The phase III ANDROMEDA study evaluates the safety and efficacy of subcutaneous daratumumab plus bortezomib, cyclophosphamide and dexamethasone in patients with newly diagnosed light-chain (AL) amyloidosis. Primary results from the randomised portion of the trial demonstrates higher frequencies of haematologic complete response and survival free from major organ deterioration or haematologic progression.
“Systemic AL amyloidosis has a poor prognosis by multi-organ involvement, especially heart and kidneys, leading to progressive organ failure and death. The Andromeda trial added daratumumab subcutaneously to VCD induction treatment and showed rapid and high haematologic complete responses and less major organ deterioration compared to VCD alone. Longer follow up is needed to determine if adding daratumumab to standard VCD can also prolong survival. However, when we suppose that rapid and deep haematologic responses are important to stop progressive organ failure, then this combination treatment could be more than promising.”
Systemic immunoglobulin light-chain (AL) amyloidosis is characterised by deposits of light-chain amyloid fibrils produced by clonal CD38+ plasma cells. These fibrils are deposited in tissues and result in organ damage, most frequently to the heart and kidneys. To date, a combination of bortezomib, cyclophosphamide and dexamethasone is the most commonly used regimen. However, rates of haematological complete response remain suboptimal, early mortality is high and treatment-related toxicities are frequently reported. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. A safety run-in phase from the phase III ANDROMEDA trial previously demonstrated that the combination of subcutaneous daratumumab plus bortezomib, cyclophosphamide and dexamethasone in patients with newly diagnosed AL amyloidosis has an acceptable safety profile. Now, primary results from the randomised portion of the trial were reported.
The ANDROMEDA study enrolled 388 patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide and dexamethasone alone (control arm, N= 193) or with subcutaneous daratumumab, followed by single-agent daratumumab every four weeks for a total of 24 cycles (daratumumab arm, N= 195). Eligible patients were at least 18 years of age with a histopathologic diagnosis of systemic AL amyloidosis (affecting one or more organs) and measurable haematologic disease. The primary endpoint of the study was haematologic complete response.
At a median follow-up of 11.4 months, the percentage of patients in haematological complete response who were treated with daratumumab, was significantly higher when compared to those patients in the control arm (53.5% vs. 18.1%; relative risk [RR][95%CI]: 2.9[2.1-4.1], odds ratio[95%CI]: 5.1[3.2-8.2], p< 0.001 for both comparisons). Landmark analysis of haematologic complete response at six months showed percentages consistent with overall haematologic complete response (49.7% in the daratumumab group vs. 14.0% in the control group; RR[95%CI]: 3.5[2.4-5.2]; odds ratio[95%CI]: 6.1[3.7-10.0]; p< 0.001 for both comparisons). Furthermore, the median time to haematologic complete response was 60 days for patients in the daratumumab arm, as compared to 85 days for patients in the control arm. The percentage of patients who had a haematologic very good partial response or better was 78.5% in the daratumumab group and 49.2% in the control group.
Survival free from major organ deterioration, haematological progression or death was also improved with daratumumab (HR[95%CI]: 0.58[0.36-0.93], p= 0.02). By six months, treatment with daratumumab also increased the number of cardiac and renal responses, compared to the control group (41.5% vs. 22.2% ; 53.0% vs. 23.9%, respectively). The most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab arm and 10.1% in the control arm), pneumonia (7.8% vs. 4.3%, respectively), cardiac failure (6.2% vs. 4.8%) and diarrhoea (5.7% vs. 3.7%). Additionally, systemic administration-related reactions to daratumumab occurred in 7.3% of patients. Serious adverse events occurred in 43.0% of the patients in the daratumumab group and in 36.2% of those in the control group; the most common serious adverse event was pneumonia, which occurred in 7.3% and 4.8% of the patients in the respective groups. Overall, 56 patients died, 27 in the daratumumab group and 29 in the control group, with most due to amyloidosis-related cardiomyopathy.
In this study, the addition of daratumumab to a combination of bortezomib, cyclophosphamide and dexamethasone resulted in significant improvements in complete haematological response. In addition, daratumumab was associated with higher frequencies of survival free from major organ deterioration or haematologic progression. Finally, renal and cardiac responses were improved with the addition of daratumumab. Combined with a manageable safety profile, these results support the use of this daratumumab combination in patients with systemic immunoglobulin light-chain amyloidosis.
Kastritis E, Palladini G, Minnema M, et al., Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. New Eng J Med. 2021;385:46-58.