Subcutaneous Daratumumab Research Articles

Cost-Minimization Analysis for Subcutaneous Daratumumab in the Treatment of Newly Diagnosed Multiple Myeloma in Three Gulf Countries

Background: The second most common hematologic cancer worldwide is multiple myeloma (MM), with incidence and mortality rates that have more than doubled over the past 30 years. The safety and efficacy of daratumumab regimens in the treatment of newly diagnosed MM (NDMM) is demonstrated in clinical trials. Objective: To assess the financial effects of the adoption of subcutaneous daratumumab (dara-SC) rather than intravenous daratumumab (dara-IV) for the treatment of NDMM in three Gulf countries (Qatar, Oman and the United Arab Emirates; UAE), a cost-minimization model was constructed. Methods: We performed static cost minimization analyses from a societal perspective to evaluate the costs and possible reductions in resource utilization associated with a shift from dara-IV infusion to dara-SC injection for NDMM patients over a 5-year time horizon. The model included 2 scenarios: the current scenario in which 100% of patients with NDMM are treated with dara-IV infusion and a future scenario in which dara-SC injection is gradually adopted over the modeled time horizon. The model differentiated precisely between autologous stem cell transplantation (ASCT)–eligible and ASCT-ineligible NDMM patients in terms of their number in each group and the associated therapeutic regimens. One-way sensitivity analyses were also conducted. Results: The model showed that the use of dara-SC in NDMM patients who were eligible or ineligible for ASCT resulted in lower non-drug costs, including premedication drug costs, adverse-effect costs, administration costs, medical staff costs, and indirect costs. The resulting total savings over the 5-year time horizon of the model for Hamad Medical Corporation, Sultan Qaboos University Hospital/Royal Hospital, Sheikh Shakhbout Medical City (SSMC), and Tawam Hospital were QAR −2 522 686, OMR −143 214, AED −30 010 627, and AED −5 003 471, respectively. Conclusion: The introduction of dara-SC as a front-line treatment for NDMM patients in Qatar (Hamad Medical Corporation), Oman (Sultan Qaboos University Hospital, Royal Hospital-MOH), and the UAE (SSMC and Tawam Hospital) can help save resources and minimize constraints on the healthcare system.

Subcutaneous daratumumab in Chinese patients with relapsed or refractory multiple myeloma: an open-label, multicenter, phase 1 study (MMY1010).

Despite recent progress in multiple myeloma (MM) treatments, most patients will relapse and require additional treatment. Intravenous daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown good efficacy in the treatment of MM. A subcutaneous version of daratumumab was formulated to reduce the burden of intravenous infusions. We aimed to investigate the efficacy and safety of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM based on the demonstrated noninferiority of subcutaneous daratumumab to intravenous daratumumab, with a shorter administration time and reduced infusion-related reaction rate in global studies. This phase 1, multicenter study (MMY1010; ClinicalTrials.gov Identifier: NCT04121260) evaluated subcutaneous daratumumab in Chinese patients with relapsed/refractory MM after 1 prior line (n = 1) or ≥2 prior lines (n = 20) of therapy, including a proteasome inhibitor and an immunomodulatory drug. Primary endpoints were pharmacokinetics and safety. Mean (standard deviation) maximum trough concentration of daratumumab was 826 (335) μg/mL, which was consistent with prior studies of subcutaneous daratumumab and intravenous daratumumab. Safety was consistent with safety profiles observed in other daratumumab studies, with no new safety concerns identified. Incidences of infusion-related reactions and injection-site reactions were low and consistent with other subcutaneous daratumumab studies. At a median follow-up of 7.5 months, the overall response rate was 57.1%, with a very good partial response or better rate of 38.1% and complete response or better rate of 19.0%. Our results demonstrate a favorable benefit/risk profile of subcutaneous daratumumab in Chinese patients with relapsed/refractory MM, potentially impacting clinical administration of daratumumab in this population.

Evaluation of administration-related reactions with subcutaneous daratumumab with and without premedication.

Daratumumab-hyaluronidase-fihj (Dara-SQ) is frequently used in the treatment of plasma cell disorders and is associated with improved outcomes. Dara-SQ was shown to be non-inferior to intravenous daratumumab (Dara-IV) in efficacy, safety, and associated with fewer administration-related reactions (ARRs). Despite the lower ARR risk with Dara-SQ, package labeling still recommends indefinite premedication. In this study, we investigated the safety of premedication discontinuation after one cycle of Dara-SQ. This pre-post interventional quality improvement study included all patients aged 18 years and older diagnosed with multiple myeloma or light chain (AL) amyloidosis who received at least one dose of Dara-SQ. Patients in Arm 1 received Dara-SQ per package labeling, while patients in Arm 2 had premedication omitted (excluding dexamethasone) after cycle 1. The primary endpoint was the incidence of ARR after cycle 1. Overall ARR rate and therapy time saved were also evaluated. A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included. There were zero reactions in either arm after cycle 1 across 1479 Dara-SQ doses administered over a 30-month period with or without premedication omission. The overall ARR rate was 2.9% (3/102), which all occurred prior to premedication omission. Therapy timed saved from premedication omission was 194 hours in a 6-month period, equating to approximately $140 000 USD. ARRs to Dara-SQ were rare, mild, and occurred during cycle 1 prior to premedication omission. Omission of noncorticosteroid premedication is safe, feasible, and carries substantial time and cost savings for patients and infusion centers.

Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial.

