Background: Systemic light chain (AL) amyloidosis is characterized by pathologic build-up of misfolded immunoglobulin light chains in various organs, including the heart and kidneys. The combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (D-CyBorD) is standard for upfront treatment of AL based on the ANDROMEDA study [N Engl J Med 2021;385:46-58]. However, the trial primarily enrolled Caucasians, with distribution of various racial and ethnic minorities as follows: 15.4% Asian, 4.6% Hispanic or Latino, and 3.1% African American (AA). Moreover, the trial excluded patients with advanced cardiac/renal disease and myeloma. Since many AL patients belong to racial minorities and have advanced organ dysfunction at diagnosis, investigation of the efficacy and safety of D-CyBorD in the real-world population is warranted.

Methods: We conducted a single-center retrospective analysis to assess the efficacy and safety of D-CyBorD. Following IRB approval, all patients who received D-CyBorD for upfront treatment of AL from June 2021 to July 2024 were identified. All standard metrics, including serologic and biomarker data, were manually recorded. Hematologic and organ responses were evaluated based on standard consensus criteria. Toxicity assessment was performed in accordance with the NCI CTCAE v5.0.

Results: We identified 19 patients, of which 9 (47%) were female, with 6 (32%) Caucasian, 12 (63%) AA, and 1 Asian. Mean age and Charlson Comorbidity Index were 61 (range, 47-75) and 3 (2-6), respectively. Most patients had ECOG PS of 2, and 5 (26%) had ECOG 3. The median number of organs involved was 2 (2-4). Lambda-type disease was seen in 12 (63%) patients, and 8 (42%) had . Cardiac stage distribution was 1 (5%) stage I, 5 (26%) stage II, 9 (47%) stage IIIA, and 4 (21%) stage IIIB. Renal stage distribution was 9 (47%) stage I, 6 (32%) stage II, 3 (16%) stage III, and 1 unevaluable due to pre-existing ESRD. Median bone marrow plasmacytosis was 10% (4-70). Five patients also met diagnostic criteria for multiple myeloma. Median pretreatment values were as follows: serum creatinine 1.53 mg/dL (0.33-6.73), NT-proBNP 4241 pg/mL (183-28,861), and dFLC 417.24 mg/L (103.73-1146.3). Four patients, 1 Caucasian and 3 AA, experienced early death (<1 cycle) and were excluded from final efficacy analysis - 3 patients with stage III heart involvement died of cardiac causes (2 sudden death, 1 heart failure) and 1 died of unrelated respiratory failure.

At a median follow-up of 18.8 months (6-35), rates of hematological responses were as follows: 6 (40%) CR, 4 (27%) VGPR, 4 (27%) PR, and 1 (7%) NR. Cardiac responses were observed in 8 of 14 evaluable patients (57%), while renal responses were seen in 5 of 7 patients (71%). MRD data was available for 4 patients, of which 1 attained MRD-negative status. In subgroup analysis, 3 of 5 (60%) White patients achieved aCR, with 4 (80%) achieving VGPR or better. Among Black patients, 3 of 9 (33%) achieved aCR, with 6 (67%) achieving VGPR or better. One Asian patient had NR. Among the 5 patients with concurrent myeloma, 2 had aCR, 1 had VGPR, and 2 had PR. Of 7 evaluable patients with high-risk cytogenetics, 3 (43%) had aCR, 1 (14%) VGPR, 2 (29%) PR, and 1 (14%) NR. In comparison, there were 3 (38%) CR, 3 (38%) VGPR, and 2 (25%) PR in the 8 patients with standard-risk disease.

Six patients required dose reductions due to side effects, but none discontinued treatment due to toxicity. Bortezomib dose was reduced in 4 patients (2 with grade 2/3 neuropathy, and 1 each with grade 3 transaminitis and grade 1 thrombocytopenia). One patient had cyclophosphamide dose reduction for grade 2 nausea, while another had reductions in both bortezomib and cyclophosphamide for grade 3 heart failure and grade 3 nausea. Four (27%) patients switched to immunomodulator (IMiD)-based therapy for suboptimal response, while 1 with refractory disease and t(11;14) achieved aCR promptly with venetoclax-based therapy. Of the remaining patients, 5 patients completed D-CyBorD and transitioned to daratumumab maintenance, while 5 successfully completed treatment and started surveillance.

Conclusion: This preliminary analysis supports the use of the D-CyBorD for upfront treatment of AL across diverse patient populations, including ethnic minorities and those with concurrent myeloma. Further prospective study is warranted to confirm the predicted benefit.

Disclosures

Peery:Janssen: Membership on an entity's Board of Directors or advisory committees.

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2024
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