Abstract
Background:
The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after a reduced-intensity allo-HCT from HLA-matched donors in patients with high-risk multiple myeloma.
Objectives:
The primary endpoint for this study was progression-free survival (PFS) post-randomization, treated as a time to event. Secondary endpoints were grades 2–4 and 3–4 acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, non-relapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life (HRQOL).
Study Design:
In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk multiple myeloma (poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous transplant) to ixazomib (3 mg, days 1, 8, 15) or a placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD.
Results:
Fifty-seven patients were enrolled. 52 (91.2%) received allo-HCT, and 43 (82.7%) were randomized to ixazomib vs. placebo. At 21-month post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%, p=1.00) and OS (94.7% vs. 86.4%, p=0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) and chronic GVHD at 12 months (68.6% vs. 63.6%) were similar. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with corresponding non-relapse mortality of 11.7%.
Conclusions:
These results show the safety and durable disease control with allo-HCT in high-risk myeloma patients. We could not adequately assess the efficacy of ixazomib maintenance as the trial terminated early because of enrollment delays, but there was no signal of an impact on outcomes.
Keywords: Multiple myeloma, allogeneic hematopoietic cell transplantation, ixazomib, maintenance
Introduction:
Multiple myeloma (MM) is a clonal plasma cell malignancy. It is considered incurable using conventional agents and despite the availability of numerous novel anti-myeloma treatments, including proteasome inhibitors (PIs), immunomodulatory agents, monoclonal antibodies, and immune-based therapies.(1, 2) High-dose chemotherapy with autologous hematopoietic cell transplantation (auto-HCT) for consolidation is considered standard of care in transplant-eligible patients; however, the median progression-free survival (PFS) remains at 40 to 50 months even in the setting of lenalidomide maintenance.(3, 4)
Allogeneic HCT (allo-HCT) can exploit the graft-versus-myeloma (GVM) effect and the absence of contaminating myeloma cells in the autologous stem cell product, making it a potentially curative option for MM patients. The evidence of GVM effect stems from the successful use of donor lymphocyte infusions in the prophylactic setting or as a salvage strategy after allografting.(5) However, the superiority of allo-HCT over other available therapeutic options has not been established due to associated morbidity and mortality risks (3),(6, 7) The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted a prospective trial in newly diagnosed MM comparing tandem auto-HCTs vs. tandem auto-allo HCTs from an HLA-matched sibling donor on a biologic assignment (BMT CTN 0102).(8, 9) No differences were seen in PFS and overall survival (OS) between the treatment arms. Still, with a medium follow-up of over ten years, the study showed a reduction in the 6-year risk of relapse (77% vs. 47%, p=0.005) in the high-risk group (defined as beta-2 microglobulin ≥ 4 mg/dL or deletion of chromosome 13 by conventional karyotyping) undergoing allo-HCT.(9) In terms of risk vs. benefit, it is, therefore, relevant to consider allo-HCT in patients with a predicted increased early risk of relapse and mortality.
Myeloma patients with high-risk disease, commonly defined as the presence of high-risk cytogenetics or fluorescence in situ hybridization (FISH) such as 13q deletion by conventional cytogenetics, t(4;14), t(14;16), or del(17p), have much shorter PFS with inferior survival.(10) In addition, approximately 35% of MM patients relapse early (<24 months) after auto-HCT, which is a poor prognostic factor.(11) Plasma cell leukemia, while uncommon, is a very aggressive form of myeloma with dismal long-term outcomes.(12, 13) Overall, there is a significant unmet need to mitigate disease relapse and improve survival in these high-risk patients.
There is extensive preclinical and clinical data regarding PIs in preventing chronic graft-versus-host disease (GVHD) after allo-HCT.(14) Bortezomib, a PI, has been shown to cause selective depletion of proliferating alloreactive T lymphocytes while sparing regulatory T cells (Tregs), relevant for GVHD control.(15) Ixazomib, an oral PI, has also been shown to modulate GVHD in preclinical models.(14) Additionally, the PIs exert potent antimyeloma activity.(16) With emerging and encouraging data on the combination of PIs with fludarabine/melphalan before allo-HCT,(17) as well as data on the toxicity of immunomodulatory agents for post allogeneic HCT maintenance,(18, 19) we hypothesized that the addition of bortezomib to the conditioning regimen would optimize the anti-myeloma effect of fludarabine/melphalan and that post-HCT maintenance with ixazomib, would further reduce the risk of disease relapse.