7502 Background: In the primary analysis of the phase 3 PERSEUS study, subcutaneous DARA (DARA SC) + VRd (D-VRd) induction/consolidation (ind/consol) and D-R maintenance improved progression-free survival (PFS) and increased depth of response (complete response or better [≥CR] and MRD negativity [neg]) compared to VRd ind/consol and R maintenance for TE NDMM. Here, we report further results on deepening of response and MRD neg during maintenance. Methods: TE pts with NDMM were randomized 1:1 to D-VRd or VRd. Pts in both arms received up to six 28-day cycles (4 pre-ASCT ind, 2 post-ASCT consol) of VRd (V 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W during maintenance until PD. MRD-neg rate (clonoSEQ) was defined as the proportion of ITT pts who achieved both ≥CR and MRD neg. Results: In the 709 pts randomized (D-VRd, n=355; VRd, n=354), responses deepened over time with D-VRd vs VRd, including rates of ≥CR (end of consol: 44.5% vs 34.7%; P= 0.0078 and overall: 87.9% vs 70.1%; P<0.0001). MRD-neg rates increased over time and were higher with D-VRd vs VRd at 12, 24, and 36 mo after Cycle 1 Day 1 (all P<0.0001; Table). Rates of sustained MRD neg for ≥12 mo were higher for D-VRd vs VRd (10–5: 64.8% vs 29.7%; P<0.0001; 10–6: 47.3% vs 18.6%; P<0.0001); results were consistent across prespecified clinically relevant subgroups. Among pts who were MRD positive (pos) at end of consol, significantly higher proportions of pts in the D-VRd group vs the VRd group achieved MRDneg during maintenance at 10−5 (60.2% vs 40.5%; P= 0.0049) and 10−6 (56.7% vs 25.2%; P<0.0001) and sustained MRD neg for ≥12 mo at 10−5 (38.6% vs 17.4%; P= 0.0006) and 10−6 (31.3% vs 10.3%; P<0.0001). End of consol and overall MRD neg at both 10–5 and 10–6 were associated with improved PFS. Additional data on response rates in different study phases and sustained MRD neg will be presented. Conclusions: During maintenance, a greater proportion of pts with MRD-pos status achieved MRD neg with D-R vs R. The higher rates of deep (10–6) and sustained MRD neg achieved with D-VRd ind/consol and D-R maintenance vs VRd ind/consol and R maintenance translated to a clinically meaningful benefit of improved PFS. These data further support D-VRd and D-R maintenance as a new standard of care for TE pts with NDMM and highlight the benefit of DARA SC in maintenance. Clinical trial information: NCT03710603 . [Table: see text]

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BackgroundDaratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.MethodsIn this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)–negative status.ResultsAt a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P=0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.ConclusionsThe addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)

Safety and Efficacy of Subcutaneous Daratumumab in Systemic AL Amyloidosis.

Systemic AL amyloidosis, a plasma cell dyscrasia, is characterized by the production of misfolded immunoglobulin light chain. These misfolded proteins aggregate into amyloid fibrils and deposit throughout the body, resulting in widespread organ dysfunction and ultimately death. Achieving rapid and maximal elimination of the plasma cell clone is crucial to long-term survival. Daratumumab, an anti-CD38 monoclonal antibody delivered intravenously, has been swiftly incorporated into standard first-line treatment regimens. A novel formulation of daratumumab has been developed that can be injected subcutaneously. As a retrospective qualitative review of prior publications involving daratumumab, this work briefly summarizes the existing data regarding the safety and efficacy of subcutaneous (SC) daratumumab, compared to intravenous (IV) daratumumab. SC daratumumab appears to deliver the same disease benefit as IV daratumumab to patients with decreased infusion-related reactions (IRRs), decreased time for administration, and similar rates of adverse events (AEs) intrinsically related to daratumumab. SC daratumumab is preferred over IV daratumumab, but the clinical situation ultimately should determine route of administration. Further investigation into cost-effectiveness benefit is warranted.

Subcutaneous Daratumumab at Home Is a Safe and Effective Procedure for Frail Patients with Multiple Myeloma: A Myelhome Project Report

Background Treatment of Multiple Myeloma (MM) is often difficult due to patient (pts) frailty, bone lesions/fractures that can hinder transport and/or long distance from the hospital. The availability in the Viterbo province of a Domiciliary Hematologic Care Unit (DHCU) allowed to overcome these difficulties. Patients and methods Herein, the experience in 15 patients with MM treated as outpatients [10 at home (HC) and 5 in a Long Term Residential Accomodation (LTRA)] with subcutaneous (sc) daratumumab (dara) is reported, as part of the Myel-Home project. The initial 2 dara administrations, either intravenous or sc, were given in hospital to prevent side effects, while subsequent administrations were done as outpatients: the first dara administration as outpatient was done by nurse and physician, while subsequent ones by nurse only. Results: The main clinical features of pts at baseline of dara initiation are shown in the Table. Different reasons for outpatient management were: advanced age (&amp;gt; 80 years) in 3 pts, illness related symptoms in 8 pts, social conditions and/or long distance in 4 pts. Distance from DHCU to pts home was &amp;lt; 20 Km in 4 cases ( 27%), ≥ 20 &amp;lt; 40 Km in 10 (66%) and ≥ 40 Km in 1 (7%). Different lines of treatment and different schemes are reported in the Table: among 7 pts treated in 1 st line, 3 were transplant eligible and 4 transplant ineligible. On the whole, 110 administrations of sc-dara were performed by DHCU nurses as outpatient: during and/or immediately after home administration, only one pt had adverse events (grade 2 allergic reaction according WHO), leading to dara permanent discontinuation after the 2nd dose at home. Main adverse events during the course of domiciliary treatment were infections (pneumonia in 4 pts, sepsis in 2, cystitis in 1) and deep vein thrombosis in 1 pts. Moreover, 4/5 patients (80%) in LTRA had infections (which were fatal in 3 of them) compared to 3/10 pts (30%) in HC with only 1 related death. Two pts were not yet evaluable for response and one pt discontinued early: among the evaluable 12 pts, 1 achieved a stringent complete remission and 4 a very good partial remission, with an overall response rate of 42%, 5 pts had a stable disease and 2 pts a disease progression. At the last follow-up, 8 pts are alive (2 waiting for transplant procedure) and 7 pts died (3 from disease progression, 3 from infective complications and 1 from heart disease). Conclusions: Treatment at home with sc-dara in frail pts with MM is feasible and safe with improved quality of life, making possible a curative approach frontline as well as in advanced phases of disease also in subjects otherwise excluded by best available therapies or forced to long periods of hospitalization: it is worth of note that pts living in LTRA were at high risk of infective complications, thus limiting the advantages of a domiciliary management compared to pts living at our own house. In the next future, within the Myel-Home project, other monoclonal antibodies (belantamab-mafodotin and talquetamab) will be available for home administration.

