Daratumumab Research Articles

Artifactual Kappa Light Chain Restriction of Marrow Hematogones: A Potential Diagnostic Pitfall in Minimal Residual Disease Assessment of Plasma Cell Myeloma Patients on Daratumumab.

Daratumumab (DARA) is a humanized Immunoglobulin G(IgG)1-kappa monoclonal antibody against CD38 antigen that is shown to improve outcomes in relapsed/refractory plasma cell myeloma (PCM) patients. Since CD38 is expressed by different hematopoietic elements, DARA has the potential to interfere with flow cytometric assessment of bone marrow specimens. Flow cytometric analysis of bone marrow samples from 10 PCM on DARA and 5 control samples was performed using two different antibody panels. Bone marrow samples from PCM patients on DARA exhibited a population of CD19+ CD10+ B-lymphoid cells with kappa light chain restriction. Further morphological and immunophenotypic studies suggested that this population represents marrow hematogones. Marrow hematogones from control samples showed normal immunophenotypic profiles. DARA on the surface of hematogones interferes with flow cytometric clonality study leading to artifactual kappa light chain restriction, which can result in false interpretation of a concurrent clonal B-cell proliferation. In the era of rapidly growing list of therapeutic monoclonal antibodies, flow cytometry pathologists should be aware of potential interferences to avoid misdiagnosis. © 2019 International Clinical Cytometry Society.

Abstract 2970: Comparison of anti-CD38 antibodies in vitro mechanisms of action in multiple myeloma

Abstract Background: The outcome of multiple myeloma (MM) patients has been dramatically improved by the monoclonal antibody (mAb) daratumumab (DARA). DARA is a human IgG1κ mAb specific for CD38 and approved for the treatment of newly diagnosed and relapsed/refractory MM as a monotherapy and in combination with standard of care. Isatuximab and TAK-079 are additional CD38 targeting mAbs in clinical development by Sanofi and Takeda, respectively. These mAbs are reported to bind different epitopes and induce lysis of MM tumor cells via multiple mechanisms. It is unclear how the pleiotropic mechanisms collectively impact tumor cytolysis and exhibit anti-tumor effects in a comprehensive ex vivo immune milieu. Methods: For research purposes, DARA was compared with representative mAbs based on the published patent sequences for isatuximab and TAK-079, these surrogate analogs will hereafter be referred to as Sanofi anti-CD38 and Takeda anti-CD38. Mechanism of action (MOA) studies were done to compare antibody dependent cell-mediated cytotoxicity (ADCC), antibody dependent cell phagocytosis (ADCP), complement mediated cytotoxicity (CDC), and early and late detection of apoptosis. In addition, fresh whole blood from healthy donors was used to assess the cumulative effect of the MOAs on MM cell lines. Results: We tested the CDC activity of the anti-CD38s on multiple MM cell lines with a range of CD38 surface expression and CDC sensitivity levels. In LP-1 and MOLP-8 MM cell lines, DARA resulted in higher levels CDC activity as compared to the other anti-CD38 mAbs. In ADCC and ADCP assays, all 3 anti-CD38 mAbs induced similar levels of MM cell death and phagocytosis. Apoptosis was also assessed in the presence and absence of FcR crosslinking. The Annexin V assay replicated published results that only the Sanofi anti-CD38 was able to induce phosphatidylserine translocation to the cell surface without FcR crosslinking. However, in a robust 5-day cytotoxicity assay detecting metabolically active cells, all 3 antibodies elicited comparable high levels of cell death in the presence of the FcR crosslinker and low levels in its absence. We also performed assays with fresh whole blood from healthy volunteers (n=6) and determined the cumulative effect of the anti-CD38 mAbs on LP-1 and MOLP-8 MM cell lines. DARA demonstrated a higher maximal cytotoxicity than the other mAbs. Moreover, DARA had a significantly lower EC50 than Takeda anti-CD38 in both cell lines and lower than Sanofi-anti-CD38 in MOLP-8. Conclusion: DARA and surrogate analogs of Sanofi anti-CD38 and Takeda anti-CD38 have similar MOAs with the exception of higher CDC demonstrated by DARA which may contribute to the observed improved efficacy of DARA in a comprehensive immune milieu in vitro. As DARA is the only approved CD38 mAb, it remains to be determined in clinical trials if these in vitro differences lead to differences in clinical benefit. Citation Format: Michelle Kinder, Mi Ta, Amy Axel, Amy Wong, Stephen Rudnick, Bart de Goeij, Jeroen Lammerts van Bueren, Alex Babich, Mark Mendonca, Jocelyn Sendecki, Christopher Chiu, Kevin Bellew, Colleen Kane. Comparison of anti-CD38 antibodies in vitro mechanisms of action in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2970.

