Clinical Data Establish Role of Triplet Therapies in Relapsed Multiple Myeloma

Shagun D. Arora, MD

Findings from the phase 3 CANDOR, ICARIA-MM, and IKEMA studies have solidified the role of triplet regimens versus doublets in the relapsed/refractory multiple myeloma treatment landscape, explained Shagun D. Arora, MD, who added that prolonging progression-free survival (PFS) in this patient population is key.

“The treatment landscape for multiple myeloma has changed a lot,” said Arora. “We shouldn't be afraid of treating our patients with triplet therapies. Our goal should be to get our patients into a deeper state of remission and prolong their PFS. We don't know exactly how to sequence all of these drugs—that is up for debate—but at least we are where we are.”

The CANDOR study evaluated daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone compared with carfilzomib and dexamethasone alone in patients with relapsed/refractory myeloma. Results showed that the triplet induced a 37% reduction in the risk of disease progression or death versus the doublet (HR, 0.63; 95% CI, 0.464-0.854; P = .0014).¹ Moreover, the median overall survival (OS) was not yet reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08). In August 2020, the FDA approved this triplet for use as a treatment for patients with relapsed/refractory myeloma who have received 1 or more prior lines of therapy, based on the CANDOR data.

In the ICARIA-MM trial, the regimen of isatuximab-irfc (Sarclisa), pomalidomide (Pomalyst), and dexamethasone elicited more than a 40% reduction in the risk of disease progression or death compared with pomalidomide and dexamethasone alone in patients with relapsed/refractory disease (HR, 0.596; 95% CI, 0.44-0.81; P = .001).² The 1-year overall survival rate was 72% versus 63%, respectively. Based on these data, the FDA approved isatuximab plus pomalidomide/dexamethasone in March 2020 as a treatment for patients with multiple myeloma who have received 2 or more prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor.

Finally, the triplet regimen of isatuximab, carfilzomib, and dexamethasone evaluated in the IKEMA trial led to a 47% reduction in the risk of disease progression or death compared with carfilzomib/dexamethasone alone in patients with relapsed disease (HR, 0.531; 99% CI, 0.318-0.889; P = .0007).³

In an interview with OncLive® during the 2020 Institutional Perspectives on Cancer webinar on Multiple Myeloma, Arora, assistant clinical professor in the Division of Hematology/Oncology at the University of California, San Francisco, discussed the clinical implications of the CANDOR, ICARIA, and IKEMA trials in relapsed/refractory multiple myeloma and the importance of assessing minimal residual disease (MRD). 

OncLive®: What are the current goals of treatment in relapsed/refractory multiple myeloma?

Arora: The relapsed setting is a huge field, and patients need good treatment to get them into a deep remission state. Achieving MRD negativity in this location of treatment course is an important goal. We have great therapies available for achieving MRD negativity, as well as prolonging patients' PFS. Hopefully, as things go on, we will eventually have a cure for our patients.

Why is it important to choose an optimal second-line regimen in the relapsed setting?

It is important for us to treat our patients with an effective second-line regimen because our ultimate goal is to allow our patients to live as long as possible. We know that prolonging their PFS often translates to improved OS. This also allows more research to occur and newer drugs to be approved. That way if and when their disease relapses, we will have better therapies available.

There have been 3 recent trials looking at triplets in relapsed/refractory myeloma. Please discuss the CANDOR, ICARIA-MM, and IKEMA studies and the clinical implications of the respective data.

These are 3 different clinical trials, all with an CD38-directed monoclonal antibody as the backbone and a couple of different pairs. Interestingly, we have 2 different anti-CD38 agents: daratumumab and isatuximab. The latter is the new kid on the block. Isatuximab does have a few different mechanisms of action, in that it causes direct apoptosis without the need for cross-linking. We are still unsure whether that will correlate into changes in clinical outcomes, but we hope that it will.

The CANDOR trial is a comparison of daratumumab with carfilzomib and dexamethasone compared with carfilzomib/dexamethasone alone—a triplet regimen compared with a doublet.