Methods:
Study design and patients
BMT CTN 1302 was a randomized phase 2, double-blinded, multicenter trial of maintenance ixazomib vs. placebo after allo-HCT in high-risk MM (NCT#02440464). Eligible patients were 18 – 70 years of age with a 6/6 sibling donor matched for HLA-A, -B, and HLA-DRB1; or an 8/8 related (other than a sibling) or unrelated donor matched for HLA-A, -B, -C, and -DRB1.
Eligible disease conditions were (1) high-risk MM in partial response (PR) or better with no prior progression and were ≤ 24 months from auto-HCT (single or planned tandem), or were ≤ 24 months from initiation of systemic anti-myeloma therapy with no auto-HCT, (2) high-risk multiple myeloma in very good partial response (VGPR) or better with 1 prior progression occurring ≤ 24 months after auto-HCT (single or planned tandem), or ≤ 24 months after initiation of systemic anti-myeloma therapy with no auto-HCT, (3) standard-risk MM in VGPR or better with 1 prior progression occurring ≤ 24 months from auto-HCT (single or planned tandem), or (4) plasma cell leukemia in VGPR or better with no prior progression and were ≤ 18 months after auto-HCT, or were ≤ 18 months after initiation of systemic anti-plasma cell leukemia therapy with no auto-HCT. High-risk MM was defined as one or more of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional karyotyping, hypodiploidy, chromosome 1q amplification, 1p deletion, t(4;14), t(14;16), t(14;20), or deletion of chromosome 17p by FISH or conventional karyotyping, or high-risk criteria based on gene expression profiling (GEP).
Exclusion criteria were prior allo-HCT; Karnofsky performance status < 70%; non-secretory MM; uncontrolled bacterial, viral, and fungal infections; human immunodeficiency virus infection; active hepatitis B or C; hypersensitivity to bortezomib, boron, or mannitol; grade 2 or higher sensory peripheral neuropathy; pre-planned pre-emptive or prophylactic donor lymphocyte infusion; CNS involvement by multiple myeloma; known gastrointestinal disease that may interfere with oral absorption of ixazomib; multi-organ involvement by amyloidosis or amyloidosis-related organ dysfunction; radiation therapy ≤ 3 weeks before allogeneic HCT; left ventricular ejection fraction ≤ 40%; estimated creatinine clearance ≤ 40 mL/min; carbon monoxide diffuse capacity < 40% (adjusted for hemoglobin); forced expiratory volume in one second < 50%; total bilirubin ≥ 2x the upper limit of normal (ULN); alanine transaminase and aspartate transaminase ≥ 2.5x ULN.
The institutional review boards of the participating centers approved the study, and all patients provided informed consent.
Procedures
The conditioning regimen consisted of fludarabine 30 mg/m2 (reduced to 24 mg/m2 for creatinine clearance 40 – 70 mL/min) intravenously from day −6 to −3, melphalan 70 mg/m2 on day −4 and −3 intravenously, and bortezomib 1.3 mg/m2 intravenously on day −3. The initial 17 patients also received bortezomib 1.3 mg/m2 (based on actual body surface area) on days +1, +4, and +7 after transplant, but this was discontinued with a protocol amendment because of toxicity concerns. Peripheral blood donor cells were mobilized with high-dose filgrastim and collected by leukapheresis to a target stem cell dose of between 5 × 106 and 10 × 106 CD34+ cells per kg based on recipient body weight. T-cell replete unmanipulated stem cell grafts were administered on day 0 per institutional standards.
