Light-chain (AL) amyloidosis is a rare systemic disorder characterized by the deposition of misfolded protein aggregates into various organs such as the heart, kidney, liver, or gastrointestinal tract. To date, there is no standard treatment approach for previously treated AL amyloidosis. Moreover, while daratumumab, cyclophosphamide, bortezomib, dexamethasone (Dara-CyBorD) is now considered the standard-of-care in newly diagnosed AL amyloidosis 1, the use of bortezomib may be limited by pre-existing disease-related sensorimotor polyneuropathy. Thus, there remains a continued need to explore novel therapeutic approaches in AL amyloidosis with the goal of optimizing efficacy and tolerability. Daratumumab, a first-in-class human IgG1κ CD38 monoclonal antibody, initially demonstrated promising efficacy and safety in previously treated AL amyloidosis as monotherapy with a hematologic ≥ very good partial response (VGPR) rate of 48%–86% 2, 3. These findings were subsequently confirmed in the phase 3 ANDROMEDA study in newly diagnosed AL amyloidosis, resulting in the regulatory approval of Dara-CyBorD in this context 1. Ixazomib is a first-in-class oral proteasome inhibitor with a lower incidence of peripheral neuropathy (PN) relative to bortezomib, which may confer advantages in AL amyloidosis patients with baseline disease-related PN 4, 5. In phase 2 and 3 studies in previously treated AL amyloidosis, ixazomib in combination with dexamethasone demonstrated a hematologic overall response rate of 52%–53% 6, 7. Based on the promising safety and efficacy profile of daratumumab and ixazomib, we conducted a phase 1 investigator-initiated study evaluating the safety and preliminary efficacy of the novel combination of daratumumab, ixazomib, and dexamethasone (DId) in AL amyloidosis (NCT03283917). We herein report the final results of the study. Patients who enrolled on the study received daratumumab, ixazomib, and dexamethasone at standard doses on a 28-day cycle for up to 12 cycles. The primary objectives were to confirm the safety, tolerability, and recommended phase 2 dose of DId in AL amyloidosis. Planned enrollment was 20 patients. The study sponsor was The University of Texas MD Anderson Cancer Center (UTMDACC), and the study was approved by the UTMDACC Institutional Review Board. All study participants provided informed consent, and the study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Conference on Harmonization. Study funding was provided by Johnson and Johnson Innovative Medicine and Takeda Pharmaceuticals, who also provided daratumumab and ixazomib, respectively. The study population included patients diagnosed with systemic AL amyloidosis who were treatment naïve or previously treated with evidence of clonal relapse or with refractory disease defined as less than a hematologic VGPR to prior therapy. For details on other key inclusion and exclusion criteria, treatment administration, safety and efficacy evaluation, dose-limiting toxicity (DLT) criteria, and statistical methods, please refer to Supporting Information. Between October 22, 2018, and November 17, 2022, a total of 20 patients enrolled on the study, including 14 newly diagnosed patients and 6 previously treated patients. Baseline patient characteristics are summarized in Table 1. The median DId treatment cycles administered was 12 (range 1–12), and 11 (55%) patients completed all 12 treatment cycles. A total of 10 patients were treated with intravenous (IV) daratumumab, 7 patients with subcutaneous (SC) daratumumab, and 3 patients received both IV and SC daratumumab during their treatment course due to the implementation of the SC daratumumab protocol amendment mid-treatment. All but one of 20 patients escalated their weekly dexamethasone dose from 20 to 40 mg for cycle 2. The intent to proceed with high dose chemotherapy and autologous stem cell transplantation was the most common reason for early treatment discontinuation (4 patients, 20%) per treating physician discretion. A total of 9 (45%) patients underwent consolidative autologous stem cell transplant (ASCT) prior to hematologic progression on or after treatment with DId, among whom six patients were in a hematologic VGPR and three patients in a hematologic partial response (PR) at the time of ASCT. Two patients progressed during the Post-Treatment Observation