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Systemic amyloid light-chain (AL) amyloidosis is a rare disease associated with delayed diagnosis and poor prognosis due to the involvement of multiple organ systems, particularly the cardiovascular system. It is characterized by the accumulation of insoluble amyloid fibrils produced by clonal CD38+ plasma cells in tissues and organs, and the death rate within the first year of diagnosis is around 30%. Even though agents used in the treatment of multiple myeloma (MM), mainly bortezomib, are able to improve outcomes, there is no approved therapy for AL amyloidosis. There is still an unmet need for more effective therapies to achieve rapid and deep hematologic responses that reverse organ dysfunction and improve outcomes.
Efstathios Kastritis and colleagues are investigating the efficacy and safety of adding subcutaneous (SC) daratumumab (DARA) to cyclophosphamide, bortezomib, and dexamethasone (CyBorD) compared with CyBorD alone in patients with newly diagnosed AL amyloidosis, in the phase III, randomized, open-label, active-controlled ANDROMEDA study. The primary results were presented by Kastritis during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.1
CyBorD is considered a standard of care for AL amyloidosis. DARA is a human CD38-targeted antibody approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of MM. Previous studies have shown that DARA monotherapy demonstrated an acceptable safety profile in relapsed/refractory AL amyloidosis.2,3
Patients were deemed eligible if they met the following criteria:
Stratification was based on cardiac stage, whether transplantation was offered, and the level of creatinine clearance (≥ 60 mL/min or < 60 mL/min). Randomization was 1:1 to receive either of the following arms in 28-day cycles during the treatment phase:
Patients were observed every 4 weeks for the first six cycles and every 8 weeks thereafter until MOD, death, end of study, or withdrawal.
After the positive results from the safety run-in with 28 patients, a total of 388 additional patients were randomized (n = 195 in DARA + CyBorD arm; n = 193 in CyBorD alone arm). Baseline characteristics and demographics were similar between treatment arms (see Table 1).
ECOG performance status was similar: most patients had a score of 0 or 1, and a median of two organs were involved in both arms. Organ involvement was also similar across treatment arms. Approximately 35% of patients had Stage III cardiac disease, suggestive of advanced cardiac amyloidosis.
Table 1. Patient characteristics among two arms1
CyBorD, cyclophosphamide + bortezomib + dexamethasone; DARA, daratumumab; dFLC, difference between involved and uninvolved free light chains |
||
Characteristic |
DARA + CyBorD |
CyBorD |
Median age, years (range) |
62 (34–87) |
64 (35–86) |
Median time from diagnosis, days (range) |
48 (8–1,611) |
43 (5–1,102) |
Median baseline dFLC, mg/L (range) |
200 (2–4,749) |
186 (1–9,983) |
Organ involvement, % |
|
|
≥ 2 organs |
66 |
65 |
Heart |
72 |
71 |
Kidney |
59 |
59 |
Cardiac stage, % |
|
|
I |
24 |
22 |
II |
39 |
42 |
IIIA |
36 |
33 |
IIIB |
1 |
3 |
Renal stage, % (n = 193 in both arms) |
|
|
I |
55 |
52 |
II |
35 |
38 |
III |
10 |
9 |
The median duration of follow-up was 11.4 months (range, 0.03–21.3). Key findings related to treatment exposure are shown in Table 2, below.
In the safety population,
In the intent-to-treat population,
Table 2. Key findings from safety population and ITT population1
AE, adverse event; auto-SCT, autologous stem cell transplantation; CyBorD, cyclophosphamide + bortezomib + dexamethasone; DARA, daratumumab; ITT, intent to treat; IV, intravenous |
||
Safety population (≥ 1 dose of study treatment) |
DARA-CyBorD (n = 193) |
CyBorD (n = 188) |
Median duration of treatment, months (range) |
9.6 (0.03–21.2) |
5.3 (0.03–7.3) |
Deaths, n (%) |
27 (14) |
29 (15) |
Maintenance therapy with DARA SC monotherapy, (%)
|
77 |
— |
ITT population |
DARA-CyBorD (n = 195) |
CyBorD (n = 193) |
Treatment discontinuation, % Death In need of auto-SCT AE Subsequent therapy Progressive disease |
27 10 6 4 3 1 |
36 7 2 4 12 6 |
Any subsequent therapy, n (%) ASCT, n DARA IV monotherapy/combination, n |
19 (10) 13 0 |
79 (42) 20 48 |
Figure 1. Patient outcomes in both arms1
A Patient response rates and B organ responses at Month 6 in patients who received DARA-CyBorD combination, and patients who received CyBorD.
CR, complete response; CyBorD, cyclophosphamide + bortezomib + dexamethasone; DARA, daratumumab; VGPR, very good partial response
DARA-CyBorD has shown a similar safety profile to the established profiles of DARA SC and CyBorD. The number of patients experiencing a treatment-emergent adverse event (TEAE) was similar among both arms (59 in the DARA-CyBorD arm and 57 in the CyBorD arm). The number of death events were also similar (n = 27 in the DARA-CyBorD arm; n = 29 in the CyBorD arm). The key results of the safety analysis are presented in Table 3, below.
Table 3. The most common Grade ≥ 3 TEAEs (≥ 5% of patients)1
CyBorD, cyclophosphamide + bortezomib + dexamethasone; DARA, daratumumab; TEAE, treatment-emergent adverse event |
||
TEAE, % |
DARA-CyBorD (n = 193) |
CyBorD (n = 188) |
Serious TEAEs, any Grade |
43 |
36 |
Lymphopenia |
13 |
10 |
Pneumonia |
8 |
4 |
Cardiac failure |
6 |
5 |
Diarrhea |
6 |
4 |
Neutropenia |
5 |
3 |
Syncope |
5 |
6 |
Anemia |
4 |
5 |
Peripheral edema |
3 |
6 |
In AL amyloidosis, rapid hematologic response is critical to reverse organ deterioration, and it is a strong predictor of improved overall survival along with subsequent response. Adding DARA SC to CyBorD is associated with significantly higher and deeper hematological response rates, and improvements in clinical outcomes include delayed MOD-PFS, improved MOD event-free survival, and organ response in the treatment of patients with newly diagnosed AL amyloidosis. The safety profile is acceptable, and DARA in combination with CyBorD may provide a new option for this patient population.
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