among patients who had a VGPR at study entry, 43 percent of
ixazomib-treated patients improved to a CR (n=92/213), com-
pared 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 placebo-
treated 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 ixazo-
mib 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 discon-
tinuation 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 over-
all 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 regi-
men 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 perfor-
mance 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 fol-
lowing 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 treat-
ment 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 engraft-
ment among the nine patients who underwent transplant com-
pared 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 disappear-
ance 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 daratu-
mumab regimen is an effective induction therapy, but the find-
ings 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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