GVHD prophylaxis was a combination of tacrolimus and methotrexate. Tacrolimus was given to achieve a 5 −10 ng/mL target level and continued for a minimum of 3 months and then tapered in the absence of GVHD. Methotrexate was administered at 5 mg/m2 intravenously on days +1, +3, +6, and +11 after allo-HCT. Between day +60 and day +120 after allo-HCT, eligible patients were randomized to either ixazomib maintenance therapy or placebo. Subjects eligible to initiate maintenance therapy were randomized at a 1:1 ratio to ixazomib and placebo using permuted blocks of random sizes stratified on the number of prior progressions (none vs. one or more). Eligibility criteria for initiating maintenance therapy were: platelet count ≥ 75,000/mm3, absolute neutrophil count (ANC) ≥ 1,000/mm3, total bilirubin < 2x ULN (except for patients with Gilbert’s syndrome), AST and ALT < 2.5x ULN, no ≥ grade 2 visceral (gut or liver) acute GVHD, no ≥ grade 3 other acute GVHD, no disease progression of myeloma or plasma cell leukemia, peripheral neuropathy ≤ grade 3 or grade 2 with pain, tolerating GVHD prophylaxis regimen. Maintenance therapy began within 7 days of randomization. The starting dose of maintenance (ixazomib or matching placebo) was 3 mg orally once a day on days 1, 8, 15 on a 28-day cycle. If no toxicity occurred after completing 3 cycles of maintenance therapy, the dose was escalated to 4 mg/day on days 1, 8, 15 of a 28-day cycle with planned total cycles of 12. If a patient experienced toxicities requiring dose reduction, the maintenance dose was reduced to the next lower level (e.g., 4 mg to 3 mg, 3 mg to 2.3 mg) based on dose modification guidelines (see Supplement Table S1 and S2). If a dose reduction occurred at any cycle, that new level was maintained on all subsequent cycles until further toxicities occurred. No dose re-escalation was permitted. Minimal residual disease (MRD) was assessed by multiparameter flow cytometry assay of bone marrow samples at a sensitivity of 10−5, testing for CD38, CD138, CD19, CD45, CD 56, CD 117, CD81, CD27, kappa, and lambda. Time points for MRD testing were; at HCT, at randomization, and 18 months post-HCT. Planned pre-emptive or prophylactic administration of donor lymphocyte infusion was not permitted. Management of acute and chronic GVHD was conducted per institutional guidelines. During maintenance, strong CYP3A inducers were not allowed.
Outcomes
The primary endpoint was PFS as a time to event endpoint from randomization with data compared between patients randomized to ixazomib or placebo maintenance. Secondary endpoints were grades 2–4 and 3–4 acute GVHD, chronic GVHD, best response, disease progression, non-relapse mortality (NRM), OS, toxicity, infection, and health-related quality of life (HRQOL). The International Uniform Response Criteria/International Myeloma Working Group (IMWG) consensus criteria for MM were used to define myeloma response.(20, 21) Plasma cell leukemia treatment response was assessed based on the consensus statement from the IMWG.(22) HRQOL was assessed using the FACT-BMT version 4.0 instrument and MOS Short Form-36 (SF-36) at HCT, pre-randomization, at 6 months, and 24 months post-HCT. Toxicities were defined as grade 3 or higher adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Statistical analysis
The study was originally designed to randomly assign 55 patients to each maintenance arm with a planned sample size of 138 patients, accounting for 20% of enrollees not proceeding to randomization. This would provide at least 80% power to detect a treatment hazard ratio (ixazomib vs. placebo) of 0.48 for PFS post-randomization, using a one-sided log-rank test with a 10% type I error rate. The analysis included all randomized participants classified by their treatment assignments per the intention-to-treat (ITT) principle.
PFS and OS were described using the Kaplan-Meier estimator and compared between arms using the log-rank test. GVHD, progression, toxicity, and infection events were analyzed as competing risk outcomes, with death treated as the competing event; NRM was handled as a competing risk with progression as its competitor. The cumulative incidence of acute GVHD, chronic GVHD, progression, TRM, toxicity, and infection was estimated using the Aalen-Johansen estimator; GVHD outcomes, progression, and NRM were compared between arms using Gray’s test, while toxicity and infection were contrasted using pointwise comparisons of Aalen-Johansen estimators. The best response was compared using Fisher’s exact tests. The FACT-BMT total score and SF-36 physical and mental component scores (PCS and MCS) are summarized for each treatment arm but not formally compared. One-sided testing at a 5% significance level was used for all secondary survival and competing risk outcomes; two-sided testing at a 10% significance level was used for the best response.
