Key Information
The immediate goal for therapy in patients with systemic immunoglobulin light chain amyloidosis (AL) is to swiftly achieve at least a hematologic very good partial response (VGPR), given the consistently improved organ responses and survival with achievement of deep hematologic responses [1external link, opens in a new tab,2external link, opens in a new tab,3external link, opens in a new tab]. The phase III ANDROMEDA trial demonstrated that the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone (D-VCd) resulted in significantly higher hematologic CR (53%) and VGPR rates (78%) compared to VCd in previously untreated patients [4external link, opens in a new tab]. These outstanding response rates have led to D-VCd being the currently accepted frontline therapy for AL amyloidosis. However, up to one-fourth of patients do not achieve a deep response (≥VGPR) with D-VCd induction and may need subsequent treatment to improve the response depth [4external link, opens in a new tab]. Data guiding the selection of subsequent treatment in these patients are limited, and here we report on the patterns of treatment failure and subsequent therapies in this cohort of patients.
After the institutional review board approval, patients initiated on frontline D-VCd regimen between 01/2018 and 12/2022 were evaluated. Patients requiring a subsequent treatment due to suboptimal response [≤ partial response (PR)], progression, or toxicity were included in this study. Additionally, patients who received subsequent treatment for rising involved serum-free light chains (sFLC) after achieving a deep response (≥VGPR) without meeting the criteria for progression were also included. Preplanned autologous stem cell transplantation (ASCT) after achieving a deep response with D-VCd induction was not considered as second-line/subsequent therapy. The Mayo 2004 stage with the European modification (stage IIIB with NT proBNP > 8500 ng/L) was used for risk stratification, and laboratory values for troponin and BNP were harmonized using previously described conversions [5external link, opens in a new tab, 6external link, opens in a new tab]. Hematologic response was assessed from the start of subsequent treatment using the Consensus criteria [7external link, opens in a new tab]. For patients with dFLC between 2 and 5 mg/dL at initiation of subsequent therapy using, a low dFLC PR was categorized as a dFLC < 1 mg/dL [8external link, opens in a new tab]. Given the expected delay in achieving organ response, this endpoint was determined from the initiation of frontline treatment, with responses defined by the binary response criteria [1external link, opens in a new tab, 9external link, opens in a new tab]. Event-free survival (EFS) and overall survival (OS) were calculated from the start of subsequent treatment. For calculating the EFS, the events of interest included discontinuation of D-VCd treatment for progression or rising sFLC without meeting the progression criteria, suboptimal response, adverse effect, or death. All time-to-event analyses were conducted using the Kaplan–Meier method and compared using the log-rank test. Fischer’s exact test was used for comparison of nominal data and non-parametric tests were used to compare continuous data.
Of 119 patients treated with frontline D-VCd regimen during the study period, 28 (24%) patients required switching to a subsequent therapy. Patients requiring second-line therapy were younger (median age 62 years vs. 67.3 years, p = 0.042), had a higher proportion of patients with Mayo Stage I disease (41% vs 20%, p = 0.04), with a trend toward lower rates of Stage IIIB disease (4% vs 15%, p = 0.17) and higher rates of 1q gain/amplification (36% vs 18%, p = 0.06; Supplementary Table 1external link, opens in a new tab).
For the twenty-eight patients who received subsequent therapy, the median follow-up from the diagnosis of AL amyloidosis was 29 (95% CI: 25–36) months and the median follow-up from the start of subsequent therapy was 19.7 (95% CI: 16.4–26.7) months. Prior to the initiation of subsequent therapy, the median duration on D-VCd was 5.7 months (range 1.5–26 months). Six (21%) patients were receiving daratumumab maintenance at the time of initiation of subsequent therapy. Twenty-nine percent (n = 8) patients had Mayo Stage III disease and 68% (n = 19) patients had >10% bone marrow plasma cell infiltrate at diagnosis. The patient characteristics and best hematologic response to D-VCd are depicted in Table 1external link, opens in a new tab. The most common reason for the change in treatment was suboptimal response to D-VCd in 22 (79%) patients [PR in 20 patients, no response (NR) in 2 patients], hematological progression in 3 (11%) patients, rising sFLC from VGPR in 2 (7%) patients and treatment-emergent adverse effect (peripheral neuropathy) in 1 (4%) patient.
Subsequent therapies were grouped into 4 cohorts: daratumumab-based combinations (n = 11, 39%), ASCT (n = 8, 29%), BCL2 inhibitor (BCL2i)-based therapies (n = 6, 21%), and miscellaneous therapies, not classified (n = 3). The details of the salvage therapies are included in Table 1external link, opens in a new tab. Figure 1external link, opens in a new tab shows a swimmer plot with the treatment responses. Among patients switching from D-VCd due to suboptimal hematologic response (n = 22), 19 (86%) patients achieved a deeper magnitude of hematologic response with subsequent therapy. The best hematologic response with subsequent therapy was CR in 9 (32%) patients, VGPR in 12 (43%) patients, PR in 3 (11%) patients (1 patient achieved a low dFLC PR), and no response was noted in 4 (14%) patients. The rate of hematologic CR was 63% with ASCT, 50% with BCL2i-based regimens, 10% with daratumumab-based regimens, and 0% for the 3 patients receiving other therapies (p = 0.057). Of 24 organ-response evaluable patients, 11 (46%) demonstrated response in at least 1 organ. Five of the thirteen patients with cardiac involvement (38%) had a cardiac response, and 7 of the fifteen patients (47%) patients with renal involvement achieved a renal response.