Routine Clinical Practice Comparison of Ixazomib Combo vs Standard of Care in Relapsed Myeloma

With an incurable disease like multiple myeloma, treating patients is not simply about finding the right therapy. Rather, it’s about finding the right combination of therapies—and the right sequence—to extend survival as long as possible.

“I am always trying to think of what am I going to use next so that I’m not shortening or inhibiting their response to any line of therapy,” said Suzanne Fanning, DO, director of the Blood and Bone Marrow Transplant Program of Prisma Health in Greenville, South Carolina, about her approach to treating her patients across different lines of therapy.

Fanning and her colleague Joshua Richter, MD, associate professor of medicine, hematology, and oncology at the Icahn School of Medicine at Mount Sinai in New York, discussed the latest developments in treating multiple myeloma during a recent edition of Between the Lines, hosted by CancerNetwork^®. In their discussion, they primarily focused on data
related to a manuscript published by Jiri Minarik, MD, PhD, and colleagues, in which the authors examined real-world survival with the combination triplet regimen of ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone (IRd).¹

Additional data examined included those from the phase 3 TOURMALINE-MM1 study (NCT01564537), which showed that the triplet therapy had an advantage in progression-free survival (PFS) against lenalidomide and dexamethasone alone (Rd).

Five Years of Positive Data

In TOURMALINE-MM1, a double-blind trial, a total of 722 patients with relapsed and/or refractory multiple myeloma were randomly assigned to receive either IRd or Rd, with a primary end point of PFS.²

After a median follow-up of 14.7 months, patients in the IRd group had a median PFS of 20.6 months vs 14.7 months in the doublet group; the statistically significant hazard ratio for disease progression or death favored the IRd group (HR, 0.74; 95% CI, 0.59-0.94; P = .01).

Additionally, patients in the ixazomib group had better overall response rates at 78.3% vs 71.5% (P = .04), with median durations of response of 20.5 months and 15.0 months, respectively.

Latest Survival Insights

Although findings were promising, 2 key questions were left open: Would the benefit of IRd hold up in real-world clinical practice? And would the PFS advantage seen in the initial study translate into longer overall survival (OS)?

In the analysis, Minarik et al assessed the data of 344 patients with multiple myeloma from the Czech Registry of Monoclonal Gammopathies, of whom 127 were treated with IRd and 217 received Rd. After a median follow-up of 20.8 months in the IRd group, the median PFS was 17.5 months. In the doublet-regimen cohort, median follow-up was 11.5 months and median PFS was 15.5 months (P = .005). Median OS for the 2 groups were 36.6 months vs 26.0 months, respectively (P = .008).

Richter praised the study for achieving an impressive balance between the 2 study arms. “One of the things that’s difficult when looking at real-world practice is to completely balance the 2 arms,” he said. “Overall, [the treatment arms] were well balanced.”

There were, however, some key differences. For example, the IRd vs Rd group had a lower percentage of patients aged more than 75 years (8.7% vs 22.1%), yet more patients with extramedullary disease (14.2% vs 6.7%). Richter noted that extramedullary disease has a negative impact on prognosis, making the performance of IRd more impressive.

Still, the data suggested that IRd was most effective in patients who were earlier in their treatment journeys. Among patients with 3 or fewer relapses, the median PFS was 23.1 months with IRd vs 11.6 months with Rd (P = .001). Richter said that’s “crucial” because it can be difficult to know which regimens to use at which time in a patient’s cancer journey.

“Studies like this help to put [results] into context…If you’ve had success [with] or you like the oral option of IRd, it’s probably better suited as [an option for patients who have had] 1 to 3 prior lines of therapy [vs] 4, 5, 6-plus lines,” Richter explained.

New Survival Data

Although both the initial TOURMALINE-MM1 results and real-world data showed that IRd boosted PFS, new TOURMALINE-MM1 survival data released in January 2021 revealed no statistically significant OS benefit with IRd. At a median follow-up of 85 months, a median OS of 53.6 months in the IRd group vs 51.6 months in the Rd group was noted (HR, 0.939; 95% CI, 0.784-1.125; P = .495).3 When patients were stratified into subgroups by International Staging System status and refractory disease status, some groups demonstrated had lower hazard ratios with IRd suggesting it had a superior OS benefit for these patients.

Richter and Fanning agreed that although survival benefit with IRd in the TOURMALINE-MM1 trial was not statistically significant, the mere fact that OS data are available is encouraging.

“In most of our data, we’re used to seeing PFS as the primary end point
because this is an incurable malignancy,” Fanning noted. “It’s not that often that we have OS information to guide us, so I find that very reassuring and definitely encouraging for patients.”

Clinical Implications

Richter and Fanning said the data from the new reports also give clinicians a better understanding of the contours of personalized treatment regimens, particularly in challenging scenarios involving, for instance, patients with extramedullary disease.

“​​We talk about all these great new options, [but] one of the unmet needs of myeloma is how to manage patients with disease that just [seems to] do whatever it wants and grow wherever it pleases,” Richter said.

Fanning said a key consideration with such high-risk patients is finding the best sequence in which to offer therapies.

“That’s among our greatest challenges in multiple myeloma, so we’re always looking to make sure that we’re looking at the patient in front of us, knowing what risk profile they’re bringing to the table, and making sure that [what we choose is] an appropriate regimen for that patient,” she said.

Both Fanning and Richter said they use IRd with their patients when it is appropriate to do so. Fanning noted that with the COVID-19 pandemic, the availability of an all-oral option became even more attractive since it meant patients did not need to come to the clinic for treatments.

“If they can avoid it, they want to minimize coming into an office setting, which might increase their risk [of contracting COVID-19],” Fanning said. However, Fanning added that other patients benefit from an all-oral regimen, too, especially “those who are unfortunately dialysis dependent,” she pointed out. “Those patients often have [dialysis appointments] scheduled 3 times a week, so having an all-oral regimen [for multiple myeloma] makes that one less appointment that the patient [needs to attend].”

Next Up: Quadruplet Therapy

Looking forward, Richter noted that most of the trials for multiple myeloma over the past decade have compared doublet vs triplet therapies, “and 3 drugs always wins.”

Lately, though, studies have emerged using quadruplet regimens, such as the CASSIOPEIA trial (NCT02541383), which added daratumumab (Darzalex) to the backbone of bortezomib (Velcade), thalidomide, and dexamethasone in newly diagnosed patients.4 Early data, Richter said, suggest that quadruplet therapies could likewise be an improvement on triplet therapies.

“In clinical practice, every now and again we have to give a quadruplet
because someone has such horrible disease, but I’d love to see the quadruplet vs triplet version of this [TOURMALINE] study to see how that would pan out in early relapses,” Richter said.

Fanning said that a “perfect answer” is still a long way off, but the increasing number of options available give clinicians the flexibility to personalize treatment regimens. “When you look at real-world data and you see that [clinicians] are making those adjustments and are able to keep [patients] on therapy longer, it’s reassuring to all of us who are practicing as best as we can for these patients,” she said.

References

1. Minarik J, Pika T, Radocha J, et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer. 2021;21(1):73. doi:10.1186/s12885-020-07732-1
2. Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-1634. doi:10.1056/NEJMoa1516282
3. Richardson PG, Kumar SK, Masszi T, et al. Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2021;39(22):2430-2442. doi:10.1200/JCO.21.00972
4. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1