Phase 1/2 study of ixazomib with cyclophosphamide and dexamethasone in newly diagnosed AL amyloidosis

TO THE EDITOR:

Immunoglobulin light chain (AL) amyloidosis is a rare clonal plasma cell disorder producing misfolded immunoglobulin light chains that deposit as fibrils in tissues and organs, leading to multiorgan dysfunction.^1,2  Historically, high-dose melphalan and autologous hematopoietic cell transplantation resulted in the best long-term outcomes for patients with AL amyloidosis, but many are ineligible for intensive therapy owing to their advanced organ disease and poor performance status. Bortezomib, a first-in-class proteasome inhibitor, emerged as standard induction therapy based on promising results in the relapsed setting and rapid and deep responses to bortezomib combined with cyclophosphamide or melphalan and corticosteroids.^3-7 

Ixazomib is an oral proteasome inhibitor with a favorable toxicity profile and known activity against amyloidogenic plasma cells.⁸  The current trial was designed to investigate the combination of ixazomib (Ixa), cyclophosphamide (Cy), and dexamethasone (D) before the recent US Food and Drug Administration approval of daratumumab with bortezomib, cyclophosphamide, and dexamethasone in 2021.⁹  This study indicates that IxaCyD is a safe and effective all-oral induction regimen for treatment-naive patients with AL amyloidosis.

This multicenter phase 1/2 trial (NCT03236792) had the primary objectives of establishing a recommended phase 2 dose (RP2D) and determining the best hematologic response to 6 cycles of IxaCyD in patients with newly diagnosed AL amyloidosis. Secondary endpoints included event-free survival (EFS), overall survival (OS), and organ response rates. Eligible patients had untreated, biopsy-proven AL amyloidosis with a difference in the involved and uninvolved free light chains ≥50 mg/L, ≥1 organ (renal, cardiac, gastrointestinal, and/or nervous system/soft tissue) involved, and Eastern Cooperative Oncology Group performance status ≤2. Patients were excluded for New York Heart Association class III/IV heart failure, cardiac stage IIIb, hemodialysis-dependent renal failure, and/or painful grade ≥2 peripheral neuropathy. Patients gave written informed consent as approved by Institutional Review Boards.

In phase 1, patients received escalating doses of Ixa and Cy, with D 20 mg orally, on days 1, 8, and 15 every 28 days. A standard 3 + 3 dose-escalation design was used, with dose-limiting toxicities assessed according to NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) v4.03. The highest tolerated dose was expanded and designated the RP2D. Phase 2 enrolled patients at the RP2D. Hematologic response and organ response, when evaluable, were assessed according to standard criteria.^10,11  The dose levels (DLs) were: DL−1 (Ixa, 3 mg/Cy, 300 mg/D, 20 mg), DL1 (Ixa, 3 mg/Cy, 400 mg/D, 20 mg), DL2 (Ixa, 4 mg/Cy, 400 mg/D, 20 mg), and DL3 (Ixa, 4 mg/Cy, 500 mg/D, 20 mg). Treatment was discontinued for unsatisfactory response, toxicity, hematologic or organ progression, or completing 6 cycles of IxaCyD. EFS (hematologic progression, next treatment, or death) and OS were estimated by the Kaplan-Meier method. Differences between groups were compared using the log-rank test. The duration of follow-up was calculated by the reverse Kaplan-Meier estimate of OS. All analyses were performed using R statistical package v4.0.3 (R Core Team 2020).

Between June 2017 and October 2020, 24 patients were enrolled. The first patient in phase 1 experienced cardiopulmonary arrest at DL1, requiring 3 patients to be enrolled at DL−1. In the absence of toxicity, dose-escalation continued with DL1, DL2, and DL3 accruing 3, 3, and 6 patients, respectively. DL3 was determined as the RP2D. Eight additional patients were enrolled at the RP2D in phase 2. Two patients with cardiac stage IIIb disease at screening were excluded from the analysis. Patient characteristics are reported in Table 1, including the total intention to treat (ITT) (n = 22) and RP2D (n = 14) populations.

Figure 1A shows the best hematologic response. By ITT, the overall hematologic response rate was 55% (12 of 22), including 9 very good partial responses (VGPRs) and 3 partial responses (PRs). No complete responses(CRs) were observed during study treatment, although 1 patient in VGPR converted to CR off therapy at the 3-month follow-up. Among patients treated at RP2D, the hematologic response rate was 64% (9 of 14), including 8 VGPRs and 1 PR. The median number of IxaCyD cycles was 2.5, and the median times to the first and best hematologic responses were 35 and 45 days, respectively.