New daratumumab quadruplets and triplets for newly diagnosed MM.

New daratumumab quadruplets and triplets for newly diagnosed MM.

PS1392 CONSOLIDATION WITH A SHORT COURSE OF DARATUMUMAB CAN SIGNIFICANTLY IMPROVE COMPLETE RESPONSE RATES IN PATIENTS WITH AL AMYLOIDOSIS OR LCDD

Background:A deep hematologic response is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib‐based therapy is the primary therapy for patients with AL amyloidosis but less than 40% achieves a CR. Further improvement of hematologic response may be achieved by consolidation strategies but HDM‐ASCT is associated with significant toxicity, and only a minority of AL patients is eligible for this treatment. Recent data indicate that even a short course of daratumumab (DARA) was able to induce hematologic responses in patients with relapsed or refractory AL. Thus, DARA may be a unique treatment to improve the outcomes of patients with AL amyloidosis.Aims:To evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, in patients with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy, with bortezomib‐based therapy.Methods:The endpoint of this exploratory approach was improvement of response post completion of DARA consolidation. All patients received 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre‐emptive therapy for IRR was given starting two days before the first infusion of DARA. In all patients next generation flow (NGF) according to Euroflow protocol was performed before and after consolidationResults:26 patients (23 AL and 3 with LCDD) received DARA consolidation. Median age is 67 and 73% were males. Kidneys and heart were involved in 80% and 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (19/23 of AL patients were lambda). Median time from start of first line therapy to DARA consolidation was 8 months and all patients had completed the planned bortezomib‐based treatment. Before consolidation all patients were in either VGPR (23/23 AL patients and 2/3 LCDD patients) or in PR (1/3 LCDD patients); all patients had positive serum and/or urine immunofixation with or without abnormal FLC ratio. All but one patient received the planned 4 infusion of DARA. Mild IRR (Gr1) were observed in 3 patients. After consolidation with DARA, 42% of the patients (10/23 with AL and 1/3 with LCDD) achieved a CR. In 9/26 patients small monoclonal IgGk was observed 1 month post DARA and in all but one patient IgGk resolved at 2–3 months post DARA. The patient that received only one dose of daratumumab also achieved a CR. In all patients MRD by NGF was positive before DARA consolidation while DARA 6/11 patients in CR became MRDnegative. All patients that did not achieve a VGPR remained MRD positive. One patient with IgGk AL that remained with positive immunofixation after DARA was MRD(neg). Because of interference with daratumumab we repeated immunofixation, which 2 months after daratumumab became negative.Summary/Conclusion:Consolidation with a short course of DARA can improve the depth of response in patients with AL or LCDD that have not achieved a CR after primary therapy, including MRD negative disease in some.We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further.

