TOURMALINE-AL1 | Ixazomib-dexamethasone for relapsed/refractory systemic AL amyloidosis

Systemic amyloid light chain (AL) amyloidosis, like multiple myeloma (MM), results from clonal plasma cell proliferation and production of misfolded immunoglobulin light chains. However, unlike MM, in AL amyloidosis these toxic proteins are deposited in tissues, leading to organ damage. The most frequently involved organs are the heart and kidney.¹ Currently, there are no specific treatment options for patients with relapsed/refractory AL amyloidosis (RRAL) with multi-organ dysfunction and therefore MM treatment strategies are often used for these patients.²

Ixazomib (ixa), an oral proteasome inhibitor (PI), was found to be active and well tolerated in patients with RRAL in a phase I/II study³. Based on these results, a phase III study, TOURMALINE-AL1 (NCT01659658), was initiated. At the 61^st American Society of Hematology  Annual Meeting & Exposition, Angela Dispenzieri, Division of Hematology, Mayo Clinic, Rochester, US, presented the results from the first planned interim analysis of the TOURMALINE-AL1 trial, comparing the combination of ixa plus dexamethasone (dex) to physician’s choice of therapy in patients with RRAL.⁴

Study design and patients characteristics⁴

• Patients with RRAL (N= 168) ≥ 18 years old, with measurable disease (serum difference between involved and uninvolved free light chain ratio [dFLc] concentration ≥ 50mg/L), major organ involvement (cardiac and/or renal), who relapsed after 1–2 prior therapies, and were not refractory to prior PI therapy, were randomized to:
  • Ixa-dex (n= 85):
    • Ixa: 4mg on Days one, eight, 15
    • Dex: 20mg on Days one, eight, 15, 22
  • Physician’s choice (n= 83):
    • Melphalan (M) + dex: n= 24
    • Cyclophosphamide (Cy) + dex: n= 10
    • Thalidomide (T) + dex: n= 2
    • Lenalidomide (R) + dex: n= 47
• Patients were treated in 28-day cycles until progression of disease (PD) or unacceptable toxicity
• Patients were stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure
• In the ixa-dex arm vs the physician’s choice arm:
  • Median age was 65 (range 38–84) vs 66 (33–82) years
  • Median time from diagnosis was 34.5 vs 32.6 months
  • At initial diagnosis organ involvement was:
    • Cardiac: 29% vs 42%
    • Renal: 38% vs 29%
    • Both: 33% vs 29%
• The most common prior therapies were dex and M but also included bortezomib, Cy, and immunomodulatory drugs. These prior therapies were equally distributed between arms
• In both arms, 80% of patients had relapsed and 20% were refractory to prior therapy
• Primary endpoints were:
  • Hematologic overall response rate (ORR)
  • Vital organ deterioration or death rate at two years (to be assessed at a later data cut-off)
• Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate. Other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety

Results⁴

Efficacy

• At the data cut-off, the most common reason for study discontinuation was PD (44% in the ixa-dex arm vs 35% in the physician’s choice arm)
• The primary endpoint of ORR was not met as shown in Table 1, alongside further efficacy data

Table 1: Efficacy data by treatment arm

CI; confidence interval, CR; complete response, HR; hazard ratio, NE; non-evaluable, PFS; progression-free survival, OR; odds ratio, ORR; overall response rate, OS; overall survival. acardiac deterioration, need for hospitalization for cardiac events, and kidney deterioration, need for hemodialysis or renal transplantation; bmedian vital organ PFS, time from randomization to vital organ progression or death; cmedian hematologic PFS, time from randomization to hematologic progression or death; dfor the OS data were immature with ~40% of OS events having occurred at data cut-off. Data here are given at a median follow-up of 44.9 months
Outcome measure	Ixa-Dex n= 85	Physician’s choice n= 83
ORR, %	53	51
OR= 1.1 (95% CI, 0.60─2.01), p= 0.7623
CR, %	26	18
Median duration of hematologic response, months	46.5	20.2
Vital organ response, %	36	11
OR= 4.72 (95% CI, 2.08─10.73), p= 0.0001
Cardiac response, %	18	5
OR= 4.23 (95% CI, 1.34─13.35), p= 0.0089
Renal response, %	28	7
OR= 5.05 (95% CI, 1.94─13.13), p= 0.0004
Median time to vital organ deterioration or deatha, months	34.8	26.1
HR= 0.525 (95% CI, 0.316─0.873), p= 0.0116
Median vital organ PFSb, months	18	11
HR= 0.615 (95% CI, 0.408─0.928), p= 0.0193
Median hematologic PFSc, months	20.1	16.7
HR= 0.79 (95% CI, 0.513─1.217), p= 0.283
Median time to treatment failure, months	10.1	5.2
HR= 0.604 (95% CI, 0.423─0.864), p= 0.005
Median time to subsequent therapy, months	26.5	12.5
HR= 0.615 (95% CI, 0.398─0.951), p= 0.0274
Median OSd, months	NE	40.8

Safety

Given as ixa-dex (n= 85) vs physician’s choice (n= 81)

• At data cut-off, median treatment duration was 11.7 vs five months
• Grade ≥ 3 adverse events (AEs) were seen in 62% vs 56% of patients:
  • Drug-related grade ≥ 3 AEs: 34% vs 41%
  • Serious AE: 47% vs 33%
  • AEs resulting in discontinuation of study drug: 26% vs 20%
  • On-study deaths: 6% vs 5%
• AEs of clinical importance occurring in ≥ 20% of patients in either arm were:
  • Fatigue: 45% vs 43%
  • Peripheral edema: 46% vs 32%
  • Diarrhea: 34% vs 30%
  • Insomnia: 38% vs 17%
  • Rash: 33% vs 20%
  • Constipation: 21% vs 26%
  • Dyspnea: 24% vs 19%
  • Upper respiratory tract infection: 24% vs 16%
  • Nausea: 24% vs 14%
• Due to the longer duration of treatment in the ixa-dex arm, patients had more time to experience AEs

Conclusions⁴

• TOURMALINE-AL1 is the first phase III trial in patients with RRAL to show a significant clinical outcome improvement
• Despite the trial not meeting the first primary endpoint of hematologic ORR, ixa-dex treatment resulted in an improved CR rate and DOR
• Hematologic/vital organ PFS, time to vital organ deterioration/death, time to treatment failure, and time to subsequent therapy data all favored patients treated with ixa-dex vs physician’s choice
• Considering that the duration of treatment in the ixa-dex arm was twice that of the physician’s choice arm, continuous ixa-dex was generally well tolerated
• Based on these results, ixa-dex may be considered a new option for patients with RRAL