Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice

Patient-reported outcomes in AL amyloidosis have not been well-studied. We analyzed health-related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE-AL1 trial (NCT01659658) (ixazomib-dexamethasone, n = 85; physician's choice of chemotherapy [PC], n = 83). HRQOL and symptom burden were measured with the SF-36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated-measures linear mixed models; analyses were not adjusted for multiplicity. Least-squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib-dexamethasone at several cycles for SF-36v2 Role Physical and Vitality subscales ( p < .05); no subscales demonstrated significant differences favoring PC. For FACT/GOG-Ntx, small but significant differences in LS mean changes

favored ixazomib-dexamethasone over PC at multiple cycles for seven items and both summary scores; significant differences favored PC for one item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib-dexamethasone over PC at some cycles (p < .05). Patients with relapsed/refractory AL amyloidosis treated with ixazomibdexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy.

| INTRODUCTION
Systemic immunoglobulin light chain (AL) amyloidosis, a protein misfolding disease, is characterized by conversion of immunoglobulin light chains from their soluble states into amyloid fibril deposits, most commonly in the heart and kidneys, which in turn lead to organ dysfunction. 1 AL amyloidosis is a rare but serious disorder, affecting approximately 40 individuals per million annually, with an estimated incidence of 10.5 per million person-years. 2,3 AL amyloidosis is progressive, and early diagnosis is critical to prevent irreversible organ damage. 1 Treatment of AL amyloidosis is particularly challenging, as it involves treatment directed against the plasma cell clone/dyscrasia that itself can cause deterioration of organ function, often in elderly and/or comorbid patients. 4 Drugs used to treat AL amyloidosis are derived from experience with multiple myeloma or other B-cell malignancies. Several classes of drugs, such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), as well as high-dose chemotherapy and autologous hematopoietic stem cell transplantation, have yielded effective suppression of production of amyloidogenic precursor protein for many patients. Recently, the combination of daratumumab with bortezomib, cyclophosphamide, and dexamethasone was approved as the first treatment ever for newly diagnosed patients. 5 However, no treatments are approved for AL amyloidosis in the relapsed/refractory setting, and effective therapies for patients with advanced cardiac involvement, in particular, represent an unmet need.
Although difficult to measure, health-related quality of life (HRQOL) can be profoundly affected in patients with systemic AL amyloidosis owing to multiorgan involvement and treatment. 1 Patient-reported outcomes (PROs) in AL amyloidosis are poorly understood and challenging to summarize given the heterogeneity of clinical characteristics and severity levels seen in patients presenting with the disease. Symptoms and outcomes may vary depending upon where the amyloid deposition occurs (e.g., heart, kidneys, liver, nervous system) but commonly include fatigue, weakness, dyspnea, neuropathy, edema, dizziness/lightheadedness, and gastrointestinal symptoms. 6 While no standardized disease-specific assessment tools or approaches with which to evaluate PROs in AL amyloidosis are available, 7  In the phase 3, open-label TOURMALINE-AL1 trial, patients with relapsed/refractory AL amyloidosis were randomized 1:1 to receive either oral ixazomib plus dexamethasone or physician's choice of chemotherapy (PC) in 28-day cycles and were followed until progression or unacceptable toxicity. An interim analysis demonstrated that ixazomib-dexamethasone was well-tolerated and, although the primary endpoint of overall hematologic response rate was not met, time-toevent efficacy analyses consistently favored ixazomib-dexamethasone. 8 Here, we report an analysis of PRO data on HRQOL and AL amyloidosis symptom severity from the phase 3 TOURMALINE-AL1 trial.

| Study design and population
The design and primary results of the phase 3, randomized, open-label TOURMALINE-AL1 trial (NCT01659658) have been reported previously. 8 Briefly, eligible participants were adults with a biopsyconfirmed AL amyloidosis with measurable major organ amyloid involvement (cardiac or renal) that was relapsed or refractory after 1 or 2 prior therapies. A total of 168 patients were randomized 1:1 to receive oral ixazomib (

| Patient-reported outcomes measures
The following PRO measures were collected during the trial: the 36-item Short Form General Health Survey version 2 (SF-36v2) 9,10 was used to evaluate HRQOL, and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/ GOG-Ntx; Version 4) 11 and a novel amyloidosis symptom questionnaire (ASQ) 12 were used to evaluate AL amyloidosis symptom burden.
The SF-36v2 evaluates eight health-domain scales of functional health and well-being (Vitality, Physical Functioning, Bodily Pain, General Health, Role Physical, Role Emotional, Social Functioning, and Mental Health), as well as Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. All SF-36v2 scales and summary scores are transformed into a 0-100 scale, where higher scores indicate better health. The recall period is primarily the past 4 weeks, with some general health items referring to current health status, and one item comparing current health to health 1 year prior.
The FACT/GOG-Ntx is an 11-item questionnaire evaluating concerns with symptoms of neurotoxicity on a scale of 0 (not at all) to 4 (very much) within a recall period of the past 7 days. The 11 items (numbness or tingling in hands, numbness or tingling in feet, discomfort in hands, discomfort in feet, joint pain or muscle cramps, feeling weak all over, trouble hearing, ringing or buzzing in ears, trouble buttoning buttons, trouble feeling shape of small objects, trouble walking) yield two subscales: a sensory subscale with a score range of 0 to 44, and a neurotoxicity subscale with a score range of 0 to 16. For items and subscales, symptom scores are inverted so that higher scores indicate lower symptom burden.
In addition, the novel, study-specific ASQ was developed to evalu- answered. If fewer than 50% of subscale items were answered, proration was not allowed, and the subscale score was set to missing.

