alloHCT With Reduced Intensity Conditioning Shown Safe in Myeloma Despite Low Accrual Leading to Early Trial Termination

Taiga Nishihori, MD

Allogeneic hematopoietic cell transplantation (alloHCT) was shown to be safe when performed with a reduced-intensity conditioning regimen of bortezomib (Velcade), fludarabine, and melphalan (Evomela) in patients with high-risk multiple myeloma. The treatment method may also promote disease control, according to findings from the multicenter phase 2, double-blind placebo-controlled Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1302 trial (NCT02440464) presented during the 2021 ASCO Annual Meeting.

Since 2011, investigators have been exploring the curative ability of alloHCT in select patients with high-risk multiple myeloma. A previous study from BMT CTN (0102, NCT00075829), demonstrated improvement in long-term progression-free survival in the patient group with alloHCT compared with tandem autologous-allogeneic HCT. Further, there was emerging data showing that it is feasible to combine the proteasome inhibitor bortezomib with fludarabine and melphalan as conditioning therapy for high-risk multiple myeloma.

Based on these earlier findings, the investigators “…hypothesized that the combination of a proteasome inhibitor with fludarabine and melphalan conditioning followed by proteosome inhibitor maintenance would result in better outcomes,” explained Taiga Nishihori, MD, assistant member in the Blood and Marrow Transplantation Department at Moffitt Cancer Center and an assistant professor in the Department of Oncologic Sciences at the University of South Florida, during his presentation of the study for the 2021 ASCO Annual Meeting.

The study was originally designed to evaluate maintenance with ixazomib (Ninlaro) 3 mg on days 1, 8, and 15 versus placebo for 12 cycles. Patients with high-risk multiple myeloma aged 18 to 70 years first received alloHCT from human leukocyte antigen – matched donors and bortezomib, fludarabine, and melphalan, then they were randomized 1:1 to receive either maintenance ixazomib or placebo. The study had a target sample size of 110 patients for randomization and in preparation for a 30% drop-out rate, the target accrual was 138 patients. The primary end point of the study was PFS from randomization.

During the conditioning portion of treatment, patients were administered fludarabine 30 mg/m², melphalan 70 mg/m², and bortezomib 1.3 mg/m² 3 to 6 days prior to transplant. Patients then underwent alloHCT and were administered tacrolimus and methotrexate as graft-vs-host disease (GVHD) prophylaxis.

The 1302 study first opened for accrual in 2015 but was placed on hold in 2016 due to mortality after 17 patients were enrolled. The hold was later lifted allowing 57 patients to be enrolled. Of the 43 patients who were randomized to either ixazomib (n = 21) or placebo (n = 22), the ixazomib arm received a median of 12 cycles of maintenance therapy (range, 5-12) and the placebo arm received a median of 6 cycles (range, 2-12). Overall, in the experimental arm, maintenance therapy was initiated in 85.7% of patients, all cycles of therapy were complete by 57.1% of patients, and 28.6% of patients initiated maintenance but discontinued early. The reasons for early discontinuation include toxicity for 2 patients and progressive disease (PD) for 4 patients.

In the placebo arm, 95.5% of patients initiated maintenance, 31.8% completed 12 cycles of maintenance, and 63.6% started maintenance therapy but discontinued early. Nine of those who discontinued early did so due to toxicity, 3 because of PD, and the remaining 2 patients discontinued due to physician decision or refusal.

In 2018, the study closed as a result of slow accrual. At the time, 14.3% of the ixazomib arm and 4.5% of the placebo arm had not initiated maintenance therapy. However, survival data was evaluated for those randomized.

The 12-month probability of PFS for those treated with ixazomib was 65.3% (80.0% CI, 50.0%-77.0%). The 21-month PFS estimate for those who received ixazomib was 55.3% (80% CI, 40.0%-68.1%). In comparison, the 12-month PFS estimate in the placebo arm was 72.7% (80.0% CI, 58.4%-82.8%), and the 21-month estimate was 59.1% (80.0% CI, 44.5%-71.1%; log-rank P = 1.000).

Overall survival (OS) estimates were also provided and showed a 100% 12-month OS rate for ixazomib versus 90.9% (90% CI, 73.7%-97.1%) for placebo (log-rank P = .174). The 21-month OS rate was estimated to be 94.7% (90.0 CI, 75.6%-99.0%) with ixazomib compared with 86.4% (90.0% CI, 68.4%-94.5%) with placebo.

An evaluation of the cumulative incidence of acute or chronic GVHD was executed. Nishihori stated that the “estimated grade 3 to 3 acute GVHD rate at day 100 was 9.5% for ixazomib, and 0% for placebo. There was no statistical significance. The cumulative incidence of chronic GVHD at 12 months was 68.6% for ixazomib and 63.6% for the placebo group. There was no statistical significance.”