Among the 14 patients treated at the RP2D, 6 completed all planned cycles of IxaCyD and achieved sustained VGPR. Two additional patients achieved VGPR but were taken off the study by treating physicians for lack of CR after 1 and 4 cycles, respectively. Four patients who had <PR at the RP2D discontinued IxaCyD to start alternative therapy. One patient treated at the RP2D who achieved PR as the best response had progressive disease on treatment. One patient treated at the RP2D experienced cardiac complications and was taken off the study after cycle 1; hematologic response is not available, although the patient is included in both efficacy and safety analyses. Of the 8 patients in the RP2D cohort who did not complete 6 planned cycles, the median duration of time on treatment was 3 months, and the overall hematologic response rate was 38% (2 VGPRs and 1 PR).

Among the 12 and 15 patients from the phase 1/2 ITT population evaluable for renal and cardiac responses, respectively, 5 (42%) renal and 4 (27%) cardiac responses were achieved at 6 months. Of the 6 and 9 RP2D patients evaluable for renal and cardiac responses, respectively, 3 (50%) renal and 2 (22%) cardiac responses were achieved at 6 months. Among all evaluable patients, 9 had cardiac progression, 67% (6 of 9) of whom had never achieved a hematologic response. Renal progression occurred in a single patient.

With a median follow up of 23 months, EFS and OS for all patients were 53.4% (95% confidence interval [CI], 23.3%, 1) and 56.5% (95% CI, 24.8%, 1), respectively. All patients who achieved a hematologic response (≥PR) remained alive and had significantly improved OS compared with nonresponders (P = .011) (Figure 1B).

IxaCyD was well tolerated, and no patient discontinued treatment because of treatment-related adverse events (AEs). In the ITT population, 9 of 22 patients (41%) experienced grade 3/4 AEs, including hyponatremia (n = 2), lower extremity edema (n = 1), weakness (n = 1), anemia (n = 2), and lymphocytopenia (n = 2). Nine grade 3/4 serious AEs occurred, including hyponatremia (n = 2) and cellulitis, sinusitis, weakness, syncope, dehydration, diarrhea, and heart failure exacerbation (n = 1 each). One patient died on treatment (DL1) because of cardiopulmonary arrest not related to treatment. Fourteen patients did not complete all planned cycles of treatment owing to hematologic progression (n = 1), organ progression/complications because of organ disease (n = 3), lack of optimal response/change of therapy (n = 9), and lost to follow-up (n = 1).

In summary, this phase 1/2 trial demonstrates the safety and efficacy of the oral IxaCyD regimen in newly diagnosed AL amyloidosis. An overall hematologic response rate of 55% was observed in the phase 1/2 ITT population. At the RP2D (Ixa, 4 mg/Cy, 500 mg/D, 20 mg), 64% of patients achieved a hematologic response, including 57% who rapidly achieved VGPR in a median of 1.5 cycles. This hematologic response led to renal responses in 50% of evaluable RP2D patients at 6 months, but cardiac responses in only 22% of evaluable RP2D patients at 6 months.

All patients who achieved a hematologic response are alive. Patients with suboptimal responses to IxaCyD received second-line therapy with daratumumab-based regimens (data not shown). The FDA approval of daratumumab in the upfront setting has changed the treatment paradigm for AL amyloidosis. Given the rate of hematologic VGPR and renal responses observed with this all-oral combination, the potential for use as a backbone with the addition of a CD38 monoclonal antibody in a frailer patient population should be investigated.

Acknowledgments: Suzanne Lentzsch was instrumental in helping with the concept for this trial and the preliminary design. Editorial support was provided by Hannah Rice.

This study was supported in part by a grant from Takeda Pharmaceutical and by Memorial Sloan-Kettering Cancer Center Core Grant (P30 CA008748).

Contribution: K.O., H.L., and U.Ö. designed the study; K.O., H.J.L., L.S., H.H., O.L., R.N., and C.A.R. evaluated patients and collected data; K.O., H.J.L., L.S., and C.A.R. analyzed data and wrote the manuscript; J.L. and A.A. collected data; U.Ö. carried out statistical and bioinformatics analyses; and all the authors reviewed, commented, edited, and approved the final version of this manuscript.

Conflict-of-interest disclosure: H.J.L. has participated on the advisory board for Takeda, Sanofi, Janssen, Karyopharm, Pfizer, Celgene/BMS, and Caelum Biosciences and has received research support from Takeda. C.A.R. has participated on the advisory board for Takeda, Janssen, GlaxoSmithKline, Oncopeptides, and Akcea and has received research support from Janssen, Karyopharm, GlaxoSmithKline, and Amgen. K.O. has served on the advisory board for Kite Therapeutics and has received research support from Takeda. O.L. served on advisory boards for MorphoSys Inc. U.Ö. is currently employed by Eli Lilly and Company. The remaining authors declare no competing financial interests.

Correspondence: Keren Osman, Ichan School of Medicine at Mt. Sinai and the Mount Sinai Hospital, One Gustave L. Levy Place, Box 1410, New York, NY 10029; e-mail: keren.osman@mountsinai.org.