Isatuximab Combination Shows Deeper Responses in R/R Multiple Myeloma

CASE SUMMARY

A 60-year-old White woman, with a history of heavy smoking, was diagnosed with stage II multiple myeloma. Cytogenetics showed gain(1q21)​ and her ECOG performance score was 0. At the time, she was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy, followed by autologous stem cell transplant. She achieved a complete remission with VRd and transplant and was also minimal residual disease (MRD) negative. The patient was then placed on lenalidomide maintenance therapy.

Targeted Oncology^TM: What was the set up and patient demographics for the phase 3 IKEMA study (NCT03275285)?

DOUGLAS SBOROV, MD: Patients with relapsed/refractory multiple myeloma received 10 mg/kg of isatuximab [Sarclisa] with carfilzomib [Kyprolis] and dexamethasone [Isa-Kd], with isatuximab given weekly for the first cycle and then every other week thereafter.¹ Carfilzomib, in this case, started at 20 mg/m2 in phase 1 and 2, then at 56 mg/m2 given twice weekly on days 1, 8, and then 15 and 16, then dexamethasone was given with each dose. The comparator arm was [Kd alone] and the primary end point was progression-free survival [PFS] by an independent review committee with key secondary end points being response.

Douglas Sborov, MD, MS​

Associate Professor

Division of Hematology and Hematologic Malignancies

Huntsman Cancer Institute​

University of Utah​

Salt Lake City, UT​

Patients were about 65 years old in both cohorts, but 10% of the patients were over 75 years old with Isa-Kd and about 8% were over 75 in the Kd arm. So, this is speaking to if we can use triplets in older patients, especially this one, and with daratumumab [Darzalex] as well. We did have 15% of patients who had international staging system [ISS] stage 3 disease, which was not a lot, but it's in line with what we see in a lot of our trends that we don't see a lot of patients with high-risk staging. We do see, in this case, the traditional high-risk features, [such as] high cytogenetic risk features in 23.5% [of patients in the Isa-Kd arm] and 25% in the Kd arm.

What were the efficacy results of this trial?

[At a median follow up of 44 months], the median PFS was 41.7 months in the Isa-KD arm [95% CI, 27.1–not complete (NC)] vs 20.8 months [95% CI, 16.2-28.2] in the Kd arm.² The 41.7 months of PFS was after initial disease progression of 2 or more therapies, as well.

This was an important number, and when we look at [further data] for PFS, across the board, you can see that the triplet was favored in all subgroups. Not surprising, but it's very clear the HR favorability was seen in patients with 1q21+ disease [HR, 0.58; 95% CI, 0.38-0.92], patients who were lenalidomide [Revlimid] refractory [HR, 0.58; 95% CI, 0.35-0.97], as well as patients with estimated glomerular filtration rate [eGFR] less than 60 [HR, 0.56; 95% CI, 0.26-1.18], so those are 3 important subgroups that we examined in this trial.

The overall response rate [ORR] was not drastically different between the 2 arms, but you're still looking at 86.6% with the triplet. Where the [important data to highlight] comes in is for patients on the triplet got deeper responses, so the rates of stringent complete response [sCR] and CR was 44.1% in the triplet and 28.8% with the doublet.³ Then, in the rates of [MRD] negativity of 10-5, the MRD negativity rate was 33.5% with the triplet and 15.4% in the doublet. If you were to compare that number with the DKd patients, it's about 20% higher with Isa-Kd.

The median time to next treatment was 44.9 months [95% CI, 31.6–NC] in the triplet arm, and interestingly 44.1% went on to receive further anti-myeloma therapy, whereas 64% in the Kd arm went on to receive further anti-myeloma therapy. I don't know exactly why that number is so low in the triplet arm, but it may speak to the attrition that we see, especially in newly diagnosed disease. We started seeing patients really drop off after the first 1, 2, or 3 prior lines of therapy, so that may be what we're seeing in this patient population. We haven't reached overall survival yet, and we haven't reached a median overall survival in either arm.

Which safety results should physicians know about with this regimen?

When we're looking at treatment-emergent adverse events [TEAEs], any TEAEs that led to definitive discontinuation was less in the triplet arm than what we saw with Kd. Any TEAE that lead to premature discontinuation [in the Isa-Kd arm] was much higher with carfilzomib [at 17.5%] than it was with the other 2 drugs at [0.6% and 13%, respectively. So very interestingly, isatuximab wasn't the cause of premature discontinuation. I think that goes in line with what we see in the clinic. We see that these CD38 monoclonal antibodies are pretty well tolerated.

Now, potential cardiac failure is probably the biggest AE to look at with this. When we're looking at both arms, we aren’t seeing a big difference between all grades of cardiac failure with 8.5% in the Isa-Kd arm and 7.4% in the Kd arm. When we get a grade 3 or higher event, not terribly high [usually], it was 4.5% with Isa-Kd and 4.1 with Kd. This is maybe a little bit lower than what we see in some of the other carfilzomib trials, but I think it speaks to the fact that cardiac toxicity and pulmonary hypertension is a drug class toxicity that we see with carfilzomib, it's something that we need to be thinking about.

Before starting somebody on carfilzomib, I get an echocardiogram. I want that baseline, because what can happen is these patients can show up with shortness of breath, and a bunch of swelling, and I want to make sure that this was drug related, and that's the best way for me to do that. The other thing to highlight here is the rates of infusion reaction. This is consistent with what we see with daratumumab infusion, and in the Isa-Kd arm 45.8% had any grade reactions, but these are events that we can mitigate with the use of prophylaxis.

How have these results impacted your treatment decisions?

The 42 months of PFS is significant, and that makes me think quite a bit when I'm thinking about whether I'm going to go with DKd or Isa-Kd. For me, the decision is not necessarily Isa-Kd vs DKd but between DPd [daratumumab, pomalidomide (Pomalyst), and dexamethasone] vs Isa-Kd. This comes back to what I'm asking of the patient. If I'm asking the patient to come in and get carfilzomib, I'm not adding too much clinic time—if I'm asking them to get an infusion of both carfilzomib and isatuximab. You can get isatuximab down to 60 to 90 minutes tops after the first cycle, and so it's not a big ask, if I'm asking them to come in for carfilzomib anyway.

The ask is to have them come in [for a long time], and that's where the DPd discussion comes in to play. So, as Isa-Kd performs very well in those patients with 1q21 that informs me, and this isn't fully supported by the data. I'm extrapolating here, that it's a less high-risk disease, maybe with some high-risk features, but I want a more aggressive regimen.

Those are the patients that I will consider for infusion therapy. Those are the patients that I'm trying to talk about Isa-Kd much more seriously with. In somebody who has got relatively standard risk disease and doesn't want to come in to see me, I talk about Isa-KD vs DPd, but I'm definitely helping them move towards [the IKEMA triplet].

^References

^{1. Moreau P, Dimopoulos MA, Mikhael J, et al; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4}

^{2. Moreau P, Dimopoilos M, Mikhael J, et al. Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Presented at: 2022 Annual European Society of Medical Oncology Meeting; May 19-20, 2022, Paris, France. Abstract VPS-2022. https://bit.ly/3N2cc2d}

^{3. Martin T, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023;13(1):72. doi:10.1038/s41408-023-00797-8}