The weighted cumulative incidence estimator of Yavuz(23) was used to obtain survival and cumulative incidence estimates under both treatment policies: allo-HCT+ixazomib and allo-HCT+placebo; this method provides unbiased estimates of what the post-transplant outcomes would be had the entire transplanted cohort been treated under each policy. Analyses were performed using SAS version 9.4 and R version 3.5.
Role of funding source
The funding source did not play any role in the study design, data collection, analysis, interpretation of the data, or writing of the report.
Results:
Patient Characteristics
Fifty-seven patients from 15 centers were enrolled between August 2015 and September 2018. Due to concerns for toxicity of the conditioning regimen, a clinical hold was placed by the Food and Drug Administration (FDA) in March 2016 and lifted in October 2016 after the protocol was amended to omit bortezomib doses on days +1, +4, and +7 after stem cell infusion. Due to slower than anticipated accrual, the study enrollment was closed after 57 patients. Of the 57 patients enrolled, 52 patients (91.2%) received allogeneic HCT (Supplement Figure 1). Reasons for not receiving HCT included disease progression (n=2), toxicity (n=2), and withdrawal (n=1). Of the 52 transplanted patients, 43 (82.7%) proceeded to randomization, 21 to ixazomib, and 22 to the placebo maintenance arm. Among the 9 HCT recipients not randomized, reasons were death before randomization (n=5), disease progression (n=1), neuropathy (n=1), severe infection (n=1), and study withdrawal (n=1).
Among enrolled patients (N=57), the median age was 56 (range, 35–65), 27 (47.4%) were male, and 51 (89.5%) were white. Thirty-three (57.9%) patients had high-risk MM, 15 patients (26.3%) had standard-risk MM with early post auto-HCT progression, and 9 patients (15.8%) had plasma cell leukemia. Disease response prior to HCT was very good partial response (VGPR) in 38.6%, and the majority (71.9%) had prior auto-HCT. An HLA-matched unrelated donor (MUD) was the most common (50.9%) donor type. Other patient characteristics are shown in Table 1.
Table 1:
Patient characteristics
| Treatment Arm | ||||
|---|---|---|---|---|
| Ixazomib (N=21) N (%) | Placebo (N=22) N (%) | Not Randomized1 (N=14) N (%) | Total (N=57) N (%) | |
| Gender | ||||
| Female | 12 (57.1%) | 11 (50.0%) | 7 (50.0%) | 30 (52.6%) |
| Male | 9 (42.9%) | 11 (50.0%) | 7 (50.0%) | 27 (47.4%) |
| Ethnicity | ||||
| Hispanic or Latino | 2 (9.5%) | 2 (9.1%) | 0 (0.0%) | 4 (7.0%) |
| Not Hispanic or Latino | 18 (85.7%) | 19 (86.4%) | 14 (100.0%) | 51 (89.5%) |
| Unknown | 1 (4.8%) | 0 (0.0%) | 0 (0.0%) | 1 (1.8%) |
| Not Answered | 0 (0.0%) | 1 (4.5%) | 0 (0.0%) | 1 (1.8%) |
| Race | ||||
| American Indian/Alaska Native | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Asian | 0 (0.0%) | 1 (4.5%) | 0 (0.0%) | 1 (1.8%) |
| Hawaiian/Pacific Islander | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Black or African American | 3 (14.3%) | 0 (0.0%) | 1 (7.1%) | 4 (7.0%) |
| White | 18 (85.7%) | 20 (90.9%) | 13 (92.9%) | 51 (89.5%) |
