Evaluating Ixazomib Regimens in Patients With Newly Diagnosed Myeloma

Two studies presented at the 2018 ASH Annual Meeting explored the use the oral proteasome inhibitor (PI) ixazomib in patients with newly diagnosed multiple myeloma (MM). The first evaluated its efficacy as maintenance therapy for patients who underwent post-autologous hematopoietic cell transplantation (AHCT) and the second examined the feasibility and efficacy of an ixazomib and daratumumab combination as induction therapy.

Ixazomib Maintenance

For the substantial portion of patients with MM who relapse following AHCT, maintenance therapy with ixazomib could offer a new treatment option to delay disease progression and extend survival, according to results from the phase III, double-blind, placebo-controlled, multicenter TOURMALINE-MM3 trial.1 The drug also was associated with deeper responses, while maintaining a “favorable” safety profile, lead author Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece, said during his presentation.

While lenalidomide is a commonly used post-AHCT maintenance therapy, Dr. Dimopoulos noted that nearly one-third of patients discontinue the drug due to toxicity. However, as an oral PI, ixazomib has a less frequent administration and has been shown to have manageable toxicity. “We think that these findings show ixazomib to have a very good therapeutic value,” he added.

The TOURMALINE-MM3 trial enrolled 656 adult patients with newly diagnosed MM who had received standard of care with a PI or immunomodulatory drug (IMiD) prior to undergoing a single AHCT with high-dose melphalan. Eligible patients had experienced at least a partial response to AHCT; those whose disease relapsed, were unresponsive to frontline therapy, or underwent a tandem AHCT or received post- AHCT consolidation therapy were excluded from the analysis.

Patients were stratified based on induction protocol, preinduction International Staging System (ISS) stage disease, and response following AHCT, then randomized 3:2 to receive either weekly ixazomib (n=395) or matched placebo (n=261). Ixazomib 3 mg was administered on days 1, 8, and 15 of 28-day cycles for two years or until disease progression or unacceptable toxicity, up to 26 cycles. If patients tolerated ixazomib 3 mg during the first four cycles, dose was increased to 4 mg (n=317 in the ixazomib group and n=222 in the placebo group).

“We think that these findings show ixazomib to have a very good therapeutic value.”

—Meletios Dimopoulos, MD

Participants’ median age was 58 years; “however, 15 percent of patients were older than 65 years,” Dr. Dimopoulos noted. Nearly one-fifth of patients in each group had high-risk cytogenetics.

Other baseline characteristics were similar between the treatment groups: Most patients in each group (59%) had induction therapy with a PI, while 11 percent in each group received an IMiD and 30 percent in each group received both agents. Also, a similar portion of patients in each group had achieved minimal residual disease (MRD)–negative status (33% for both).

Most patients had experienced a very good partial response (VGPR) following AHCT (45% in the ixazomib arm and 44% in the placebo arm), and approximately one-third in each group had a complete response (CR; 33% and 36%, respectively).

As of April 16, 2018 (data cutoff), the median duration of treatment at 4 mg was 15.2 months (range = 0-22 months) in the ixazomib arm and 16.6 months (range = 0-21 months) in the placebo group.

Results from the primary endpoint analysis showed that maintenance treatment with ixazomib prolonged median PFS, compared with placebo (26.5 months vs. 21.3 months; hazard ratio [HR] = 0.72; 95% CI 0.58-0.89; p=0.002).

The benefit in PFS was observed across subgroups, including:

  • age (≥60 years vs. <75 years): HR=0.662 ISS stage III disease: HR=0.0661
  • cytogenetic risk: HR=0.625 for high risk and HR=0.648 for standard risk

Patients who received maintenance therapy with ixazomib also had deeper responses, Dr. Dimopoulos noted. For example, among patients who had a VGPR at study entry, 43 percent of ixazomib-treated patients improved to a CR (n=92/213), compared with 32 percent in the placebo arm (n=48/152; p=0.004). Ixazomib-treated patients also had a higher rate of conversion from MRD-positive to MRD-negative status, compared with placebo (12% vs. 7%; p value not provided).

All-grade treatment-related adverse events (AEs) occurred in 78 percent of ixazomib-treated patients and 58 percent of placebotreated patients, but “there were very few side effects that were greater than 10 percent more common in the ixazomib arm,” Dr. Dimopoulos said. These included nausea, diarrhea, and arthralgia.