Outcomes of Incorporating IV Daratumumab for the Treatment of AL Amyloidosis in Real World Patients from a Multicenter Registry in Latin America

Introduction: AL amyloidosis is characterized by the extracellular deposition of immunoglobulin light chains. Daratumumab is an anti-CD38 monoclonal antibody that has demonstrated outstanding results in the treatment of AL amyloidosis, achieving rapid and deep responses and improving OS. Nevertheless, patients with advanced cardiac disease have been usually excluded from clinical trials and data from real world patients in Latin America is lacking. Moreover, subcutaneous Daratumumab is not available in most countries in the region. Objective: To describe hematological (HR) and organ response, overall survival (OS) and event-free survival (EFS) of incorporating IV Daratumumab for the treatment of AL amyloidosis in real world patients from 5 centers in Argentina Materials and methods: Multicenter, retrospective cohort study of patients older than 18 years with a histopathological diagnosis of AL Amyloidosis and treated with at least one cycle in first-line (Group 1) or subsequent lines of treatment (Group 2) with Daratumumab IV, included in the registry of amyloidosis (RIA, NCT01347047). Data were collected from medical records in an standardized electronic clinical report form (RIA Redcap). The registry includes data for baseline demographics, medical history, comorbidities, physical examinations, laboratory, and imaging exams. Treatments were prescribed by the physician, according to the hospital's protocol. All patients were followed from first daratumumab infusion till death or lost to follow up for HR (as per response criteria by the International Amyloidosis Society, complete response [CR], very good partial response [VGPR], partial response [PR], no response [NR]), OS (time from diagnosis to death), progression free survival (PFS: time from diagnosis to disease progression or death). Adverse events were reported based on CTCAE. Overall and progression-free survival was estimated using Kaplan Meier. Results Thirty-seven patients with AL amyloidosis were included in the study. The characteristics of the population are summarized in Table 1. Twenty-four patients (65%) had cardiac involvement, 25 (68%) renal involvement, and 14 (40% ) both. Of the patients with cardiac involvement, 20 had cardiac stages Mayo 2012 III/IV. Group 1 included 18 patients who received daratumumab (48%), 17 in combination with CyborD. Group 2 included 19 patients (51%), 12 received Daratumumab in combination with dexamethasone, 5 with CyborD and 2 with lenalidomide. Thirty-three patients (90%) achieved HR, the median time to best hematologic response was 2 months (IQR 1-9 months). Seventeen patients (59%) achieved CR (group1 n=8 Group2 n=9), 9 MBRP (group1 n=4 group2 n=5), 7 PR (group1 n= 5 group2 n=2). Of the 20 patients with Mayo stages III/IV, 18 achieved hematologic response and 9 cardiac response. Three patients had stable disease, all of them were relapsed.. Three patients presented subsequent relapses. The Organ response rate was 59% (n=22, IC 45-75), 14 renal response, median time to response 8 months (IQ R4,6-14,1), 13 cardiac response, median time to response 6,4 months (IQR 6,4-6,4). Five patients had response of both organs. The median follow-up of the entire cohort was 18 months (CI 11-75). The median EFS at 1 year was 88% (CI 71-95) and at 2 years 83% (CI 64-93). Median OS at 12 months was 91% (CI 75-97) and at 24 months 86% (CI 68-95). There were 7 deaths in the entire cohort, 5 were due to cardiac complications associated with amyloidosis. Five of the deceased patients had achieved a HR. Eleven patients presented adverse events, mainly infectious complications, 5 of them grade 3 or 4. Conclusions: This study provides real-world evidence for Daratumumab IV treatment in patients with AL amyloidosis in the first line and at relapse, achieving fast and profound HR, which translated into a high organ response rate and improvement in OS and PFS. In our cohort, most patients achieved HR with a median time to best response at 2 months consistent with what is reported in the bibliography. This study is relevant since it is a real life study, in which intravenous daratumumab was used since the subcutaneous formulation is not available in most Latin American countries and also included patients with advanced stages achieving responses in this high risk subgroup. Treatment with Daratumumab should be considered a therapy of choice in AL amyloidosis, even in patients with advanced cardiac stages.