| More than One Race | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Other, Specify | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Not Answered | 0 (0.0%) | 1 (4.5%) | 0 (0.0%) | 1 (1.8%) |
| Age (years) | ||||
| Mean (SD) | 51.3 (8.0) | 57.0 (5.0) | 55.4 (8.3) | 54.5 (7.4) |
| Median (Range) | 52.6 (35.3, 63.9) | 57.5 (44.9, 64.7) | 58.7 (39.4, 65.3) | 56.0 (35.3, 65.3) |
| Disease Classification | ||||
| High Risk Multiple Myeloma | 12 (57.1%) | 12 (54.5%) | 9 (64.3%) | 33 (57.9%) |
| Standard Risk Multiple Myeloma | 6 (28.6%) | 6 (27.3%) | 3 (21.4%) | 15 (26.3%) |
| Primary Plasma Cell Leukemia | 3 (14.3%) | 4 (18.2%) | 2 (14.3%) | 9 (15.8%) |
| High Risk Myeloma Cytogenetics 2 | N = 12 | N = 12 | N = 9 | N = 33 |
| Chromosome 13 deletion | 3 (25.0%) | 4 (33.3%) | 0 (0.0%) | 7 (21.2%) |
| Hypodiploidy (<46 chromosomes and/or ploidy index < 0.95) | 0 (0.0%) | 1 (8.3%) | 0 (0.0%) | 1 (3.0%) |
| Chromosome 1 abnormality (1q amplification or 1p deletion) | 6 (50.0%) | 8 (66.7%) | 5 (55.6%) | 19 (57.6%) |
| t(4;14), t(14;16), t(14;20), or 17p deletion | 6 (50.0%) | 4 (33.3%) | 5 (55.6%) | 15 (45.5%) |
| High risk criteria based on gene expression profile (GEP) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Karnofsky Score | ||||
| 100 | 2 (9.5%) | 5 (22.7%) | 0 (0.0%) | 7 (12.3%) |
| 90 | 12 (57.1%) | 9 (40.9%) | 8 (57.1%) | 29 (50.9%) |
| 80 | 5 (23.8%) | 5 (22.7%) | 5 (35.7%) | 15 (26.3%) |
| 70 | 2 (9.5%) | 3 (13.6%) | 1 (7.1%) | 6 (10.5%) |
| Number of Prior Progressions | ||||
| 0 | 13 (61.9%) | 13 (59.1%) | 8 (57.1%) | 34 (59.6%) |
| 1 | 8 (38.1%) | 9 (40.9%) | 6 (42.9%) | 23 (40.4%) |
| Prior Autologous Transplant | ||||
| Yes | 16 (76.2%) | 15 (68.2%) | 10 (71.4%) | 41 (71.9%) |
| No | 5 (23.8%) | 7 (31.8%) | 4 (28.6%) | 16 (28.1%) |
| Disease Status | ||||
| Very Good Partial Response (VGPR) | 11 (52.4%) | 13 (59.1%) | 8 (57.1%) | 32 (56.1%) |
| Partial Response (PR) | 10 (47.6%) | 9 (40.9%) | 6 (42.9%) | 25 (43.9%) |
| Planned Donor Type | ||||
| Related Sibling Donor | 13 (61.9%) | 9 (40.9%) | 6 (42.9%) | 28 (49.1%) |
| Unrelated Donor | 8 (38.1%) | 13 (59.1%) | 8 (57.1%) | 29 (50.9%) |
| CMV Status | ||||
| Positive | 13 (61.9%) | 12 (54.5%) | 5 (35.7%) | 30 (52.6%) |
| Negative | 8 (38.1%) | 10 (45.5%) | 4 (28.6%) | 22 (38.6%) |
| Missing | 0 (0.0%) | 0 (0.0%) | 5 (35.7%) | 5 (8.8%) |
| Days from Transplant to Randomization | N = 21 | N = 22 | N = 43 | |
| Mean (SD) | 92.5 (16.8) | 81.9 (16.4) | N/A | 87.1 (17.3) |
| Median (Range) | 97.0 (69.0, 119.0) | 85.0 (60.0, 108.0) | N/A | 85.0 (60.0, 119.0) |
| Maintenance Therapy for Randomized Patients | N = 21 | N = 22 | N = 43 | |
| Patients Initiating Maintenance | 18 (85.7%) | 21 (95.5%) | N/A | 39 (90.7%) |
| Patients Completing 12 Cycles | 12 (57.1%) | 7 (31.8%) | N/A | 19 (44.2%) |
| Median # Cycles (Interquartile Range) | 12 (5 – 12) | 6 (2 – 12) | N/A | 7 (3 – 12) |
Reasons for non-randomization include death within 60 days of transplant (n=5), disease progression (n=3), withdrew consent (n=2), severe infection (n=1), cardiac issues preventing transplant (n=1), neuropathy (n=1), and sepsis preventing transplant (n=1). Nine participants received a transplant but were not randomized.
