Novel Triplet Combos Offer Deep Remissions in Relapsed/Refractory Multiple Myeloma

Joshua Richter, MD

Triplet combinations, such as isatuximab-irfc (Sarclisa) plus pomalidomide (Pomalyst) and dexamethasone, offer another option to patients with relapsed/refractory multiple myeloma who have progressed on lenalidomide (Revlimid), explained Joshua Richter, MD. While the disease was once considered incurable, he added, recently approved treatment regimens have been touted as potential means to cure select patients.

“There are still many different options in the relapsed/refractory setting,” said Richter. “A lot of us are very comfortable with some of the more classically used drugs, such as immunomodulatory agents and proteasome inhibitors, but it's really important to recognize that there is a role for newer classes of drugs, such as selective inhibitors of nuclear export. [There's] even a role for new monoclonal antibodies, such as isatuximab, especially in novel combinations compared with what patients have previously [received]. The simple fact of the matter is, we have an option for everyone out there and for every patient in every clinical setting.”

In March 2020, the FDA approved isatuximab for use in combination with pomalidomide and dexamethasone for the treatment of patients with myeloma who have received 2 or more prior therapies, including lenalidomide and a proteasome inhibitor. The approval is based on data from the phase 3 ICARIA-MM trial, in which patients were randomized 1:1 to receive either isatuximab plus pomalidomideand low-dose dexamethasone or pomalidomide/dexamethasone alone. Aftera median follow-up of 11.6 months, the median progression-free survival was 11.53 months in the triplet arm versus 6.47 months in the doublet arm (HR, 0.596; 95% CI, 0.44-0.81; P = .001).¹

Similarly, the phase 3 IKEMA trial evaluated the combination of isatuximab, carfilzomib (Kyprolis), and dexamethasone in patients with relapsed myeloma. The triplet regimen led to a 47% reduction in the risk of disease progression or death compared with carfilzomib/dexamethasone alone (HR, 0.531; 99% CI, 0.318-0.889; P = .0007).²

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Richter, an assistant professor of medicine and hematologist/oncologist at Mount Sinai Hospital, discussed the importance of optimizing these novel therapies to make way for precision medicine in multiple myeloma.

OncLive®: What role does isatuximab play in multiple myeloma?

Richter: A lot of [physicians] may be more familiar with daratumumab (Darzalex), which has been out for some time. Earlier this year, a new CD38-directed antibody, isatuximab, was approved based on the results from the phase 3 ICARIA-MM trial. Here we see the combination of isatuximab, pomalidomide, and dexamethasone compared with pomalidomide and dexamethasone alone. Daratumumab, pomalidomide, and dexamethasone is already a utilized regimen, but [the supporting data] was from the phase 1/2 data EQUULEUS trial. Here, with isatuximab, we see the direct head-to-head comparison and the superiority of isatuximab, pomalidomide, and dexamethasone. It essentially provides another option for patients who are progressing on lenalidomide.

[This is] really important because many patients progress on lenalidomide, and when they go into the second-line setting, [they’re given] either lenalidomide maintenance after transplant or continuous lenalidomide from induction therapy. [Therefore], isatuximab, pomalidomide, and dexamethasone provides another option.

The isatuximab, carfilzomib (Kyprolis), and dexamethasone [regimen, as shown in] the IKEMA trial, provides another regimen that is highly advantageous for patients who are either progressing with very aggressive disease and are about to go into the second-line [setting] or for whom patients an immunomodulatory drug backbone is either not enough or not appropriate. Isatuximab, carfilzomib, and dexamethasone is an extremely effective regimen for more aggressive relapses.

Could you touch on the safety data from the ICARIA-MM trial?