PB2132 DARATUMUMAB MONOTHERAPY FOR RELAPSED AND REFRACTORY MULTIPLE MYELOMA REAL CLINICAL PRACTICE. A MULTICENTRIC RETROSPECTIVE STUDY

Background:Daratumumab (DARA) was first approved as monotherapy for patients (P) with relapsed and refractory (RR) multiple myeloma (MM) after treatment with immunomodulatory drugs and proteasome inhibitors, and who have progressed on the last therapy, based on data from the phase 2 SIRIUS trial. Its results show 29% of P with at least partial response, progression‐free survival (Sv) (PFS) of 3.7 months(m) and overall survival (OS) of 17.5 m, and acceptable toxicity.Aims:So far, there are scarce data on treatment with DARA monotherapy in routine clinical practice.MethodsObservational, retrospective and multicenter study of P with RRMM treated with DARA in monotherapy outside clinical trial (CT) in various Spanish regions: Galicia, Asturias, Cantabria y Castilla y León. Statistical descriptive analysis with SPSS®: Sv curves by Kaplan‐Meier and measures of statistical association using Chi2.Results:There were 80 P (61% males) evaluable. Characteristics at diagnosis: age 64.8 years (y) (IQR 57.1‐73.3); previous COPD/asthma: 11.25%; myeloma stage ISS 3: 37.5%, and 2: 31.25%; adverse cytogenetics (del17p, t(4;14), t(14;16)): 21.25%. Characteristics at starting of DARA: age 70.5 y (IQR 60.9‐76.1); adverse cytogenetics: 17/33 P (52.5%); previous lines of treatment: median 3 (1‐10), in 52.5% of P including carfilzomib and/or pomalidomide; previous ASCT: 51.25%.The median of DARA doses administered per patient were 10 (1‐26); it should be pointed out tha t5 P only received 1 dose. The majority (78.7%) received the 1st dose hospitalized, and in 38.7% montelukast was associated to the conventional premedication. The rate of infusion‐ related reactions (IRR) is 23.7% for the 1st dose (grade 1: 78.9%, grade 3: 15.8%), with no difference according to premedication. Only 3 P suffered IRR grade 1 after 2nd dose.Response. Overall R (OR) 66.6% (CR 13.3%, PR + VGPR 33.3%, MR/SD 20%), progression 33.3%. With a median follow‐up of 243 days (IQR 113‐392), 48.7% have died (cause of death 79.4% MM) with no toxic mortality, and 25% continue treatment. PFS and OS are 111 days (87‐252) and 280 days (173‐700), respectively.Adverse events. Any grade adverse events occurred in 38.7%, being the most frequent neutropenia and/or infection (52%), thrombocytopenia (26%), nausea/vomiting (10%) and peripheral neuropathy (4%). All grade 3 (34%), and 4 (18%) adverse events were due to myelotoxicity and infection. In 25% of P a dose of DARA was delayed, for an average of 11 days (2‐30), 55% of them due to infection. None had to discontinue DARA because of toxicity.Summary/Conclusion:Our experience outside clinical trials confirms that DARA monotherapy is a safe and well‐tolerated drug, even in this population of elderly P with advanced disease and multiple previous lines of therapy. There are no serious IRR and the main toxicity, as otherwise should be expected, has been myelosuppression and infections. The OR rate is high, highlighting 46.6% with at least PR, but in spite of this PFS and OS are short, 3.7 m and 9.3 m respectively; in special OS is much lower than previously referred in SIRIUS trial. It should be noted out that 17 P did not complete the 1st cycle of DARA (4 doses) and 5P received only 1 dose, so a better selection of candidates for this Trt will probably improve these results.

PB2445 PRE‐TRANSFUSION IMMUNOHEMATOLOGY TESTING INTERFERENCE WITH DARATUMUMAB: PRELIMINARY EXPERIENCE FROM THE FIRST PATIENTS TREATED AT ASST GOM NIGUARDA