Outcomes
Maintenance Therapy:
The median number of completed cycles was 12 (range, 5–12) for the ixazomib group and 6 for the placebo (range, 2–12). Twelve patients (57.1%) completed 12 cycles of ixazomib maintenance, and 7 patients (31.8%) completed 12 cycles of placebo maintenance. Common reasons for maintenance discontinuation were disease progression (n=4) and toxicity (n=2) in the ixazomib maintenance, and toxicity (n=9) and disease progression (n=3) in the placebo arm. Three patients in the ixazomib group (14.3%) and 1 patient in the placebo group (4.5%) could not initiate assigned maintenance therapy.
Response:
The best responses after randomization were not significantly different between ixazomib and placebo arms for both patients in stringent CR (sCR)/CR at randomization and those not in sCR/CR at randomization (p=0.89 and 0.75, respectively) [Table 2A and 2B].
Table 2A and 2B.
(A) Best Response to Treatment Post-Randomization for Participants in sCR/CR at Randomization
(B) Best Response to Treatment Post-Randomization for Participants not in sCR/CR at Randomization
| Ixazomib (N=9) N (%) | Placebo (N=11) N (%) | p-value* | |
|---|---|---|---|
| Response | 0.890 | ||
| Stringent Complete Response (sCR) | 6 (66.7%) | 5 (45.5%) | |
| Complete Response (CR) | 2 (22.2%) | 4 (36.4%) | |
| Very Good Partial Response (VGPR) | 0 (0.0%) | 1 (9.1%) | |
| Partial Response (PR) | 0 (0.0%) | 0 (0.0%) | |
| Stable Disease (SD) | 0 (0.0%) | 0 (0.0%) | |
| Disease Progression (PD) | 1 (11.1%) | 1 (9.1%) |
| Ixazomib (N=12) N (%) | Placebo (N=11) N (%) | p-value* | |
|---|---|---|---|
| Response | 0.754 | ||
| Stringent Complete Response (sCR) | 3 (25.0%) | 4 (36.4%) | |
| Complete Response (CR) | 2 (16.7%) | 3 (27.3%) | |
| Very Good Partial Response (VGPR) | 4 (33.3%) | 4 (36.4%) | |
| Partial Response (PR) | 2 (16.7%) | 0 (0.0%) | |
| Stable Disease (SD) | 0 (0.0%) | 0 (0.0%) | |
| Progressive Disease (PD) | 1 (8.3%) | 0 (0.0%) |
Fisher’s exact test
Fisher’s exact test
GVHD:
The cumulative incidence of grade III-IV acute GVHD at 100 days post-randomization was 9.5% (90%CI: 2.2–23.4%) for the ixazomib arm and 0% (90%CI: N/A) for the placebo arm (p=1.00) [Figure 1]. The cumulative incidence of chronic GVHD at 21 months after randomization was 68.6% (90%CI: 46.8–82.9%) for the ixazomib arm and 63.6% (90%CI: 43.3–78.3%) for the placebo arm (p=1.00) [Figure 2].
Figure 1.
Cumulative Incidence of grade III-IV acute GVHD by treatment arm
Figure 2:
Cumulative incidence of chronic GVHD by treatment arm
NRM and Toxicity:
The cumulative incidence of NRM at 21 months post-randomization was 0.0% (90%CI: N/A) for the ixazomib arm and 4.5% (90%CI: 0.5–16.5%) for the placebo arm (p=0.17) [Figure 3]. Among 9 patients who were not randomized, 3 (33.3%) experienced grade 5/fatal toxicities early after transplant, with 2 possibly related to bortezomib administration on days +1, +4, and +7 after the stem cell infusion (primarily gastrointestinal toxicity). This led to the temporary hold of the study and subsequent restart, omitting bortezomib doses on days +1, +4, and +7. After this modification, 40 patients were enrolled, and there were 4 cases of NRM during the entire follow-up period. After randomization, 61.9% in the ixazomib group and 72.7% in the placebo group experienced grade 3–5 toxicities. Causes of death are shown in Supplement Table S4.
