Novel treatment strategies for light-chain amyloidosis: Updates from EHA 2023

Light-chain amyloidosis (AL amyloidosis) is the most common type of systemic amyloidosis caused by plasma cell dyscrasia and is characterized by a build-up of immunoglobulin light chains, which will progressively generate amyloid fibril deposits in various organ sites, including the heart.^1,2 These deposits cause organ failure and, eventually, death.² The current standard-of-care regimen is aimed at targeting the malignant plasma cell to reduce the formation of these fibrils.¹ However, there are no current therapies that remove existing deposits from organs.²

CAEL-101 is a novel, chimeric monoclonal antibody that targets fibrils directly and has the potential to remove them from organ sites. Belantamab mafodotin targets B-cell maturation antigen plasma cells expressed in AL amyloidosis. During the European Hematology Association Congress 2023, Michaela Liedtke presented the results from a phase II trial of CAEL-101 in patients with AL amyloidosis,^1,2 and Efstathios Kastritis shared the findings from a phase II trial of belantamab mafodotin.³ We are pleased to summarize the key data from these trials here.

CAEL-101 – phase II trial¹

• This is an open-label, multicenter, phase II trial (NCT04304144) evaluating the safety and tolerability of CAEL-101 in 25 patients with AL amyloidosis.
• Patients were administered ≤1,000 mg/m² of CAEL-101 together with cyclophosphamide + bortezomib + dexamethasone -/+ daratumumab in part A of the study.
• Part B of the study consisted of CAEL-101 and anti-plasma cell dyscrasia therapy together with daratumumab treatment.
• Cardiac response was defined as a 30% decrease in N-terminal pro-brain natriuretic peptide or >300 ng/L decrease if baseline levels were ≥650 ng/L.
• Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

Characteristic (% unless otherwise stated)	N = 25
Median age, years	65.2
Male	72
Race
White/Caucasian	92
Black/African American	8
Mayo stage at screening
I	8
II	76
IIIa	16
Patients with cardiac involvement	88
Prior anti-PCD therapy	80
PCD, plasma cell dyscrasia. *Adapted from Valent.1

Efficacy

• After 18 months of treatment, 23% of cardiac evaluable patients experienced a response (Figure 1).
• One patient experienced cardiac disease progression.
• Responses in patients were observed even after anti-plasma cell dyscrasia therapy cessation.

*Adapted from Liedtke.¹

Safety

• All patients experienced ≥1 treatment-emergent adverse event (TEAEs).
  • 24% of TEAEs were possibly related to treatment.
  • ≥60% of TEAEs were Grade ≥3.
  • ≥52% of TEAEs were serious adverse events (SAEs).
• Nine patients discontinued the study; all discontinuations were considered unrelated to treatment.
• Adverse events (AEs) of any grade experienced by ≥25% of patients are shown in Figure 2.

*Adapted from Liedtke.¹

Ongoing phase III trials with CAEL-101²

• These are two ongoing international, multicenter, double-blind, randomized, phase III trials (NCT04512235) and (NCT04504825), with the aim to investigate CAEL-101 in combination with standard-of-care chemotherapy in treatment-naïve patients with cardiac AL amyloidosis in Mayo Stages IIIb or IIIa.
  • 267 and 124 patients with amyloidosis Stage IIIa are currently enrolled in trial NCT04512235 and NCT04504825, respectively.
• Eligible patients are randomized 2:1 to receive 1,000 mg/m² of CAEL-101 intravenously once weekly or placebo for 4 weeks, followed by maintenance dosing every 2 weeks.
• The primary endpoint in both trials is overall survival.
  • Secondary endpoints include functional outcomes, quality of life and echocardiography.

Conclusion

The phase II trial showed that CAEL-101 was well tolerated among patients with AL amyloidosis and presented no evidence of organ toxicity. Most TEAEs were mild or moderate in severity. Further data on the efficacy and safety of CAEL-101 will become available from the two ongoing phase III trials.

Belantamab mafodotin³

• This is an open-label, multinational, phase II trial assessing the efficacy and safety of belantamab mafodotin in patients with relapsed or refractory AL amyloidosis.  

• Eligible patients had Mayo Stage I–IIIA.
• Patients were administered 2.5 mg/kg of intravenous belantamab mafodotin monotherapy every 42 days for up to 8 cycles.
• The primary objective of the study was to present an interim efficacy and safety analysis of belantamab mafodotin from the prospective EMN27 study.
• Secondary endpoints included the safety profile of patients, secondary efficacy evaluations, and characterization of the pharmacokinetic profile.
• Full baseline patient characteristics are shown in Table 2.

Table 2. Baseline patient characteristics*

dFLC, difference between involved free light-chain and uninvolved free light-chain; NT-proBNP, N-terminal pro-brain natriuretic peptide levels; NYHA, New York Heart Association. *Adapted from Kastritis.3
Characteristic (% unless otherwise stated)	N = 25
Median age, years (range)	66 (46–80)
Sex
Male	60
Female	40
NYHA class
I	24
II	76
NT-proBNP, ng/L	1,197
Median dFLC, mg/L (range)	117.1 (37.8–2791)
Median number of previous treatments, n (range)	3 (1–10)
Prior treatments
Daratumumab	72
Borterzomib	92
Organ involvement
Heart	76
Kidney	64
Peripheral nervous system	24
Liver	16
Soft tissue	20
GI tract	12

 Efficacy

• At a median follow up time of 11 months, 25 patients were included, of whom 18 were previously treated with daratumumab.
• The overall hematological response rate for all patients was 60%, and 36% of all patients experienced a very good partial response (Figure 3).
• The overall hematologic response rate for patients with prior daratumumab exposure was 56%, and 38.9% experienced a very good partial response (Figure 3).

dFLC, difference between involved free light-chain and uninvolved free light-chain; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
*Adapted from Kastritis.^3
†Patients experienced a response to treatment but had persistence of small, non-measurable amounts of monoclonal protein that could still affect outcomes.

• The median time to first hematologic response was 0.5 months (range, <0.1–4.9).
• The median time to first very good partial response was 1.4 months (0.5–3.5).
• The median duration of response was 5.8 months.
• The 3-month response rate for involvement of any organ was 20%, 12% for heart, and 8% for kidney.

Safety

• All patients experienced at least one AE.
  • 32% experienced hematologic toxicity and 16% cardiac disorders.
  • Cardiac disorders were unrelated to belantamab, and no new cardiac or renal toxicity signals were observed.
• Grade ≥3 TEAEs were experienced by 72% of patients.
• At least one SAE occurred in 32% of patients.
  • Fatal SAEs were observed in 12% of patients.
• At least one ocular TEAE occurred in 96%.
  • Grade 3 or 4 ocular TEAEs were recorded in 48% of patients.
  • A breakdown of ocular AEs is shown in Figure 4.

AE, adverse event.
*Adapted from Kastritis.³

Conclusion

The phase II trial of belantamab demonstrated a high hematologic response rate in heavily pre-treated patients with relapsed or refractory AL amyloidosis. The trial did not identify any new toxicity signals. Despite the prolonged administration period of belantamab, ocular toxicity could not be prevented. These results highlight a potential treatment option for patients with relapsed or refractory AL amyloidosis, particularly those with prior exposure to daratumumab and bortezomib.