Background:Daratumumab is a human anti‐CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma (MM). Due to the physiological presence of the antigen CD38 on the red blood cell (RBC) membrane, Daratumumab (DARA) inteferes with the classical pre‐transfusion tests, impairing the identification of potential auto‐ or alloantibodies whenever present. The duration of this interference has been reported to be of 2‐6 months after the last DARA administration [Oostendorp M, Transfusion 2015].Aims:The present analysis aims at evaluating the duration of DARA‐related pre‐transfusion testing interference after the end of treatment at our Center, in order to better define an optimal strategy to assign compatible packed RBCs for transfusion therapy.Methods:According to our policy, all patients were typed for AB0, full Rh phenotype, K/k, direct/indirect antiglobulin tests and extended sierological RBCs typing before starting with DARA [2016 SIMTI recommendations]; the identification of compatible packed RBCs was obtained after crossmatching using dithiothreitol‐treated patient's blood sample.Results:From October 2017, a total of n = 7 MM patients received DARA at a median age of 68y (range: 50‐79); median number of previous therapeutic lines was 3 (range: 1‐7) and the median number of weekly administrations was 7 per patient (range: 1‐12). Two patients are still receiving DARA (1 and 12 administrations respectively). As expected, both direct and indirect antiglobulin tests were positive for all patients; moreover, one patient had also a well‐identified allo anti‐D antibody. Among the n = 5 ongoing patients, n = 4 are evaluable because they underwent the subsequent pre‐transfusion tests after the end of DARA treatment: n = 1 still presents interference 50 days after the end of DARA whereas interference disappeared in n = 3 patients at 48, 65 and 111 days after the last treatment.Summary/Conclusion:Our preliminary data confirm the persistence of DARA‐related pre‐transfusion testing interference after the end of treatment for a median period of 2 months in this cohort of MM patients treated at our Institution. Futher follow‐up and the analysis of additional patients in the next future will allow to better determine the duration of interference; we believe these data are worthy of note due to increasing use of DARA, even for other clinical situations [Chapuy CI, NEJM 2018; Kwun JEB, Am J Transplant 2017]

PS1425 RESULTS OF THE DARATUMUMAB MONOTHERAPY EARLY ACCESS TREATMENT PROTOCOL (EAP) IN PATIENTS FROM EUROPE AND RUSSIA WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA

Background:Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed or refractory MM (RRMM) and in combination with standard‐of‐care regimens for RRMM and transplant‐ineligible newly diagnosed MM. Despite the demonstrated benefit of DARA in patients with MM, not all patients are eligible for inclusion in clinical trials or have access to commercially available DARA.Aims:The purpose of this multicenter, open‐label, EAP was to provide early access to DARA monotherapy to eligible patients with RRMM, while collecting safety and patient‐reported outcomes (PRO) data. We report results from a pooled analysis of patients enrolled in 4 countries: Spain, Italy, Russia, and the United Kingdom.Methods:Patients eligible for study inclusion had to have ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or were double refractory to both a PI and IMiD. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression, unacceptable toxicity, study conclusion, or if DARA became available with reimbursement. Grade ≥3 treatment‐emergent adverse events (TEAEs), serious TEAEs (SAEs), infusion‐related reactions (IRRs), PRO, investigator‐assessed best response, and progression‐free survival (PFS) data were collected.Results:A total of 293 patients (median [range] age: 64 [32–85] years) were enrolled and received ≥1 dose of DARA. Baseline Eastern Cooperative Oncology Group score was 0, 1, and 2 for 38.2%, 50.5%, and 11.3% of patients, respectively. The median duration of treatment was 4.2 months (range: 0.03–24.08), with a median number of 13 infusions (range: 1–37). Median duration of infusions was 7.1, 4.3, and 3.5 hours for the first, second, and all subsequent infusions, respectively. Grade 3/4 TEAEs were reported in 176 (60.1%) patients; the most common (>10%) included thrombocytopenia (18.8%), anemia (11.9%), and neutropenia (11.6%). Common (>3%) SAEs included pneumonia (4.4%), pyrexia (4.1%), lower respiratory tract infection (3.8%), general physical health deterioration (3.8%), hypercalcemia (3.8%), and thrombocytopenia (3.4%). Primary reasons for treatment discontinuation included progressive disease (64.8%) and market authorization/reimbursement (16.7%), AE (11.3%), and death (2.7%). Sixty‐one (20.8%) patients discontinued treatment due to TEAEs (3.8% drug‐related). Forty (13.7%) patients had a fatal TEAE (none were drug‐related). IRRs occurred in 132 (45.1%) patients, including 10 (3.4%) with grade 3/4 IRRs (grade 3, n = 9 [3.1%]; grade 4, n = 1 [0.3%]). IRRs occurred in 44.4%, 1.8%, and 1.5% of patients during the first, second, and all subsequent infusions, respectively. The most common (>5%) any grade IRRs were dyspnea (8.9%), nasal congestion (8.9%), and cough (5.1%). A total of 97 (33.1%) patients achieved a partial response or better, with 36 (12.3%) patients achieving a very good partial response or better. Median PFS was 4.63 months (95% confidence interval [CI], 3.75–5.75), and the 12‐month PFS rate was 20.8% (95% CI, 15.9–26.2). The median change from baseline in all domains of the EQ‐5D‐5L, EORTC QLQ‐C30, and EORTC QLQ‐MY20 questionnaires was 0 or close to 0, which indicates no clinically significant changes.Summary/Conclusion:These EAP results are consistent with previously reported trials of daratumumab monotherapy, and confirm the safety of daratumumab in patients from Europe and Russia with heavily pretreated RRMM. ClinicalTrials.gov identifier: NCT02477891.

