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3402 Daratumumab, Pomalidomide and Dexamethasone (DPd) in Relapsed/ Refractory Light Chain Amyloidosis Previously Exposed to Daratumumab

Program: Oral and Poster Abstracts
Session: 654. MGUS, Amyloidosis and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Non-Biological therapies, Clinical Research, Chemotherapy, Combination therapy, Diseases, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Cara Rosenbaum, MD1, Michaela Liedtke, MD2, Paul Christos, DrPH, MS3*, Hyemin Kim, MD4*, Kathleen Pogonowski, RN4*, Natalie Agudo, RN4*, Bruna Barroso, BSN, RN5*, Anthony Shelton, RN, BS6*, Samantha Reilly, BS5*, Courtney Gadbois, BS7*, John Mark Sloan, MD8, Vaishali Sanchorawala, MD9 and Anita D'Souza, MD, MS10

1Division of Hematology & Medical Oncology, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
2Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA
3Division of Biostatics, Department of Population Heath Sciences, Weill Cornell, New York
4Weill Cornell Medicine, New York
5Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston
6Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
7Medical College of Wisconsin, Milwaukee
8Section of Hematology and Medical Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
9Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, MA
10The Medical College of Wisconsin Inc, Milwaukee, WI

Introduction: Daratumumab (Dara) has changed the treatment paradigm in newly diagnosed and relapsed AL amyloidosis (RAL). Efficacy of Dara retreatment in RAL and Dara reexposure with (w/) effective partners such as IMiDs is unknown. We hypothesize that DPd [Dara, pomalidomide (Pom) and dexamethasone (dex)] in previously Dara exposed RAL patients (pts), including pts with low dFLC (20-50 mg/L), will yield deeper hematologic (hem) responses.

Primary objective is to determine hem best response w/in 12 months (mos) of DPd treatment. Secondary objectives include hem overall and very good partial response rates (ORR and VGPR), stringent dFLC response, low-dFLC PR rates (in low dFLC pts only), minimal residual disease (MRD) negative rates using next generation sequencing (NGS), serum mass spectrometry (MS) M protein detection, time to first/ best hem responses, time to next therapy, median hem PFS/OS, organ response rates and duration of/ time to organ response.

Methods: Multicenter phase 2 trial w/16 pts planned to receive DPd for 12 cycles. Eligibility include RAL, ≥ 1 prior line, ≥ 8 prior doses of Dara given in any prior line and negative CRAB criteria. Low dFLC pts were eligible w/ adapted response criteria used for low-dFLC PR (dFLC <10mg/L). Pts received DPd x 12 cycles with optional continuation of Dara and/or Pom w/ or w/out dex per MD discretion if ≥ VGPR achieved after 12 cycles (C). Dara 1800mg SQ weekly (qwk) x 8, every 2 wk X 8 doses & monthly starting C7; Pom 4mg PO Days(D)1-21/28; dex C1: 20mg IV D1/8, 20mg PO D2/9 & 40mg PO C1D15 wkly through C6, then 20mg IV monthly starting C7D1 & 20mg PO D8,15, 22. A reduced starting dose of dex 20mg was allowed for significant cardiac and/or renal disease. Serum MS and NGS from bone marrow were collected at baseline, best response, after 12 cycles, and at 18 and 24 mos follow-up. All pts gave written IRB-approved informed consent.

Results: Between 3/2021- 6/2023, 9 pts were enrolled, including 5 w/ low dFLC. Tables 1& 2 show baseline pt characteristics. Five pts completed all 12 cycles (2 w/ measurable dFLC at enrollment and 3 w/ low dFLC); 3 of 5 remain on therapy beyond 12 cycles [DPd (1 pt) & Pom (2)]. An additional 3 pts have completed 1, 5 and 6 cycles of DPd and receive ongoing therapy. One heavily pretreated pt w/ 6 prior lines w/o response (NR) after C2 came off study due to worsening preexisting peripheral neuropathy (PN) and a treatment-emergent grade 3 PN. Of the 5 pts evaluable for response, both measurable dFLC pts achieved CR and negative serum MS; time to best response was 3 and 4 mos. Two of the 3 low dFLC pts (67%) achieved low-dFLC PR; the other had NR despite a decreasing dFLC which started rising w/in 2- 5 mos off therapy. All 3 pts who continue on study therapy past 12 cycles have sustained hem and renal responses at 12, 18 & 26 mos from treatment start. Of the pts on active therapy who have received 1, 5 and 6 cycles to date, 2 achieved VGPR after 1 and 2 cycles, and 1 low dFLC pt achieved low-dFLC PR after 1 cycle. 67% (6/9) and 56% (5/9) are evaluable for renal and cardiac responses, resp. 83% (5/6) achieved renal responses in a median of 2 cycles and cardiac response was seen in 20% (1/5) after 1 cycle (a low dFLC pt). Only 1 renal progression at 14 mos was seen in a low dFLC pt who had therapy held after 12 cycles. This pt also had a renal response after 1 cycle which was sustained through 24 mos. 40% of evaluable cardiac pts (2/5) had cardiac progression after 1 and 2 cycles, resp. All pts remain alive.

DPd was well tolerated w/ expected adverse events (AEs), mostly grade (gr) 1/2 cytopenias and dex related AEs. Gr 3/4 neutropenia in 2 pts was associated w/ gr 1/2 infections only (1 pt w/ suspected undiagnosed benign familial neutropenia (Duffy null phenotype). Both pts continued Pom reduced from 4mg to 2mg on study. Gr 3 non-hem AEs included 2 pts w/ respiratory infections (both w/ gr 1/2 neutropenia) and a pt w/ pulmonary emboli after air travel who was started on apixaban. All pts had full recovery and remained on study therapy. There were no gr 4 infections/ non-hem AEs or discontinuations due to TEAEs other than the previously described gr 3 PN.

Conclusions: We show evidence of safety and efficacy of DPd in previously Dara exposed RAL among the first 5 evaluable pts completing 12 cycles. Hem responses were early and deep in measurable dFLC (CR 100%) and low dFLC (PR 67%) cohorts. An 83% renal response rate occurred early (median 2 cycles). The study is ongoing and updated outcomes including MRD analyses will be presented at the meeting.

Disclosures: Rosenbaum: Janssen Pharmaceuticals: Research Funding. Liedtke: Allogene: Other: Grants or contracts; BMS: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board; Caelum: Other: Grants or contracts; Adaptive: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Abbvie: Other: Grants or contracts; Seagen: Other: Grants or contracts; Janssen: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board; Kite: Other: Participation on a Data Safety Monitoring Board or Advisory Board. Sloan: Nuvectis Pharaceuticals: Consultancy; Stemline Pharmaceuticals: Consultancy; Servier Pharmaceuticals: Honoraria; Seagen: Research Funding; CTI Biopharma: Honoraria; Abbvie: Consultancy. Sanchorawala: Janssen, Alexion, Prothena, Celgene, Takeda, Abbvie, Regeneron, Pfizer, AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. D'Souza: Imbrium, Pfizer, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen, Prothena: Consultancy; Abbvie, Sanofi, Takeda, TeneoBio, Caelum, Prothena: Research Funding.

OffLabel Disclosure: Pomalidomide (considered off-label in systemic light chain amyloidosis) but supported by peer reviewed literature for relevant off-label use in this disease as an active drug.

*signifies non-member of ASH