Figure 3:
Cumulative incidence of NRM by treatment arm
Survival and Progression:
At 21 months after randomization, PFS was 55.3% (80% confidence interval (CI): 40–68.1%) for the ixazomib arm and 59.1% (80% CI: 44.5–71.1%) for the placebo arm (Figure 4. p=1.00). The hazard ratio (HR) of PFS for ixazomib vs. placebo was 1.16 by a univariate Cox proportional hazards model. The cumulative incidence of progression at 21 months post-randomization was 44.7% (90%CI: 25.6–62.1%) for the ixazomib arm and 36.4% (90%CI: 19.8–53.3%) for the placebo arm (p=1.00) [Figure 5]. With a median follow up among survivors of 24.4 months, the estimated OS at 21 months post-randomization was 94.7% (90%CI: 75.6–99%) for the ixazomib arm and 86.4% (90%CI: 68.4–94.5%) for the placebo arm (p=0.17) [Figure 6].
Figure 4:
PFS by treatment arm
Figure 5:
Cumulative incidence of progression by treatment arm
Figure 6.
OS by treatment arm
Minimal Residual Disease:
At HCT, 47.1% (95%CI: 23.0–72.2%) of patients (n=17) had MRD positivity which decreased to 33.3% (95%CI: 7.5–70.1%) for the ixazomib group and 28.6% (95%CI: 3.7–71%) for the placebo group at randomization (Supplement Table S3). The number of evaluable patients for MRD at the end of maintenance was too low for further assessment (n=2 for ixazomib and n=3 for placebo).
Quality of Life Assessment:
For the FACT-BMT total score (n=38), the change from HCT to randomization was minimal (mean −0.6 [SE 2.4]); the mean changes from randomization to 24 months post-HCT were 10.6 (SE 5.6) for the ixazomib group and 3.2 (SE 7.5) for the placebo group. For MOS SF-36 (n=37), the respective mean changes of the PCS and MCS from HCT to randomization were −4.3 (SE 1.6) and 2.3 (SE 1.7). The mean changes of PCS and MCS from randomization to 24 months were 4.2 (SE 4) and 4.0 (SE 2.1) for the ixazomib group and 4.5 (SE 3.5) and −6.5 (SE 4.8) for the placebo group, respectively. Due to the small sample size, no formal comparisons were conducted.
Outcomes of The Entire Transplanted Population:
Secondary analysis of the entire transplanted population showed post-HCT PFS estimates of 64.5% (90%CI: 52.2–74.3%) at 12 months, 52% (90%CI: 39.8–62.9%) at 24 months; post-HCT OS estimates of 86.3% (90%CI: 76.0–92.4%) at 12 months, 82% (90%CI: 70.9–89.2%) at 24 months; and post-HCT NRM of 9.7% (90%CI: 4.3–17.8%) at 12 months and 11.7% (90%CI: 5.5–20.4%) at 24 months. Among the patients transplanted with modified conditioning after initial hold, NRM at 12 months was 5.6% (90%CI: 1.4–14.3%) and 8.7% (90%CI: 2.8–18.8%) at 24 months. Post hoc analysis did not show a significant difference in PFS or OS when stratified by no or one prior progression (Supplement Figure 2).
Discussion:
BMT CTN 1302 demonstrated the feasibility of Flu/Mel/Bort reduced-intensity conditioning (RIC) regimen followed by HLA-matched related or unrelated donor HCT for high-risk MM and plasma cell leukemia. The study was prematurely closed for slow accrual; thus, the study’s null hypothesis that ixazomib maintenance therapy results in improved PFS in patients with high-risk multiple myeloma after allo-HCT compared to placebo maintenance could not be rejected.
Prior studies in auto-HCT explored the combination of bortezomib and melphalan for conditioning regimen to augment the anti-myeloma effect of alkylating agents.(24–26) A single-center study demonstrated promising efficacy of bortezomib administered on day −3 along with the backbone of Flu/Mel conditioning regimen in allo-HCT for MM.(17) Bortezomib has also been utilized in mismatched unrelated donor HCT without excess toxicity when administered on post-transplant days +1, +4, and +7 after busulfan/fludarabine-based conditioning.(27, 28) However, in the current study, bortezomib given pre-transplant on day −3 and also after HCT on days +1, +4, and +7; was associated with intolerable toxicity resulting in three deaths in the first seventeen patients. The precise delineation of factors driving such toxicity is unclear, perhaps a combination of administering bortezomib pre-HCT and early after stem cell infusion with melphalan-based conditioning in MM patients.