Phase 2 Study of Daratumumab (DARA) Plus Bortezomib, Cyclophosphamide, and Dexamethasone (D-VCd) in a Diverse Patient Population with Newly Diagnosed Amyloid Light Chain (AL) Amyloidosis: Aquarius

Background: AL amyloidosis is a rare disorder in which deposition of insoluble amyloid fibrils composed of misfolded light chains in vital organs, such as the heart or kidney, leads to serious and life-threatening organ dysfunction. Cardiac involvement is the primary determinant of clinical outcomes for patients with AL amyloidosis, and survival expectations decrease with increasing cardiac stage. Subcutaneous DARA (DARA SC) in combination with VCd recently became the first and only approved treatment for newly diagnosed AL amyloidosis based on results of the phase 3 ANDROMEDA study. In the ANDROMEDA study, a higher hematologic complete response rate was consistently achieved with D-VCd versus VCd in patients with newly diagnosed AL amyloidosis, regardless of baseline cardiac stage (Kastritis E, et al. N Engl J Med. 2021;385[1]:46-58). However, cardiac involvement leads to challenges in the attribution of cardiac events to underlying disease and/or treatments. Additionally, among patients randomized to receive D-VCd in the ANDROMEDA study, 15.4% were Asian, 4.6% were Hispanic or Latino, and 3.1% were Black or African American, limiting the interpretation of safety, efficacy, and pharmacokinetic results among patients of different racial and ethnic backgrounds. Therefore, the ongoing phase 2 AQUARIUS (AMY2009) study will characterize the cardiac safety of different D-VCd treatment regimens in patients with newly diagnosed AL amyloidosis with cardiac involvement to identify potential mitigation strategies for cardiac toxicity, as well as better characterize the safety, efficacy, and pharmacokinetics of D-VCd among racial and ethnic minorities. Study Design and Methods: This ongoing multicenter, multicohort, open-label phase 2 study will enroll ~150 patients aged ≥18 years with newly diagnosed systemic AL amyloidosis and measurable disease from ~45 sites across 10 countries. Patients in Cohort 1 (n = ~120) will have cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ involvement. Patients in Cohort 2 (n = ~30) will be of racial or ethnic minority (including ≥15 Black or African American patients) and have ≥1 organ affected by systemic AL amyloidosis. Patients in Cohort 1 will be stratified by baseline cardiac stage (Stages II and IIIa) and randomly assigned (2:1) to receive DARA SC plus immediate VCd (Arm A) or DARA SC plus deferred VCd (Arm B; Figure 1). In both arms, DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) will be administered QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter until a maximum of 24 cycles or the start of subsequent therapy. In Arm A, starting at Cycle 1 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. In Arm B, starting at Cycle 4 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. Patients in Cohort 2 will receive DARA SC plus immediate VCd. Several unique initiatives were incorporated into the study to enhance enrollment of patients of racial or ethnic minority in Cohort 2, including selecting sites from the ANDROMEDA study that enrolled racially/ethnically diverse patients, targeting new sites in diverse communities, raising awareness of AL amyloidosis and the AQUARIUS study among minority patients at the local and national levels, and educating sites on engagement of patients from diverse backgrounds. The first primary endpoint is incidence of any toxicity grade cardiac events for the different D-VCd treatment regimens (DARA SC + immediate VCd and DARA SC + deferred VCd). The second primary endpoint is trough serum concentration (C trough) of DARA at the end of QW dosing (Cycle 3 Day 1 predose). Efficacy evaluations include assessment of hematologic response and organ response. Data will be summarized using descriptive statistics. The first patient was enrolled on March 17, 2022. As of July 10, 2023, the study has enrolled 75 patients; 71 in Cohort 1 and 4 in Cohort 2. In the US, 2 of the 8 patients enrolled were of racial minority ( Figure 2). Efforts to increase enrollment of minorities continue to be optimized and new collaborative initiatives explored to ensure representative and diverse enrollment in clinical trials. The ClinicalTrials.gov Identifier is NCT05250973.

Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Vrd Alone in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial

Introduction: DARA plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy has shown clinical benefit versus VTd alone and is approved for transplant-eligible pts with NDMM. VRd induction followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide (R) maintenance is also considered a standard of care for transplant-eligible NDMM. In the phase 2 GRIFFIN study, intravenous DARA combined with VRd (D-VRd) induction/consolidation followed by D-R maintenance improved depth of response and progression-free survival (PFS) versus VRd induction/consolidation and R maintenance in transplant-eligible pts with NDMM after &amp;gt;4 years of follow-up. The phase 3 PERSEUS study is evaluating subcutaneous DARA (DARA SC) in combination with VRd induction/consolidation followed by D-R maintenance versus VRd induction/consolidation and R maintenance in transplant-eligible NDMM. Here we report the primary analysis of PERSEUS. Methods: Pts with NDMM who were aged 18-70 years and eligible for high-dose therapy and ASCT were randomized 1:1 to D-VRd or VRd, stratified by International Staging System (ISS) stage and cytogenetic risk. All pts received up to six 28-day cycles (4 pre-ASCT induction, 2 post-ASCT consolidation) of VRd (V: 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R: 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance therapy (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks during maintenance until PD. The primary endpoint is PFS; key secondary endpoints include overall complete response or better (≥CR) rate, overall minimal residual disease (MRD)-negativity rate (10-5 threshold; clonoSEQ®), and overall survival. Response and disease progression were assessed using a computerized algorithm based on IMWG response criteria. Overall MRD-negativity rate was defined as the proportion of pts who achieved MRD negativity and ≥CR at any time. Results: 709 pts were randomized (D-VRd, n=355; VRd, n=354). Median (range) age was 60 (31-70) years; 14.8% had ISS stage III disease, and 21.7% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]). At clinical cutoff, 314 pts in the D-VRd arm and 299 pts in the VRd arm had completed all 4 induction and 2 consolidation cycles, 309 and 294 pts had undergone ASCT, and 322 and 300 pts entered maintenance. At a median follow-up of 47.5 months, PFS was significantly improved with D-VRd versus VRd (HR, 0.42; 95% CI, 0.30-0.59; P &amp;lt;0.0001 [crossing the prespecified stopping boundary of 0.0126]; Figure). Median PFS was not reached in either arm; estimated 48-month PFS rates were 84.3% for D-VRd versus 67.7% for VRd. Prespecified subgroup analyses showed a consistent PFS improvement with D-VRd versus VRd across clinically relevant subgroups, including pts with ISS stage III disease and pts with high cytogenetic risk. Overall rates of ≥CR (87.9% vs 70.1%; P &amp;lt;0.0001) and MRD negativity (75.2% vs 47.5%; P &amp;lt;0.0001) were significantly higher with D-VRd versus VRd. Overall survival was immature, with 78 deaths on study (D-VRd, 34 [9.6%]; VRd, 44 [12.4%]). Overall, 7 deaths due to COVID-19 occurred (D-VRd, 4; VRd, 3). The most frequent (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) for the D-VRd/VRd arms were neutropenia (62.1%/51.0%), thrombocytopenia (29.1%/17.3%), diarrhea (10.5%/7.8%), pneumonia (10.5%/6.1%), and febrile neutropenia (9.4%/10.1%). For D-VRd and VRd, serious TEAEs occurred in 57.0% versus 49.3% of pts, and TEAEs leading to treatment discontinuation occurred in 8.8% versus 21.3% of pts. Conclusions: DARA SC combined with VRd in transplant-eligible pts with NDMM significantly improved PFS and increased depth of response (≥CR and MRD negativity), with consistent PFS benefit across clinically relevant subgroups. The safety profile was consistent with the known safety profiles for DARA SC and VRd. These data, together with results from the phase 2 GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet DARA plus VRd followed by D-R maintenance versus triplet VRd followed by R maintenance and support the combination of DARA plus VRd followed by D-R maintenance as a new standard of care for transplant-eligible NDMM.

