In a letter published in HemaSphere, Claudia Bellofiore, MD, of the University of Pavia in Italy, and colleagues highlighted the need to expand clinical trial eligibility criteria for patients with immunoglobulin light chain (AL) amyloidosis due to the “critical impact” it has on treatment and survival.
AL amyloidosis research and treatment has been limited, with few clinical trials assessing upfront anti-plasma cell therapies. Recent phase 3 trials, however, have resulted in the approval of the current standard of care, though clinical evidence for the treatment of AL amyloidosis is primarily based on retrospective studies.
Dr. Bellofiore and colleagues assessed eligibility criteria for phase 3 clinical trials of newly diagnosed AL amyloidosis and how that affects outcomes in this patient population. They searched the ReAL registry for all newly diagnosed patients between 2004 and 2021, as well as ClinicalTrials.gov for frontline phase 3 clinical trials in AL amyloidosis that were initiated between 2002 and 2021, identifying three trials.
Among a cohort of 1726 consecutive patients, 42% (n=734) met at least one exclusion criteria for the phase 3 trials, most commonly:
- Cardiac stage IIIb (44%)
- Eastern Cooperative Oncology Group performance status >2 (35%)
- Estimated glomerular filtration rate <30 mL/min/1.73 m2(23%)
Bortezomib-based regimens were the most common first-line treatment in patients eligible for clinical trials (60% vs 49%; P<0.001). Patients eligible for clinical trials had a greater rate of hematologic response, with an overall response rate of 45% versus 31% in ineligible patients (P<0.001). The advantage for eligible patients was maintained in those receiving upfront bortezomib-based regimens (49% vs 31%; P<0.001).
Patients eligible for clinical trials had a substantially longer median overall survival (OS; 68 vs 9 months; P<0.001), and mortality rates 24 months after diagnosis were significantly lower in eligible patients across all cardiac stages.
Specifically looking at patients with cardiac stage IIIb (n=322; 18%), ineligible patients had significantly lower OS than eligible patients (2.9 vs 4.5 months; P=0.039).
The authors noted that current exclusion criteria can compromise the generalizability of findings; however, exposing novel treatments to potentially more “fragile” patients enhances the risk of toxicity and worse outcomes. Despite this, not assessing tolerability and dosing strategies in fragile patients makes standardizing safe treatment approaches a challenge. “This underscores the need for trial designs that incorporate dose-escalation strategies or dedicated subgroups to better inform clinical decision-making and improve treatment access without compromising patient safety,” the authors noted.
Prospectively maintained registries may be a valuable resource to assess treatment outcomes in a wider patient cohort.
“By broadening eligibility criteria and incorporating real-world evidence, future research can provide more comprehensive and applicable insights into the optimal management of this disease,” they concluded.
Reference
Bellofiore C, Basset M, Nuvolone M, et al. Eligibility criteria for clinical trials in AL amyloidosis result in exclusion of nearly half of real-world patients. HemaSphere. 2026. doi:10.1002/hem3.70320