Further, Nishihori said that “the incidence of disease progression was 34.7% for ixazomib and 27.3% for placebo at 21 months. [The] ixazomib group had a 44.7% incidence and placebo was 36.4%. There was no statistically significant difference between the groups. Transplant-related mortality [TRM] after randomization remained low for both groups.”

Finally, the investigator evaluated responses to therapy in the ixazomib versus placebo groups. The achievement of either stringent complete responses (CRs) or CRs was observed in a large percentage of each study arm.

“The best response to treatment after randomization for patients [was] stringent CR or CR at the time of randomization. There was no difference between the ixazomib and the placebo groups and the best response to treatment after randomization for patients not in stringent CR or CR at randomization showed that more than 40% of patients were able to achieve stringent CR or CR. However, there was no difference between the groups,” said Nishihori.

To determine the safety of treatment, Nishihori et al looked at estimates of OS in comparison with estimates of TRM. The data showed that TRM at 12 months was estimated at 5.6% (90.0% CI, 1.4%-14.3%), and 8.7% (90.0% CI, 2.8%-18.8%) at 24 months. A total of 3 patients had TRM during this period.

The primary cause of death of the 1 patient who died in the experimental arm was recurrence/persistence. In the placebo arm, there were 2 recurrence/persistence events and 1 death due to interstitial pneumonia. Among those who were transplanted but not randomized, 3 deaths were related to acute GVHD, 1 due to multiple organ failure, and 1 caused by adult respiratory distress syndrome.

A secondary analysis was performed on the entire transplanted population. Nishihori explained the findings stating: “[The] progression-free survival estimate at 12 months was reasonable at 64.5%, and at 24 months, it was 52%. The cumulative incidence of grades 3 to 4 acute GVHD for day 100 was 15.4%. For chronic GVHD, cumulative incidence at 12 months was 50.3% and at 24 months, it was 59.3%, reflecting peripheral blood graft. The cumulative incidence of progression at 12 months was 25.9%, and at 24 months, it was 36.3%. We observed relatively limited progression considering the high-risk nature of our population.”

The study’s inclusion criteria allowed for a diverse group of high-risk participants including those with high-risk multiple myeloma who achieved a partial response (PR) or better less than 24 months from autologous HCT or 24 months after the start of induction therapy.

Patients with high-risk multiple myeloma with 1 prior case of progressive disease (PD) who achieved a very good partial response (VGPR) or better from autologous HCT less than 24 months after the start of induction were also allowed.

Individuals with standard-risk multiple myeloma with 1 prior PD and at least a VGPR less than 24 months from autologous HCT were permitted to enroll, along with patients who had plasma cell leukemia and achieved at least a VGPR less than 18 months from autologous HCT or less than 18 months after the start of induction.

Nishihori et al defined high-risk multiple myeloma as having deletion 13 by conventional karyotyping; hypodiploidy; a 1q amplification or 1p deletion; translocations 4;14, 14;14, or 4;20; deletion of 17p by fluorescence in situ hybridization or conventional karyotyping; high-risk gene expression profiling; and/or a beta-2 macroglobulin of 5.5 mg/L or higher.

With 21 patients randomized to the ixazomib arm and 22 to the placebo arm, the population was predominantly female (57.1% vs 50.0%, respectively). Patients in the ixazomib arm were slightly younger with a median age of 52.6 years (range, 35.3-63.9) compared with a median of 57.5 years (range, 44.9-64.7) in the placebo arm. In terms of disease classification, more than half of the patients in both arms had high-risk multiple myeloma, but 28.6% of the ixazomib arm was considered standard risk versus 27.3% of the placebo arm. Also, there was a small percentage of patients with primary plasma cell leukemia including 14.3% of the ixazomib arm compared with 18.2% of the placebo arm.

In the group of patients treated with ixazomib, 31.1% had prior PD compared with 40.9% of the placebo arm. Baseline information also showed that 76.2% of the ixazomib arm versus 68.2% of the placebo arm had undergone prior autologous HCT. More than half of patients in both arms previously had a VGPR and less than half had a PR. The most common planned donor type for the ixazomib population was related sibling donor and for the placebo arm, it was an unrelated donor.

The study overall did not fully assess ixazomib versus placebo due to its early closure. Therefore, the role of allogeneic HCT in patients with multiple myeloma and high-risk features must be further explored in other studies. Nishihori believes the era of cellular immunotherapy will provide answers in this regard.

_Reference:

_{Nishihori T, Bashr Q, Pasquini MC, et al. The results of multicenter phase II, double-blind placebo-controlled trial of maintenance ixazomib after allogeneic hematopoietic cell transplantation (alloHCT) for high-risk multiple myeloma (MM) from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1302). J Clin Oncol. 2021;39(suppl 15; abstr 7003). doi:10.1200/JCO.2021.39.15_suppl.7003}