Efficacy and Safety of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM): Final Analysis of the Phase 2 Centaurus Study

Introduction: SMM is a precursor disorder to multiple myeloma (MM) (Rajkumar SV, et al. Blood. 2015;125[20]:3069-3075). Current guidelines for SMM recommend active monitoring, with treatment initiation only upon progression to MM. However, therapeutic intervention at the SMM stage may help delay the progression to MM (Lonial S, et al. J Clin Oncol. 2020;38[11]:1126-1137; Mateos MV, et al. ASH 2022. Abstract 118). DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Given the deep and durable responses and favorable safety profile of DARA monotherapy in patients (pts) with relapsed/refractory MM (Usmani SZ, et al. Blood. 2016;128[1]:37-44), we hypothesized that DARA could delay the progression of SMM to MM. In the primary analysis of the phase 2 CENTAURUS study (NCT02316106), after a 15.8-month median follow-up, DARA monotherapy showed activity and was well tolerated in pts with intermediate- or high-risk SMM (Landgren CO, et al. Leukemia. 2020;34[7]:1840-1852). Activity and tolerability of DARA monotherapy were also observed in CENTAURUS after an additional 10 months of median follow-up (Landgren CO, et al. ASH 2018. Abstract 1994). Here, we present the final analysis of the CENTAURUS study, with a median follow-up of 85.2 months (~7 years). Methods: Eligible pts had a diagnosis of intermediate-risk or high-risk SMM for &amp;lt;5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously (IV) on 1 of 3 dosing schedules. In the Intense dosing arm, pts received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). In the Intermediate dosing arm, pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). In the Short dosing arm, pts received 1 cycle of DARA QW. For pts in the Intense and Intermediate arms, there was an option to extend treatment (Extension phase) with DARA IV or with subcutaneous DARA (DARA SC; DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [2,000 U/mL; Halozyme, Inc.]) Q8W after the end of Cycle 20 per investigator discretion if there was a positive benefit/risk ratio, no grade ≥3 treatment-related toxicity, and at least stable disease had been achieved. Rate of complete response or better (≥CR) was a primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Results: A total of 123 pts (41 pts per arm) were randomized. Median (range) age was 61 (31-81) years. Median duration of study treatment overall during the study was 44.0 months in the Intense arm, 35.2 months in the Intermediate arm, and 1.6 months in the Short arm. A total of 36 pts (21 pts in the Intense arm and 15 pts in the Intermediate arm) continued to receive DARA Q8W in the Extension phase (Cycles 21+). During the Extension phase, median duration of study treatment was 45.2 months in the Intense arm and 46.1 months in the Intermediate arm ( Table 1). 16 pts in the Intense arm and 10 pts in the Intermediate arm switched from DARA IV to DARA SC during the Extension phase. Efficacy results are summarized in Table 2. At a median (range) follow-up of 85.2 (0-94.3) months, ORR and ≥CR rate were higher in the Intense and Intermediate arms than in the Short arm. In the Intense and Intermediate arms combined, the ≥CR rate was 8.5%. Median OS was not reached in any dosing arm; the 84-month OS rate was 81.3%, 89.5%, and 88.1% in the Intense, Intermediate, and Short arms, respectively. Safety results are summarized in Table 1. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 65.9%, 41.5%, and 15.0% of pts in the Intense, Intermediate, and Short arms, respectively; grade 3/4 TEAEs were reasonably related to DARA in 12.2%, 2.4%, and 5.0% of pts, respectively. TEAEs that led to discontinuation of DARA occurred in 7.3%, 2.4%, and 5.0% of pts in the Intense, Intermediate, and Short arms, respectively. Conclusions: Findings from this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in pts with intermediate- or high-risk SMM after a median follow-up of ~7 years. A high proportion (44%) of pts in the Intense and Intermediate arms completed 20 cycles and remained on DARA monotherapy per investigator discretion, with a median duration of additional treatment of 46.0 months (~4 years) in the Extension phase. No new safety concerns were observed with extended follow-up.

Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone (DIPD) As Salvage Therapy in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with RRMM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with RRMM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report results from a phase 2 multicenter trial of the addition of Ixazomib to DPd (DIPd) in patients with early RRMM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR) and safety of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or Ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB for subsequent patients. An amendment allowed for subcutaneous (SC) Daratumumab administration and all active patients transitioned to or started with SC dosing for ongoing therapy. MRD assessments were performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: The study has completed the planned enrollment of 46 patients. The median age is 61.6 years (range 41-87), with 47% female, 72% White, 17% Asian, and 5% Black patients. Patients had a median of 1 prior line of therapy (range 1-3), and 56% (23/41) of patients had at least one high-risk cytogenetic abnormality including del 17p, +1q, t(14;16), t(14;20), or t(4;14). Grade 3-4 treatment emergent adverse events (AE) include neutropenia (72%), infection (19%), febrile neutropenia (8%), lymphopenia (8%), electrolyte disturbance (6%), leukopenia (3%), thrombocytopenia (3%), respiratory condition (3%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). ORR to date is 83% (38/46) in evaluable patients, and best responses include 12 (26%) sCR, 12 (26%) VGPR, and 14 (30%) PR. The median duration of response (DOR) is 21.1 months for all patients, with 11 patients currently remaining on DIPd therapy, and 9 deaths all unrelated to study treatment (5 progressive disease [PD], 2 sepsis, 1 COVID, 1 unrelated surgical complication). Of the 35 patients off therapy, 20 patients had PD, 6 patients had AEs, 5 patients stopped per physician discretion or withdrew consent, and 4 patients received an autologous stem cell transplant. After a median follow up of 15 months, the median PFS is 16.6mo (95% CI: 8.19-NR ) for all patients, 16.6mo (6.9-NR) for standard risk patients, and 22.3mo (7.6-NR) for high risk patients (p=0.9). The median OS for all patients is 30.3mo (95 CI: 30.3-NR). Data will be updated for the conference to include MRD negativity rates and completed data analysis of the primary endpoint. Conclusion: The quadruplet regimen DIPd shows that the addition of a 4 th agent results in high overall response rates and early PFS rates, with manageable toxicity, and the convenience of a nearly all-oral drug regimen in patients with early RRMM. These data are particularly compelling for high-risk disease as more than half of the patients treated had at least one high-risk cytogenetic abnormality, offering a promising option for the management of early relapse in high-risk patients.

A Phase II, Open-Label Study of an Accelerated Infusion Rate of Daratumumab in Patients With Relapsed and Refractory Multiple Myeloma.

Daratumumab is an anti-CD38 monoclonal antibody initially approved as a single agent for the treatment of relapsed and refractory multiple myeloma. The infusion-related reactions (IRRs) commonly seen with intravenous daratumumab have been managed by prolonging the first infusion, temporarily stopping/slowing the rate if reactions occur and using adequate pre- and post-infusion medications. Several retrospective studies have evaluated shorter infusions after ≥ 2 prior doses administered at the standard rates. Although the shorter infusions were well-tolerated, patients in these reports were given heterogeneous daratumumab regimens and had often already received multiple doses at the longer standard rates. CMRG-009 is a prospective study designed to demonstrate the safety of accelerated daratumumab infusions commencing with the second dose. After an initial dose on Cycle 1 Day consisting of 8 mg/kg over 4 hours, all subsequent doses were given over 90 minutes. No grade 3 IRRs were observed with the 90-minutes infusions. Both the safety profile and anti-myeloma effects were otherwise similar to those observed with other single agent daratumumab studies using longer infusion times. This is the first formal prospective trial using infusion times shorter than the standard schedule directly after an initial 4-hours dose. This rapid infusion protocol has resulted in more efficient resource utilization and has become the standard protocol for the use in all intravenous daratumumab regimens in Canada. This approach has been particularly helpful in shortening chair time during the COVID-19 pandemic and providing a useful alternative in jurisdictions without access to subcutaneous daratumumab.

EXCALIBER-RRMM: A phase 3, two-stage study of iberdomide, daratumumab, and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

TPS8069 Background: New treatments (Txs) are needed to achieve deep and durable responses in RRMM. Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory drugs (IMiDs). IBER has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT) in vitro. In a phase 1/2 trial, IberDd demonstrated efficacy with a manageable safety profile in pts with RRMM (Lonial S, et al. HemaSphere 2021;5(S2):S187). The EXCALIBER-RRMM phase 3 trial (NCT04975997) will compare the efficacy and safety of IberDd with that of DVd in pts with early RRMM. Methods: This multicenter, open-label study will be conducted in 2 stages: in Stage 1, ≥ 200 pts will be randomized 1:1:1:1 to 1 of 3 IBER doses (1.0, 1.3, or 1.6 mg) + DARA and DEX or to the DVd arm to identify optimal IBER dose when combined with DARA + DEX; in Stage 2, ≈ 664 additional pts will be randomized 1:1 to IberDd at the selected IBER dose or to DVd, for efficacy and safety analyses (Stage 1 pts in IBER selected dose cohort and DVd arm to be also included). Pts will be stratified by number of prior Tx lines (1 vs 2), age (≤ 70 vs &gt; 70 y), and ISS stage at study entry (I–II vs III). Primary efficacy endpoint is progression-free survival (PFS), which is defined as the time from randomization to progressive disease (PD) or death. Assuming a decrease in PFS risk by 25% (HR = 0.75) with IberDd, under exponential distribution assumption of PFS (1-sided α = 0.025) and adjusted for 3 interim analyses, 458 PFS events will have ≈ 84% power to detect an improvement in Tx effect. The 3 planned interim analyses are: for IBER dose selection at end of Stage 1; and to examine PFS futility and superiority when ≈ 138 (30%) and ≈ 344 (75%) events, respectively, have been accumulated. Secondary endpoints include overall survival, duration of response, time to progression, overall response rate, measurable residual disease negativity rate, safety, and quality of life. Tx in the IberDd arm will consist of 28-day (D) cycles (C) with IBER on D1–21; 1800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥ C7; and 40 mg oral DEX (20 mg in pts &gt; 75 y of age) on D1, 8, 15, and 22. Tx in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥ C9; 1800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for ≥ C4; 1.3 mg/m² SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg in pts &gt; 75 y of age) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Tx will continue until confirmed PD, unacceptable toxicity, or consent withdrawal. Key eligibility criteria include age ≥ 18 y, 1–2 prior lines of antimyeloma Tx, partial response or better to ≥ 1 prior Tx, and documented PD during or after the last regimen. Prior anti-CD38 Tx is allowed only in Stage 2 (≤ 10% of pts). Enrollment began in June 2022 and is currently ongoing. Clinical trial information: NCT04975997 .