The ICARIA-MM trial looks at isatuximab with pomalidomide/dexamethasone compared with pomalidomide/dexamethasone alone. We know this is really important because most of our patients are treated with lenalidomide up front, often with bortezomib (Velcade) and dexamethasone. Having pomalidomide as a second-line immunomodulatory drug (IMiD) was important to combine with an anti-CD38 agent.

Finally, IKEMA evaluated isatuximab combined with carfilzomib/dexamethasone compared with carfilzomib and dexamethasone alone.

In the 3 trials, we found that we were able to, even in the relapsed setting, get these great very good partial responses (VGPRs). Of course, we shouldn't compare them against each other, but they all had equally great outcomes for our patients. Ultimately, our goal should be to get patients into a VGPR or better state. Again, we want to prolong PFS and hopefully OS, and also ensure that we can get them onto the next clinical trial when relapse occurs and keep their body healthy.

What we found in these clinical trials is that MRD negativity was achieved at higher rates with all of the triplet regimens compared with the doublets. MRD assessment wasn't obtained in ICARIA-MM in as high of a frequency as it was obtained in CANDOR and IKEMA. However, the MRD negativity rate was 31% in IKEMA with the triplet compared with 13% with the doublet, so these were still very impressive results.

Should MRD assessment be incorporated into all trials going forward?

I do. Some data have shown that deeper responses do correlate with longer PFS. There is still a debate regarding that, but it has been studied. That can help us guide therapy. As more results come out and more clinical trials are done to look at MRD assessment, we will have more data. I look forward to seeing these mature data from the 3 different clinical trials.

With more agents added to a regimen, there becomes a greater concern for safety. Were there any notable safety differences between the triplet and doublet regimens?

There was an interesting hint toward increased treatment-related fatalities in the CANDOR study that was described very well in the clinical trial. Five patients died on the triplet regimen compared with 0 on the doublet. Those deaths were specifically related to infections. I didn't see the same results come out from IKEMA. I am not sure if the data are too new, but I am interested to hear the final results from IKEMA.

How are you interpreting and applying these data to your practice?

Another part of all of these trials were that the adverse effects (AEs), other than what I mentioned with regard to fatality, were pretty minimal. The regimens were well tolerated, and toxicities were managed in an outpatient setting in academic centers and private practices.

Secondly, quality of life (QOL) was comparable in all of the trials. You should choose a proteasome inhibitor versus an IMiD based on what you think your patient will tolerate best, as they both can cause potential negative AEs.

Third, I strongly feel that this does prove that we must be using triplet regimens to treat our patients in the relapsed setting. Five to 10 years ago, we may have chosen doublets instead of triplets, but we have seen that these amazing CD38-directed monoclonal antibodies should be paired with something else, plus dexamethasone, to treat our patients who are relapsing.

What emerging or investigational therapeutic modalities are you excited about?

The idea of using bispecific T-cell engagers or CAR T-cell therapies early on to see if we can, with a one-time infusion, give patients a long PFS. We don't use the word cure often, but perhaps we could even cure patients. 

We now have multiple FDA-approved triplet regimens that can be used in relapsed multiple myeloma. It will be a conversation between you and the patient about which regimen is best to use based on their comorbidities, QOL, and whether they want [oral or intravenous therapy]. It is nice to have a lot of options, so we are able to have those open conversations with our patients.

References

1. 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; abstr LBA-6). doi:10.1182/blood-2019-132629
2. Richardson PG, Attal M, Rajkumar SV, 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). J Clin Oncol. 2019;37(suppl 15; abstr 8004). doi:10.1200/JCO.2019.37.15_suppl.8004
3. Sarclisa® (isatuximab) combination therapy demonstrated superior progression free survival and clinically meaningful depth of response in patients with relapsed multiple myeloma. News release. Published June 2, 2020. Accessed August 21, 2020. https://bit.ly/2YkA1YX