phase of the study, and both were subsequently treated with Dara-CyBorD. The most common treatment emergent adverse events (TEAEs) of any grade regardless of attribution were dyspnea (70%), nausea (70%), and hypoalbuminemia (65%) (Table S1). The most common grade ≥ 3 TEAEs were lymphopenia (35%), lung infection (30%), and hypertension (25%) (Table S2). Treatment emergent PN occurred in 5 patients (25%, all grade 1 and 2), among whom 4 of 5 had baseline grade 1 PN and/or prior bortezomib exposure. A total of four (20%) patients required a dose reduction of ixazomib due to TEAEs, all of which were related to PN. A total of 8 (40%) of patients required a dexamethasone dose reduction due to TEAEs, with the most common reason being edema and/or weight gain occurring in 6 patients. There was one DLT (grade 3 lung infection) which was deemed possibly related to study treatment. Safety stopping rules for the study were not met as per the protocol specified toxicity monitoring plan. Please refer to Supporting Information for additional safety data. Among all 20 patients treated on study, the overall best hematologic response rate was 100%, hematologic ≥ VGPR rate was 80%, and hematologic complete response (CR) rate was 15% (Table 2, Figure 1). Notably, the daratumumab immunofixation (IFE) reflex assay 8 was not utilized in this study to discriminate between a patient's endogenous M-protein and daratumumab, which could potentially underestimate the true hematologic CR rate. Nonetheless, among four patients in the study who had an IgG kappa and/or kappa light chain disease related monoclonal protein isotype, only one patient had a residual IgG kappa on IFE but would have been otherwise considered to be in a hematologic CR. The dFLC ≤ 10 mg/L response was 40% and iFLC ≤ 20 mg/L was 45% 9. Response rates were comparable between the newly diagnosed and previously treated patient cohorts, and the hematologic ≥ VGPR rate among 8 patients with t(11;14) was 75%. The cardiac response rate was 75% among 8 response evaluable patients (baseline NT-proBNP ≥ 650 ng/L), and the renal response rate was 73% among 11 renal amyloid patients (Table S3). At a median follow-up of 32.3 months, the median overall survival (OS) had not been reached (Figure S1). The 2-year OS probability was 80% (95% confidence intervals (CI): 0.643–0.996). The median hematologic progression free survival (PFS) when censoring occurred at last disease evaluation or subsequent treatment date including ASCT (whichever occurred first) was 20.3 months (95% CI: 13.6—not reached (NR) months). The 2-year PFS probability with this censoring approach was 49.6% (95% CI: 0.244–1). Median hematologic PFS when censoring occurred only at last disease evaluation (i.e., excluding censoring at the time of consolidative ASCT) was not reached (Figure S2). The 2-year PFS probability when not censoring for ASCT was 66.5% (95% CI: 0.473–0.933). The median PFS among 6 patients who were previously treated with censoring at last disease evaluation was 20.3 months (95% CI 5.8—NR months). Among all patients, the median duration of response when censoring occurred at last disease evaluation or subsequent treatment date including ASCT (whichever occurred first) was 19.4 months (95% CI: 12.7—NR months). Attaining a hematologic VGPR or better has been long considered the minimum acceptable response for AL amyloidosis treatment 10. However, emerging data has suggested that deeper responses including hematologic CR and/or stringent dFLC < 10 mg/L response may correlate with superior long-term outcomes including overall survival 9, 11, 12. The relatively lower 6-month landmark hematologic CR rates of 14% among 14 newly diagnosed patients with DId compared to 50% with Dara-CyBorD in ANDROMEDA may suggest that the addition of the alkylating agent cyclophosphamide to a daratumumab and proteasome inhibitor backbone may be important for deepening hematologic responses. Alternatively, the choice of proteasome inhibitor of bortezomib versus ixazomib may have also played a role in the lower hematologic CR rates with DId. From a safety standpoint, the rate of treatment emergent PN with DId was relatively low at 25%, all grade 1 and 2, among whom 4 of 5 pts. had baseline grade 1 PN and/or prior bortezomib exposure. This was also similar to the rates of treatment emergent PN observed