While the use of maintenance therapy after auto-HCT is firmly established, the case for post-allo-HCT maintenance in MM remains unsettled. In the auto-HCT setting, lenalidomide is most extensively studied and associated with superior PFS and possibly OS.(4) However, the early experience with post-allo-HCT lenalidomide maintenance raised a signal concerning the increased incidence of GVHD and other toxicities.(18, 19) For this reason, and also the increased efficacy of PIs in high-risk MM,(16, 29) we studied ixazomib in the allo-HCT setting. The study failed to meet the primary objective of PFS improvement with ixazomib; however, the results are confounded by premature study closure, thus preventing definite conclusions. The question of ideal post-allo-HCT maintenance in MM, therefore, remains largely unanswered.
Our study is limited by the early closure, which diminished the power to detect differences between the two randomized arms or the differences in MRD rates and health-related QOL. The major weakness of the study was the initial inclusion of bortezomib early after stem cell infusion, which had not been fully piloted in the MM population and likely resulted in excessive toxicity leading to a study hold and subsequent slow-down in accrual. There is a substantial unmet need for patients with primary PCL; however, our study could not evaluate the outcomes of PCL patients separately due to the small number (N=9).
In summary, the Flu/Mel/Bort RIC regimen with tacrolimus/methotrexate GVHD prophylaxis can be a good platform for allografting in myeloma patients. The category of MM that would derive the most benefit from allo-HCT is still a matter of debate. It is also unclear whether maintenance therapy with PIs or other drugs would further reduce relapse. However, given a lower long-term NRM of approximately 10%, clinical trials could be designed focusing on high-risk MM, relapsing early after auto-HCT, PCL, or those who progress after chimeric antigen receptor (CAR) transduced T cells based therapies.
Supplementary Material
Allogeneic Hematopoietic cell transplantation with a conditioning regimen of Fludarabine/Melphalan/Bortezomib is associated with low non-relapse mortality in high-risk myeloma patients.
High-risk myeloma patients (poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous transplant) can have durable disease control with allografting.
The benefit of maintenance therapy after allografting with Ixazomib could not be firmly established.
Acknowledgments:
Firoozeh Sahebi (City of Hope National Medical Center), Amelia Langston (Emory University), Tulio Rodriguez (Loyola University Medical Center), Lawrence E. Morris (Northside Hospital), Racquel Innis-Shelton (University of Alabama), Gerhard Hildebrandt (University of Kentucky), Brian McClune (University of Minnesota), Abraham Kanate (West Virginia University)
Funding:
Support for this clinical trial was provided to the BMT CTN by a grant (U01HL069294) from the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute of the National Institutes of Health, along with contributions from Millennium Pharmaceuticals/Takeda Oncology.
The content of the reported study is solely the authors’ responsibility and does not necessarily represent the official view of the National Institute of Health or Millennium Pharmaceuticals.
Footnotes
Financial Disclosures:
QB: Research funding from Stemline and Acrotech pharma.
YE: On speaker’s bureau and advisory for Oncopeptide, Sanofi, GSK, Janssen. Received honoraria from Janssen, Takeda, GSK, Oncopeptide, Sanofi. Research funding from BMS/Celgene
PM: Consulted for or received honoraria from Bristol Myers Squibb, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, Oncopeptides, Takeda, and Bluebird Biotech.
DV: On speaker’s bureau for Takeda, BMS, GSK, Amgen, Karyopharm, Sanofi, Janssen
Data Sharing Statements:
Deidentified participant data for BMT CTN 1302 will be deposited in the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) (https://biolincc.nhlbi.nih.gov/home/); a publicly available database. Study documents, including the study protocol, informed consent form, data dictionary, case report forms for data collection are also available via the repository. Data will become accessible 3 years after the end of clinical activity and 2 years after the primary publication, as anticipated in 2023. Instructions on specimen or data requests and contact information for BioLINCC are also available.
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