?

There are a number of different precision medicine approaches that are currently being evaluated. In myeloma, we've been targeting different groups for years. Younger, less fit [patients] have received transplants. Patients with t(4;14) have received bortezomib or another proteasome inhibitor.

Now, there is some movement towards using venetoclax (Venclexta). Venetoclax is used a lot in CLL and is a BCL-2 inhibitor. It appears that patients who have t(11;14) have high BCL-2 levels, and many of those patients respond exceptionally well to venetoclax. There was a little bit of trouble a little while ago because one of the studies that read out suggested that there may be an increase in toxicity. That study looked at all-comers with myeloma, not just targeting those patients with a t(11;14). The [partial hold is now lifted] and the drug is going forward in patients with t(11;14). The results seem to be very promising.

The other precision medicine approach, which has an evolving story, is whether you can target other specific mutations. Many patients have a mutation of the RAS pathway. Drugs that are commonly used in melanoma and lung cancer could potentially be used in multiple myeloma. Those drugs are in the experimental phase, and there are a number of trials looking at them. They may only be effective for a short time, and may need to be combined with other drugs.

What advice do you have for physicians who are treating patients with relapsed/refractory multiple myeloma?

Monitor patients closely, be proactive when patients relapse, and remember that there isn't a wrong answer. Each patient is different. Knowing what treatment the patient had before, what adverse events they had from that treatment, and what problems they have now will enable us to personalize the therapy to an individual patient and make sure that we give that patient the best treatment for them at that particular time.

References

1. Richardson PG, Attal M, S. Rajkumar V, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).&#8239;J Clin Oncol. 2019;37(suppl; abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004
2. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi: 10.1016/S1470-2045(19)30152-4
3. Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Blood. 2019;134 (suppl_2):LBA-6. doi: 10.1182/blood-2019-132629