with ixazomib and dexamethasone in the TOURMALINE AL-1 study where the any-grade PN rate was 19% and grade ≥ 3 PN rate was 1% 13. In contrast, PN occurred in 31% of patients treated with Dara-CyBorD in ANDROMEDA, including a 3% incidence of grade ≥ 3 PN. Limitations of this study included the small sample size (N = 20) and a large proportion of newly diagnosed patients (8 of 14, 57%) who eventually underwent ASCT prior to hematologic progression, thus limiting interpretation of long-term efficacy. Overall, DId was safe and generally well-tolerated with preliminary efficacy observed with deep (≥ VGPR) hematologic responses in the majority (80%) of patients as well as high cardiac (75%) and renal (73%) organ response rates. These results support the use of DId as a neuropathy-sparing therapeutic option in AL amyloidosis. However, the modest hematologic CR rate of DId may limit its use as a preferred regimen in routine clinical practice in the current and emerging treatment paradigm of AL amyloidosis, beyond patients with significant pre-existing disease-related and/or treatment-related neuropathy. H.C.L. designed the study, treated patients, collected data, analyzed data, and wrote the initial draft of the manuscript. L.F. performed biostatical analysis. M.R.B., O.P., S.K.T., Q.B. M.H.Q., R.S., S.P.I., D.M.W., K.K.P. G.P.K. E.E.M, and R.Z.O. treated patients. A.M. and R.J.J. collected data. All authors reviewed and approved the manuscript. This work was supported in part by The MD Anderson Cancer Center Support Grant (P30 CA016672). H.C.L. would like to acknowledge support from the William and Darrene Baer Family Fund and the Goff-Street Foundation. R.Z.O., the Florence Maude Thomas Cancer Research Professor, would like to acknowledge support from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Riney Family Multiple Myeloma Research Fund at MD Anderson from the Paula and Rodger Riney Foundation, the Brock Family Myeloma Research Fund, the Yates Ortiz Myeloma Fund, and the Diane & John Grace Family Foundation. This work was supported by the MD Anderson Cancer Support Grant (National Institutes of Health, P30 CA016672) This is an investigator-initiated study sponsored by The University of Texas MD Anderson Cancer Center. Study funding was provided by Johnson and Johnson Innovative Medicine and Takeda Pharmaceuticals, who also provided daratumumab and ixazomib, respectively. H.C.L. reports consulting fees from Alexion Pharmaceuticals, Bristol Myers Squibb, Janssen, Regeneron, GlaxoSmithKline, Sanofi, Takeda Pharmaceuticals, Allogene Therapeutics, Pfizer, and Menarini and research funding from Amgen, Bristol Myers Squibb, Janssen, GlaxoSmithSkine, Regeneron, Takeda Pharmaceuticals, and Alexion. M.H.Q. reports research funding from Amgen, Angiocrine Bioscience, BioLineRx, Janssen Pharmaceuticals, and NexImmune. S.K.T. reports consulting fees from Abbvie, Cellectar Biosciences, Mustang Bio and research funding: Abbvie, Ascentage Pharma, Acerta Pharma, Bristol Myers Squibb, Cellectar Biosciences, Genentech, Janssen, Sanofi, X4 Pharma. R.S. reports research funding from Seagen, BMS, GSK, Rafael Pharmaceuticals, NCI CTEP. K.K.P. reports consulting fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Caribou Sciences, Janssen, Genentech, Kite, Merck, Oricel, Poseida, Sanofi, and Takeda. G.P.K. is an employee of Kelonia Therapeutics, unrelated to the scope of this work. E.E.M. is an employee of GlaxoSmithKline unrelated to the scope of this work. R.Z.O. is a founder of Asylia Therapeutics with an equity interest, and reports consulting fees from Amgen, Bristol Myers Squibb, Celgene, EcoR1 Capital, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech, Molecular Partners, Sanofi, Servier, Takeda Pharmaceuticals North America, and research funding from Asylia Therapeutics, BioTheryX, and Heidelberg Pharma AG. M.R.B., L.F., O.P., A.M., R.J.J., Q.B., S.P.I., and D.M.W. have nothing to declare. The underlying data of this study are available upon request to the corresponding author. Data S1: ajh70239-sup-0001-Supinfo.docx. Table S1: All grade treatment emergent adverse events. Table S2: Grade ≥ 3 treatment emergent adverse events. Table S3: Organ response rates. Figure S1: Overall survival. Figure S2: Hematologic progression free survival. 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