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4780 Reduced Early Mortality with Daratumumab-Based Frontline Therapy in Systemic AL Amyloidosis- Experience from the Columbia Amyloidosis Multidisciplinary ProgramClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 654. MGUS, Amyloidosis and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical Research, Plasma Cell Disorders, Diseases, real-world evidence, Lymphoid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Rajshekhar Chakraborty, MD1, Divaya Bhutani, MD2, Markus Mapara, MD3, Ran Reshef, MD, MSc4, Mathew S Maurer, MD, PhD5*, Jai Radhakrishnan6* and Suzanne Lentzsch, MD, PhD7

1Columbia University Irving Medical Center, Thornwood, NY
2Columbia University, College of Physicians and Surgeons, New York, NY
3Columbia University College of Physicians and Surgeons, New York, NY
4Division of Hematology & Oncology, Columbia University Medical Center, New York
5Columbia, New York Presbyterian Hospital, New York, NY
6New York Presbyterian Hospital - Columbia Campus, New York, NY
7Division of Hematology & Oncology, Columbia University Medical Center, New York, NY

Introduction: Despite advances in treatment of systemic light chain (AL) amyloidosis, early mortality (EM) has been substantial up until recently, with a 6-month EM rate of approximately 25% in the era preceding daratumumab (Muchtar et al. Blood. 2017). Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) is the first FDA-approved therapy for systemic AL amyloidosis based on the ANDROMEDA trial with an unprecedented hematologic complete response (Heme-CR) rate ≈ 50%. However, data on hematologic and cardiac organ response rate and estimated early mortality (EM) in different stages since routine introduction of daratumumab-based frontline therapy are lacking.

Methods: We performed a retrospective cohort study of all consecutive patients treated with daratumumab-based combination therapy at Columbia Amyloidosis Multidisciplinary Program (CAMP). Hematologic and cardiac organ response rates are reported on an intention-to-treat (ITT) basis, with patients who died prior to response evaluation or those with missing data classified as non-responders. Time-to-event analyses were performed by the Kaplan-Meier method.

Results: Eighty-three consecutive patients treated with daratumumab-based frontline therapy were included in the analysis. The baseline characteristics of our cohort in comparison with Dara-VCD arm of ANDROMEDA is shown in Table 1. The median age at diagnosis was 68 years (range, 40-91), with 65% being males and 13 patients (16%) of Black/African-American race. The median dFLC (involved – uninvolved) was 21.9 mg/dl, with 61% of patients having baseline dFLC>18 mg/dl. Mayo 2004 stage IIIa/IIIb comprised 65% of our cohort compared to 37% of ANDROMEDA trial. Thirty-three patients (44%) had NYHA Class III/IV symptoms. The daratumumab-based frontline regimens used were Dara-VCD (n=78), Dara-VD (n=2), Dara-D (n=2), and Dara-Ixazomib-D (n=1). High-dose melphalan followed by autologous hematopoietic cell transplantation (HDM-AHCT) as a part of frontline therapy was performed in 11 patients (13.4%), with melphalan dose being 140 mg/m2 in 8, 200 mg/m2 in 2, and 100 mg/m2 in 1 patient.

Hematologic response was evaluable in 78 patients (i.e. dFLC>2 mg/dl at diagnosis). On an ITT basis, Heme-CR was achieved by 39 patients (50%), and very good partial response or better (Heme ≥VGPR) by 57 patients (73.1%). The median time to Heme-CR from treatment initiation was 2.7 months (range, 0.42-13.97). Among patients evaluable for cardiac organ response (i.e. NT-proBNP≥650 pg/ml; n=64), 35 (58.3%) achieved an organ response. The median time to initial cardiac response (>30% reduction in NT pro-BNP with absolute reduction of >300 pg/ml) was 2.95 months (range, 0.43-10.43). Figure 1 demonstrates comparable hematologic and numerically higher cardiac organ response rate in our cohort vs Dara-VCD arm of ANDROMEDA trial.

Next, we estimated the EM rate. The estimated EM at 6 months in our cohort was 7.6% (95% CI, 3.4-15.9). 6-month EM in patients with Mayo 2004 stage IIIb was 22.2% (95% CI, 9.5-43.6) vs 1.96% (95% CI, 0.27-12.65) in those with stage I-IIIa (p<0.001) [Figure 2]. By Mayo 2012 staging, the estimated 6-month EM rate in patients with stage I, II, III, and IV disease was 0% (95% CI, 0-0), 0% (95% CI, 0-0), 9.6% (95% CI, 2.4-31.3), and 12.9% (95% CI, 4.9-29.8) respectively (p=0.0425). Among patients who underwent upfront HDM-AHCT (n=11), there was no transplant-related mortality at 100 days. On evaluating the prognostic impact of individual factors in Mayo 2012 staging (NT-proBNP, Troponin, and dFLC) on OS, dFLC>18 mg/dl was no longer a significant adverse prognostic factor for survival in both univariate and multivariate analysis. Updated data will be presented at the meeting.

Conclusion: Despite a sicker population with more advanced cardiac involvement compared to ANDROMEDA trial, daratumumab-based frontline induction therapy led to similar Heme-CR rate and favorable cardiac organ response rate in our cohort. Additionally, estimated 6-month EM has decreased by approximately 3-fold compared to historical data, with dramatic reduction in Mayo 2004 stage I-IIIa and continued substantial EM in stage IIIb disease. Finally, as clone-directed therapy has significantly improved, light chain burden at baseline may not be a relevant prognostic factor in contemporary era and should be scrutinized in larger datasets to re-design the staging system.

Disclosures: Chakraborty: AbbVie: Research Funding; Sanofi: Consultancy, Honoraria; Genentech: Research Funding; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bhutani: Sanofi: Consultancy, Research Funding. Mapara: Crispr/vertex: Consultancy; Incyte: Consultancy; Bluebird bio: Consultancy. Reshef: TScan Therapeutics: Consultancy. Maurer: Alexion, AstraZeneca Rare Disease: Consultancy. Lentzsch: Regeneron: Honoraria; Oncopeptide: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinical Care Options: Honoraria; Celgene: Research Funding; Caelum Biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: January 1, 2041.

OffLabel Disclosure: Use of daratumumab in patients with advanced cardiac AL amyloidosis (Stage IIIb)

*signifies non-member of ASH