Daratumumab-VCd superior to VCd alone in newly diagnosed light chain amyloidosis
Adding subcutaneous daratumumab to bortezomib, cyclophosphamide, and dexamethasone (VCd) previously demonstrated to induce higher haematologic complete response rates with an acceptable safety profile in patients with newly diagnosed light-chain amyloidosis. Updated results from the ANDROMEDA trial further support these findings identifying the daratumumab-VCd combination as a clinically superior treatment option than VCd alone.
Systemic light chain (AL) amyloidosis is a rare plasma cell disease characterised by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study, with a median follow-up of 11.4 months, demonstrated that the addition of subcutaneous daratumumab (DARA) to the standard of care (bortezomib, cyclophosphamide, and dexamethasone [VCd]) led to superior outcomes compared to VCd alone. This included a higher hematologic complete response (CR) rate, with an improved organ response accompanied by an acceptable safety profile. At EHA 2021, updated results from ANDROMEDA were presented, with an additional follow-up of 9 months (median 20.3 months).
ANDROMEDA study design
ANDROMEDA is a randomised, open-label, active-controlled, phase III study of D-VCd vs. VCd alone in patients with newly diagnosed AL amyloidosis. Key eligibility criteria included amyloid light chain (AL) amyloidosis with at least one impacted organ, no prior therapy for AL amyloidosis or multiple myeloma, cardiac stage I-IIIA, and an estimated glomerular filtration rate of at least 20 mL/min. In total, 388 patients were randomised (1:1) to D-VCd or VCd for a total of six 28-day cycles. Bortezomib dosed at 1.3 mg/m2, cyclophosphamide at 300 mg/m2 (up to 500 mg weekly), and dexamethasone at 40 mg were administered every week. Subcutaneous daratumumab (1,800 mg) was administered once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 to 6. Patients in the D-VCd arm received only subcutaneous daratumumab after cycle 6, every 4 weeks until major organ deterioration or a maximum of 24 total cycles. Primary endpoint of the study was overall haematologic complete response rate.
Superior haematologic and organ response
After a median follow-up of 20.3 months, 40% of patients in the D-VCd arm were still receiving DARA monotherapy. The median duration of study treatment was 18.5 months in the D-VCd arm vs. 5.3 months in the VCd arm. The overall haematologic CR rate in the D-VCd arm remained significantly higher compared to the VCd arm at 59% and 19%, respectively (odds ratio [95%CI], 5.9 [3.7–9.4]; p< 0.0001). The median time to haematologic CR was 2.0 months with D-VCd vs. 2.8 months with VCd. Haematologic CR rates remained high across all prespecified subgroups. In addition, longer follow-up confirmed the significantly higher rate of haematologic overall response (92% vs. 77%) and ≥ very good partial response (VGPR, 79% vs. 50%, odds ratio [95% CI], 3.7 [2.4–5.9]; p< 0.0001) with D-VCd. Among patients who responded, the median time from randomisation to ≥VGPR was shorter in the D-VCd arm (0.56 months) compared to what was seen in the VCd arm (0.82 months). Cardiac response rates improved with longer follow-up, with a doubling of response when adding DARA to VCd at twelve months (57% vs. 28%, odds ratio [95% CI], 3.5 [2.0–6.2]; p< 0.0001). Similarly, renal response rates were greater with D-VCd versus VCd alone at six months (54% vs. 27%) and at twelve months (57% vs. 27%, odds ratio [95% CI], 4.1 [2.3–7.3]; p< 0.0001).
From cycle 7 onward in the D-VCd group (i.e. when patients switched to DARA monotherapy), any grade 3-4 treatment emergent adverse events (TEAEs) occurred in less than 5% of patients. In the two arms, the most common TEAEs were peripheral oedema, diarrhoea, constipation and fatigue. The most common grade 3-4 TEAEs were lymphopenia, pneumonia and syncope. The rate of infections was 13% with D-VCd as compared to 9% with VCd. Serious TEAEs in the D-VCd arm were reported in 38% of patients during cycles 1-6 and in 21% from cycle 7 onwards. For VCd, serious TEAEs were reported in 36% of patients. The most common serious TEAE was pneumonia. Discontinuations rates due to TEAEs were similar in both arms (5% for D-VCd and 4% for VCd). No additional systemic administration-related reaction beyond those of the primary analysis were reported. As of November 2020, there were 31 deaths in the D-VCd group vs. 40 deaths in the VCd group.
Conclusion
Longer follow-up data support the benefit of adding daratumumab to VCd, with significantly improved haematologic response and doubling rates of cardiac and renal response. No new safety signals were observed, with no grade 3-4 TEAEs occurring in ≥5% of patients in the D-VCd group during treatment with DARA monotherapy from cycle 7 onwards. As such, these data support D-VCd as a new standard of care for patients with AL amyloidosis.
Reference
Kastritis E, et al. Updated results from phase 3 ANDROMEDA study of patients with newly diagnosed light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone plus subcutaneous daratumumab. Presented at EHA 2021; abstract S189.