Open label single arm study to assess the implementation of home based daratumumab administration in patients being treated for multiple myeloma.

TPS1609 Background: Multiple myeloma (MM) is an incurable hematologic malignancy that has a high burden of care for patients and their caregivers. Over the last two decades, the treatment landscape for MM has changed dramatically. However, treatment burden with frequent visits to offices and the hospital is high. We need innovative care delivery models to alleviate these burdens. Chemotherapy at home remains uncommon in the US, though models for its use exist globally. In these models, home-based chemotherapy is safe, preferred by patients, and can be administered at lower cost. Herein, we propose a home-based subcutaneous daratumumab and hyaluronidase-fihj (dara) program for patients with MM. We hypothesize that this program will be feasible, reduce patient treatment and financial burden, and improve quality of life. Methods: We designed an open label single arm study to assess the implementation of home administration of dara. The primary objective is to evaluate (n=20) treatment satisfaction of patients, using the Cancer Therapy Satisfaction Questionnaire (CTSQ), when they receive care at home as compared to the standard of care (SOC). Secondary outcomes include evaluating adherence to home delivery, quality of life (EORTC QLQ-30), financial burden (COST survey), safety of home administration, and barriers to home administration. At the end of the study, we will conduct semi-structured interviews to assess patient experience with home administration of chemotherapy. Patients will be eligible for study participation if they have a diagnosis of multiple myeloma, are in the monthly phase of dara treatment and are treated with either monotherapy or in combination with oral agents. All participants who are interested and eligible will be on study for 8 cycles of dara (2 cycles of dara in the infusion center (IC) followed by 4 cycles at home and then 2 cycles in the IC). During the home administration phase, 1-3 days prior, patients will go to a local lab or have at home labs. On day of at home dara, the drug will be mixed and packaged by our pharmacy, and then delivered at room temperature to the patient’s home by our home infusion courier. The patient will take pre-medications 1-3 hours prior to nurse arrival. The nurse arrives, confirm pre-medications were taken. Pre-treatment vitals and post treatment vitals will be obtained. Drug will be administered as per label instructions. At the beginning of each cycle, patient reported outcome surveys and quality of life surveys will be collected. During the home administration phase, details on barriers to maintaining adherence (i.e. issues with storage, delivery, disposal of medication) will be collected. The study opened for enrollment on November 8th, 2022. As of February 1stth 2023, 9 patients have consented and 5 patients are on-treatment. Clinical trial information: NCT05511428 .

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA

Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3–53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06–0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05–0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.

Benefits of switching from intravenous to subcutaneous daratumumab: Perspectives from UK healthcare providers.

Daratumumab is a CD38-directed monoclonal antibody indicated to treat multiple myeloma (MM). Daratumumab was initially administered intravenously (IV), subsequently a subcutaneous (SC) formulation was developed to increase convenience of administration. The UK was an early adopter of SC daratumumab and, as such, this report provides consensus recommendations from a group of UK MM experts, with the aim of facilitating the transition from IV to SC daratumumab for other European healthcare providers. The switch from IV to SC daratumumab has been beneficial to patients and healthcare providers, as it simplifies treatment, reduces pressure on hospitals and can improve patients' quality of life.

Teclistamab in Combination with Subcutaneous Daratumumab and Lenalidomide in Patients with Multiple Myeloma: Results from One Cohort of MajesTEC-2, a Phase1b, Multicohort Study

Teclistamab in Combination with Subcutaneous Daratumumab and Lenalidomide in Patients with Multiple Myeloma: Results from One Cohort of MajesTEC-2, a Phase1b, Multicohort Study

Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with relapsed/refractory (R/R) MM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with R/R MM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report interim findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB. An amendment allowed for subcutaneous daratumumab administration. MRD assessments are being performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects were treated in stage 1, and 23 of 32 planned subjects in stage 2. Of the 30 evaluable patients to date, the median age was 62.5y (range 41-87), and were 50% female and 70% white. Patients had a median of 1 prior line of therapy (range 1-3), and 52% (12/23) had at least one high-risk FISH feature including -17p, +1q, t(14;16), t(14;20), or t(4;14) . Grade 3-4 treatment emergent adverse events include neutropenia (63%), lymphopenia (9%), non-specific leukopenia (3%), thrombocytopenia (9%), febrile neutropenia (13%), infection (22%), electrolyte disturbance (6%), respiratory condition (6%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). Median time on treatment (n=25) is 4.8 months (range: 0.4-30.8), with 15 patients currently remaining on DIPd therapy and 7 deaths (4 PD, 1 sepsis, 1 COVID, 1 surgical complication). ORR to date is 83% (25/30) in evaluable patients, and best responses include 8 (27%) sCR, 3 (10%) CR, 6 (20%) VGPR, 8 (27%) PR. After a median follow up of 15.1 months, the median PFS is 11.6 (95% lower bound: ≥ 7.4) months and median OS is 38.9 (95% lower bound: ≥ 18.8) months. Conclusion: The quadruplet regimen DIPd builds upon the successes of daratumumab-based triplet regimens showing that the addition of a 4th agent can result in improved overall response rates with manageable toxicity and the convenience of a nearly all-oral drug regimen in patients with early R/R MM. These data are particularly compelling for high risk disease as more than half of the patients treated to date had at least one high risk feature, offering a promising option for the management of early relapse in high risk patients.

Interim Results of a Risk-Adaptive Phase II Study: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (KRD-Dara) in Newly Diagnosed Multiple Myeloma (NDMM) at the Levine Cancer Institute (LCI)

Background: The combination of carfilzomib, lenalidomide and dexamethasone (KRd) has previously demonstrated deep and durable responses in patients with NDMM. A quadruplet regimen incorporating daratumumab (KRd-Dara) may further improve results. We report an interim analysis from stage 1 (Simon's optimal 2-stage design) of an ongoing minimal residual disease (MRD)-driven, single center phase 2 trial of KRd-Dara. Methods: The study design has been previously published (Bhutani et al, Blood 2020 Abstr 1388). Briefly, patients with NDMM (both transplant eligible and ineligible) were allowed one cycle of non-protocol therapy (if deemed necessary) and then 7 or 8 cycles of induction therapy with KRd-Dara (total induction cycles: 8). MRD assessment was performed by both next generation sequencing (NGS) and next generation flow cytometry (NGF) at the end of 8 cycles of induction, post- autologous stem cell transplantation (ASCT), and every 4 cycles of consolidation (maximum of 12 cycles). Post-induction treatment was dictated by an MRD-driven algorithm, using MRD (NGS, 10-5) to assign patients to one of the 3 study groups. The primary endpoint is complete response (CR) + stringent CR (sCR) at the completion of KRd-Dara induction therapy. Group A (MRD negative post-induction) proceeded directly to lenalidomide maintenance therapy deferring ASCT, if transplant eligible. Group B (MRD positive, transplant eligible) received upfront ASCT, KRd consolidation (maximum 12 cycles), and then lenalidomide maintenance. Group C (MRD positive after 8 cycles of induction, transplant ineligible) received KRd consolidation (maximum 12 cycles) followed by lenalidomide maintenance. Conversion to MRD negative status at any protocol specified time point allowed the patients to proceed to lenalidomide maintenance. Results: Stage 1 futility analysis criteria were met in November 2021 and stage 2 enrollment is actively ongoing. As of a data cutoff of 4/8/22, 30/39 patients have been enrolled. Twenty-three patients were enrolled in Stage 1. The median age of stage I patients was 60 (range 34- 76) years, 74% were male and 35% were Black. R-ISS stage 3 was present in 2 (8.7%), high-risk cytogenetics in 1 (4.4%) and gain 1q21 in 7 (30.4%). Fifteen patients (65.2%) received one cycle of pre-study treatment. All patients completed 8 total cycles of induction therapy. At the end of induction, CR + sCR was achieved in 15/23 (65.2%) patients with sCR in 52.2%, and very good partial response (VGPR) in 7 (30.4%). The MRD negativity rate was 69.6% (NGS, 10-5) and 43.5% (NGS, 10-6). The MRD negativity rate by NGF was 82.6% at 10-5and 47.4% at 10-6 sensitivity level in 23 and 19 evaluable patients, respectively; 43% of bone marrow specimen tested by NGF were hemodiluted. Concordance of MRD by NGS/ NGF at 10-5 was 16/23 (69.6% in agreement and 30.4% disagreement, Cohen's kappa: 0.183). Concordance of MRD by NGS/ NGF at 10-6 was 12/19 (63.2% in agreement and 36.8% disagreement, Cohen's kappa: 0.257). Grade 3-4 treatment related adverse events (>10% of patients) included hypophosphatemia (30%), hypertension (13%), and neutropenia (13%). Covid infection occurred in 7 (30.4%) patients; only one needed hospitalization. Other Infections (any grade) were seen in 15 (65.2%) patients. At least one dose reduction of carfilzomib was required in 5 (21.7%) patients, dexamethasone in 3 patients, and lenalidomide in 4 patients. Systemic injection reactions to subcutaneous daratumumab occurred in 5 (21.7%). Thromboembolic events happened in 3 patients. No patient discontinued treatment because of toxicity. There was no treatment-related mortality during stage 1. Post-induction, 16 patients (MRD negative) transitioned to lenalidomide maintenance, 5 patients (MRD positive) underwent ASCT, and 2 patients (MRD positive) proceeded to consolidation phase. Stem cell collection for eligible patients (n=22) was performed upon completion of induction; 5 patients failed to collect optimal target (3 million CD34+ cells/kg) during their first mobilization attempt. Survival results will be updated after stage 2 enrollment is completed, but as of data cutoff, no subjects in the Stage 1 cohort have progressed. Conclusions: The quadruplet regimen KRd-Dara as induction in NDMM leads to deep responses reflected in high rates of sCR and MRD negativity with an acceptable and well-tolerated safety profile. The stage 2 enrollment is ongoing.