Results of the safety run-in phase of the ANDROMEDA trial in patients with newly diagnosed AL amyloidosis

Currently, there are no therapies approved for systemic amyloid light-chain (AL) amyloidosis, a plasma cell disorder characterized by deposition of insoluble amyloid fibrils into tissues and organs. This deposition leads to progressive organ damage, with the heart, kidney, and liver being the most commonly affected organs.

Treatment strategies approved for multiple myeloma (MM) are often used for patients with AL amyloidosis. The combination of cyclophosphamide (C), bortezomib (V), and dexamethasone (d; CVd), represents the standard treatment for newly diagnosed patients. However, regimens used for patients with MM are often more toxic in patients with AL amyloidosis, thus more tolerable and effective therapies are needed.

Daratumumab (DARA), an anti-CD38 monoclonal antibody, has proven efficacious, with a manageable safety profile and no reported cardiac or renal toxicities in newly diagnosed and relapsed MM. CD38 is expressed on AL amyloidosis plasma cells and preliminary studies of DARA monotherapy in relapsed AL amyloidosis have shown overall hematologic response rates ≥ 59% without cardiac or renal toxicities.

The phase III ANDROMEDA study (NCT03201965) is designed to compare the combination of the subcutaneous (SC) formulation of DARA with CVd to CVd alone in patients with newly diagnosed AL amyloidosis. This randomized phase is preceded by a safety run-in phase; if no new safety signals are observed in the safety run-in phase (of DARA SC + CVd), approximately 360 patients will be randomized to receive CVd, with or without DARA SC. Here, we report a summary of the results of the safety run-in phase of the study that have been recently published in Blood by Giovanni Palladini and colleagues.¹

Study design and patient characteristics

• Patients ≥ 18 years with systemic AL amyloidosis, measurable hematologic disease, ≥ 1 impacted organ, Eastern Cooperative Oncology Group performance status score ≤ 2, and without prior therapy were eligible
• A total of 28 patients were included in the safety run-in phase, and their characteristics are reported in Table 1. More than half of patients had ≥ 2 organs involved, with heart and kidney being the most involved organs, as expected.
• Dosing schedule (28-day cycles)
  • DARA SC: 1,800 mg weekly in Cycles 1–2, every 2 weeks in Cycles 3–6, and every 4 weeks thereafter for up to two years
  • C: 300 mg/m² orally or intravenously on Days 1, 8, 15, and 22 of each cycle for up to six cycles
  • V: 1.3 mg/m² subcutaneously on Days 1, 8, 15, and 22 of each cycle for up to six cycles
  • d: 40 mg orally or intravenously weekly for each cycle for up to six cycles
    • Dose adjustment to 20 mg was permitted for patients > 70 years old, who were underweight, had hypervolemia, or prior intolerance to steroid therapy
  • The safety run-in phase aimed to identify any new safety signals with the DARA SC + CVd regimen

Table 1. Patient characteristics¹

FLC, free light-chain *The classification by cardiac stage, per the modified Mayo Staging system, was based on two risk factors: N-terminal pro-brain natriuretic peptide (NT-proBNP; > 332 ng/L) and high sensitivity cardiac troponin (> 54 ng/L). Based on this system, patients were classified in stage I (no factors), stage II (one risk factor), stage IIIa (two risk factors with NT-proBNP levels ≤ 8,500 ng/L), and stage IIIb (two risk factors with NT-proBNP levels > 8,500 ng/L)
Characteristic	Patients (N = 28)
Median age, years (range) ≥ 65 years, n (%)	67.5 (35─83) 16 (57)
Median time from diagnosis, days (range)	59.5 (15─501)
FLC isotype, n (%) Lambda Kappa	21 (75) 7 (25)
Immunoglobulin heavy-chain expression, n (%) IgG IgA	10 (37) 8 (29.6) 2 (7.5)
Involved organs (˃ 50% of patients), median (range) ≥ 2 organs, n (%) Kidney, n (%) Heart, n (%)	2 (1─4) 19 (67.9) 19 (67.9) 17 (60.7)
Mayo Clinic cardiac stage*, n (%) I II IIIa IIIb	6 (21.4) 16 (57.1) 5 (17.9) 1 (3.6)
Median treatment cycles, (range)	16 (1─23)
Median duration of treatment, months (range)	15.1 (0.2─20.1)

Results

At the median follow-up of 17.6 months (1.3–20.4), 25 patients (89%) received > 6 cycles of treatment. Of these, 3 patients received all 6 cycles of DARA SC plus CVd without DARA SC maintenance, while 22 patients (67%) received DARA SC maintenance (> 6 treatment cycles). At the clinical cut-off (July 23, 2019), 13 patients (46%) discontinued treatment and nine patients (32%) underwent elective ASCT.

Safety

The most common (≥ 50%) any-grade treatment-emergent adverse events (TEAEs) included diarrhea (67.9%), fatigue (53.6%), and peripheral edema (50%). Grade 3/4 TEAEs observed in more than 15% of patients were fatigue (21.4%) and lymphopenia (17.9%). TEAEs related to DARA have been observed in 75% of patients. All grade cardiac and renal/urinary TEAEs observed in ˃ 5% of patients are reported in Table 2.

Table 2. All grade cardiac and renal/urinary TEAEs (˃ 5%)¹

TEAEs, treatment-emergent adverse events
All grade TEAEs	Patients, n (%)
Cardiac Palpitations	2 (7%)
Renal/urinary Pollakiuria Acute kidney injury Hematuria Renal impairment Urinary retention	4 (14%) 3 (11%) 2 (7%) 2 (7%) 2 (7%)

Serious TEAEs (n = 12; 43%) included fall (11%), acute kidney injury (11%), pneumonia (7%), cellulitis (7%). One patient (4%) experienced an infusion-related reaction (IRR). Five deaths have occurred, three as a result of complications of ASCT and two due to progression of amyloidosis-related organ dysfunction.

Efficacy

Overall best responses, at a median follow-up of 17.6 months, are reported in Table 3.

Table 3. Patient outcomes¹

aCR, amyloidosis complete response; mCR, modified CR; NR, not reached; ORR, overall response rate; PR, partial response; VGPR, very good partial response *At a median follow-up of 17.6 months, all patients with an aCR or mCR remained in hematologic remission.
Parameter	Patients (N = 28)
ORR aCR + mCR VGPR or better PR or better 1 month 3 months 6 months	96% 54% 82%   71% 79% 61%
Median time to first response, days (range) PR or better VGPR aCR + mCR	9 (7─85) 19 (7─339) 85 (29─179)
Median duration of aCR + mCR*	NR
Overall organ response rate Heart (n = 17) Kidney (n = 18) Liver (n = 4)	64% 53% 83% 50%
Median time to organ response, days (range) Cardiac (n = 9) Renal (n = 15) Hepatic (n = 2)	114 (29─561) 57 (29─449) 330 (321─338)

Of the 9 patients who underwent ASCT, 1 was in CR prior to transplant. Currently, there are six patients evaluable for post-ASCT hematologic response, of whom four deepened their response.

Conclusion

• The combination of DARA SC plus CVd was well tolerated, with no new safety concerns compared to DARA monotherapy or CVd alone
• SC administration of DARA led to a median duration of first infusion of 5 minutes compared to the longer intravenous administration. This may provide significant benefits to the patient treatment experience. Significantly, this is also the first report of DARA SC used in a treatment regimen in an indication other than MM
• Efficacy was promising, with high rates of hematologic and organ responses; as no new safety signals were identified, the randomized portion of the study has begun