There also was no increase in hepatic, cardiac, or renal AEs and no difference in the rates of new primary malignancy (3% for both arms). Serious AEs also appeared to be more frequent in the ixazomib arm (27% vs 20%), and one patient in the ixazomib group and none in the placebo group died during follow-up. However, Dr. Dimopoulos pointed out that 86 percent of patients were able to escalate dose of ixazomib and that discontinuation related to AEs “was relatively low across both arms,” at 7 percent and 5 percent, respectively.

As a limitation of the study, Dr. Dimopoulos noted that overall survival data (a secondary endpoint of the study) were not mature and follow-up was ongoing. Researchers are continuing to study ixazomib combinations in different MM settings to further improve patient outcomes, he said.

Ixazomib Plus Daratumumab

In the second study, Shaji Kumar, MD, from the Mayo Clinic in Rochester, Minnesota, presented results from a phase II trial evaluating the feasibility and efficacy of adding the anti-CD38 monoclonal antibody daratumumab to the standard triplet regimen of ixazomib, lenalidomide, and dexamethasone (IRd).2

This all-oral, four-drug combination of daratumumab plus IRd was associated with rapid responses that deepened over time, the authors reported, with no discontinuation due to AEs and no adverse effects on the ability to collect stem cells.

Eligible patients had newly diagnosed MM, adequate organ function, and an Eastern Cooperative Oncology Group performance status score ≤2; participants had received up to one cycle of treatment, “allowing some flexibility to enroll patients who needed immediate therapy,” Dr. Kumar said.

Treatment was administered in 12 28-day cycles in the following regimen:

  • ixazomib 4 mg on days 1, 8, and 15 of each cycle
  • dexamethasone 40 mg on days 1, 8, 15, and 22 of each cycle
  • lenalidomide 25 mg on days 1-21 of each cycle
  • daratumumab 16 mg/kg weekly for 2 cycles, then every other week for cycles 3-6, and then every 4 weeks

Patients who completed induction therapy went on to maintenance therapy with ixazomib and daratumumab for a maximum of three years, or until disease progression or unacceptable toxicity.

As of July 20, 2018 (data cutoff), 38 of 40 enrolled patients (median age = 62 years; range = 41-81 years) were eligible for this analysis. During a median follow-up of 10.2 months (range = 5.7-17.5 months), participants received a median of nine treatment cycles (range = 4-18 cycles).

All 38 patients were alive at last follow-up, but three patients (7.9%) had progressive disease. Another nine patients discontinued study treatment because they became eligible for a hematopoietic cell transplantation following four cycles of induction treatment.

Dr. Kumar highlighted that 24 transplant-eligible patients went on to stem cell collection, with no differences in engraftment among the nine patients who underwent transplant compared with historical observations. “These are small numbers and it is hard to compare, but [the stem cell collection and engraftment] numbers don’t seem very different from what we typically see in patients with myeloma,” he noted.

“The majority of patients had a response by the end of cycle two, with about one-third of patients having achieved a VGPR,” Dr. Kumar reported. Response rates increased by cycle four, and the best response across all cycles included: stringent CR (11%), CR (8%), VGPR (50%), PR (29%), and minimal response (3%).

“There was a deepening of response with continued therapy among the patients who did not go into stem cell transplant,” he added, with “most patients experiencing a complete disappearance of M protein.”

Among all 40 treated patients, Dr. Kumar reported that the number of dose modifications “was fairly low,” ranging from 8 percent with ixazomib (mostly related to lab abnormalities) to 32 percent with lenalidomide (mostly related to cytopenias). Among the 38 patients in this analysis, 22 patients (58%) experienced a grade ≥3 AE, most of which were hematologic (53%). The most common, all-grade AEs were neutropenia (71%), fatigue (69%), lymphopenia (50%), and thrombocytopenia (45%).

The researchers concluded that the ixazomib and daratumumab regimen is an effective induction therapy, but the findings of this trial are limited by the single-arm design, the small number of patients, and an incomplete analysis of MRD data. Dr. Kumar noted that follow-up of a second cohort to explore the possibility of discontinuing dexamethasone after the first two cycles is ongoing.

The authors of the first study report relationships with Takeda, which sponsored the trial. The authors of the second study report relationships with Takeda, Celgene, Janssen, AbbVie, and Alexion Pharmaceuticals.

References

  1. Dimopoulos MA, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Abstract #301. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.
  2. Kumar SK, Kapoor P, Laplant B, et al. Phase 2 trial of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly diagnosed multiple myeloma. Abstract #304. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.

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