In ICARIA-MM, we had isatuximab, pomalidomide, and dexamethasone versus pomalidomide/dexamethasone alone. Any study in myeloma where you have a 3-drug regimen compared with a 2-drug regimen and the 3 drug regimen wins, you're always going to see higher rates of pneumonia, upper respiratory infection, edema, hypertension, and diabetes. This is due to increased exposure to steroids. We did see some of those increases [in the ICARIA-MM trial]. Now, again, some of this may be related to isatuximab or it may just be related to more steroids. The infusion-related [reactions to isatuximab] were mild, well-tolerated, and typically only occurred during the first or second dosing. As we see with daratumumab, there is an increase in hematologic toxicities when you add isatuximab. However, this is easily overcome either through dose adjustment of pomalidomide or through the use of growth factors.

What data came out of the IKEMA trial in terms of safety and efficacy?

In IKEMA, we took the backbone of carfilzomib and dexamethasone (Kd) that we utilized in the original ENDEAVOR trial—56 mg/m2 twice weekly—then we compared the Kd arm with isatuximab plus Kd. The importance of adding isatuximab is that we not only increased the overall response rates from about 83% to about 87%, but, more importantly, we increased the depth of response. We have a higher rate of complete responses (CRs) and very good partial responses (VGPRs). For example, the CR rate goes from a little more than 27% up to almost 40%. It's really those patients who achieve the deeper remissions that tend to get a longer duration of response, so it's very important to achieve deep responses even in the more relapsed setting. In terms of efficacy, it's an extremely efficacious regimen that can induce very deep permissions, even in more heavily pretreated patients.

In terms of safety profile, much like the ICARIA-MM trial or any triplet-based regimen, there was a higher exposure to steroids because of the longer time on therapy. [There was a] higher incidence of pneumonia and upper respiratory infection, which, again, it's difficult to say whether or not this is attributable to more steroid exposure or isatuximab. Again, infusion-related reactions to isatuximab were mild, mostly grade 1/2, and occurred predominantly during the first and/or second infusion. There was also a slightly higher rate of hematologic toxicities, but much like in the other combinations with monoclonal antibodies, this was easily managed with the utilization of growth factors.

Could you provide an overview of the BOSTON trial?

The BOSTON trial brings up a number of things that are important in heavily relapsed myeloma. The first of all being the utilization of selinexor, which was approved on July 2019 from the STORM data, [which looked at selinexor] in combination with dexamethasone alone, but we know that all drugs combined into a triplet have better efficacy. The BOSTON data really seek to determine this. The advantage of using bortezomib as the additive is that although the majority of patients in the United States receive a bortezomib-based regimen as induction, patients often don't receive it in the relapsed setting. [Patients] enter the second-, third-, fourth-, and fifth-line setting still being sensitive to bortezomib.

For patients who may have progressed beyond carfilzomib, daratumumab, and pomalidomide, the utilization of bortezomib, selinexor, and dexamethasone (SVd) may be the opportune regimen. Also, this is only a once-weekly [regimen]. In fact, when comparing the SVd once weekly versus the twice-weekly bortezomib/dexamethasone, not only did we see improvements in response rates and the duration of response, we also saw a lower incidence of sensory peripheral neuropathy, which unfortunately a lot of patients with myeloma deal with. We're very excited to not only provide a once-weekly—as opposed to twice-weekly—regimen, but also to do so without increasing toxicity.

Where should future research efforts be focused?

When I first started treating patients with myeloma, I would tell patients that it's an incurable disease. Now when I see patients, I say, "There may be some patients we cure, and my goal is to keep you alive until there's a cure." However, part of that is not just future tools, but optimizing the tools we have in front of us. [This entails] using ongoing genomics, proteomics, and the multi-omics approach to provide precision medicine. We may be able to take existing drugs and therapies that we have at our disposal today, evaluate the patient from a total standpoint, and a multi-omic approach to provide optimal therapy. There may be a better way to use the drugs we have now, and some of the research we're doing at [Mount Sinai Hospital] is going to help gain some of these answers to offer not only precision medicine, but potentially precision cures.

References

1. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096-2107. doi:10.1016/S0140-6736(19)32556-5
2. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB3603.