| Statistical analyses
To examine the impact of treatment for AL amyloidosis on QOL, using the PRO measures assessed in this trial, several descriptive and adjusted analyses were conducted. Compliance with each PRO measure was estimated at every cycle, and at EOT, and was defined as the percentage of patients remaining in the study who completed a PRO measure.

Summary statistics of mean (SD) observed values and changes
from baseline in subscale scores over time, by treatment arm, were calculated. In addition, maximum improvements in subscale scores were summarized and compared using an analysis of covariance (ANCOVA) model, adjusted for cardiac risk stage, response to most recent prior therapy, and baseline use of PI (exposed or naïve), to compare treatment arms. Maximum improvement in a subscale score was defined as the difference between the best score while on study and the baseline score. For the SF-36v2 and ASQ, cumulative distribution function (CDF) plots of maximum improvement from baseline were developed with the maximum improvement on x-axis (where positive change in the SF-36v2 indicates improvement and negative change in the ASQ indicates improvement) and the cumulative proportion of patients experiencing a change less than or equal to that change on the y-axis, P(X < =x). To our knowledge, minimal clinically important differences for the included PRO measures have not been specifically established in AL amyloidosis.
Repeated measurements analysis using a linear mixed model with repeated measures was used to compare score changes from baseline between treatment arms. The model was adjusted for the following fixed effects: cardiac risk stage, response to most recent prior therapy, baseline use of PI (exposed or naïve), treatment group, visit, treatment by visit interaction, and baseline score. PROs were included as other secondary objectives and as such, no adjustment was made for multiple comparisons. p values are descriptive in nature. The data cut-off date for the HRQOL analyses was 20 February 2019.

| Patient characteristics
All 168 patients who were enrolled and randomly assigned to receive ixazomib-dexamethasone or PC were included in the PRO analysis population. At study entry, demographic and disease characteristics were generally well-balanced between the ixazomib-dexamethasone (n = 85) and PC (n = 83) arms (Table 1). In both treatment arms, most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (91% in the ixazomib-dexamethasone arm and 87% in the PC arm), and 54% of patients in both arms were aged ≥65 years. More patients in the ixazomib-dexamethasone arm (71%) than in the PC arm (58%) had kidney involvement, whereas more patients in the PC arm (71%) than in the ixazomib-dexamethasone arm (62%) had heart involvement.
Patients in the ixazomib-dexamethasone arm completed up to 58 cycles of treatment, and those in the PC arm completed up to 43 cycles of treatment; median treatment duration was 11.7 versus 5.0 months respectively (data not shown). Compliance for all PRO measures was high at baseline (≥95%) and at all cycles before EOT (≥93%) (  Maximum improvement on the two summary scores, PCS and MCS, ranged from À10 to +15 points for almost all patients ( Figure S3).

| Symptom burden
Baseline scores on the FACT/GOG-Ntx revealed low symptom burden at baseline, leaving little room for improvement ( Table 1) Low symptom burden at baseline was also evident in the ASQ scores (Table 1) ANDROMEDA study in a newly diagnosed population support that HRQOL and symptom burden are stable to modestly improved while on treatment for AL amyloidosis. Prior research has shown that treatment of AL amyloidosis with high-dose melphalan or stem cell transplantation produces measurable and sustained improvements in HRQOL, particularly in those patients who achieve hematologic complete response. 13 The current analysis provides insight into the HRQOL impact of regimens other than stem cell transplantation for patients with relapsed AL amyloidosis.
As with many rare diseases, no validated disease-specific PRO measure exists to evaluate amyloidosis-specific symptom burden. The challenges of developing and using PRO measures to capture the experiences of patients with rare diseases are well-documented. 15,16 Based on preliminary qualitative evidence, the study-specific ASQ employed in this study to evaluate amyloidosis symptom burden was well-received by patients, 12  In conclusion, patients with relapsed/refractory AL amyloidosis who were treated with ixazomib-dexamethasone experienced HRQOL and symptom impacts that were similar to or trended better than patients treated with PC. These data suggest that treatment with ixazomib-dexamethasone, although given for a substantially longer treatment duration than PC, does not have a negative impact on HRQOL in patients with relapsed/refractory AL amyloidosis, a population with no approved treatment options.

AUTHOR CONTRIBUTIONS
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

FUNDING INFORMATION
The TOURMALINE-AL1 trial (NCT01659658) was supported by Mil-

DATA AVAILABILITY STATEMENT
The datasets, including the redacted study protocol, redacted statistical analysis plan, and data supporting the results reported in this article, will be made available to researchers who provide a methodologically sound proposal. The data will be provided after its deidentification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.