PF631 HEALTH‐RELATED QUALITY OF LIFE WITH POMALIDOMIDE + LOW‐DOSE DEXAMETHASONE + DARATUMUMAB IN PATIENTS WITH RELAPSED REFRACTORY MULTIPLE MYELOMA AFTER LENALIDOMIDE TREATMENT

Background:Treatment of relapsed refractory multiple myeloma (RRMM) is complex and requires evaluation of disease and patient factors to maximize efficacy and minimize toxicity. As survival has improved with therapeutic advances, maintaining quality of life has become an important aspect of multiple myeloma treatment. Results from cohort B of the ongoing phase 2 MM‐014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low‐dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in patients with RRMM after first‐ or second‐line lenalidomide (LEN)‐based treatment.Aims:To evaluate the impact of POM+ LoDEX + DARA on health‐related quality of life (HRQoL) in patients with RRMM who received this regimen after first‐ or second‐line LEN.Methods:Patients with RRMM and 1 to 2 prior lines of treatment, LEN‐based treatment as their most recent regimen, and progressive disease during or after their last treatment line were eligible for inclusion in cohort B. In 28‐day cycles, patients received POM 4 mg/day on days 1–21 + LoDEX 40 mg/day (20 mg/day if aged > 75 years) on days 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of cycles 1 and 2, then on days 1 and 15 of cycles 3–6, and then on day 1 of cycle 7 and beyond. Thromboprophylaxis was mandatory. The primary endpoint was overall response rate. HRQoL, an exploratory endpoint for cohort B, was assessed via EQ‐5D.Results:As of 15 October 2018, 108 patients were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ‐5D completion rates for each cycle (1–6) were ≥ 88%. Through 6 treatment cycles, mean change from baseline in the EQ‐5D index and VAS health score was stable. At cycle 6, minimum clinically important improvement in the EQ‐5D index (≥ 0.1) and VAS health score (≥ 6) was achieved by 28.8% and 39.0% of patients, respectively. EQ‐5D index values were stable; however, a trend toward improvement was observed in usual activities, pain/discomfort, and anxiety/depression (Figure).Summary/Conclusion:In patients with RRMM who received POM + LoDEX + DARA after first‐ or ‐second‐line LEN based treatment, HRQoL was maintained or trended toward improvement, despite the combination of 3 drugs with distinct toxicity profiles. In context with the previously reported safety and efficacy data from cohort B of MM‐014, the results of this HRQoL analysis further support the earlier use of POM‐based treatment in RRMM immediately following treatment with LEN.image

PB2185 DARATUMUMAB MONOTHERAPY IN REAL LIFE COMMUNITY SETTING OF REFRACTORY MYELOMA PATIENTS: A RETROSPECTIVE UNICENTRIC STUDY

Background:Daratumumab (DARA) is a first in class CD38‐directed monoclonal antibody approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). In phase I/II and III trials, DARA monotherapy can induce an overall response (partial response or better) in about one third of patients, with rapid and durable responses. High occurrence of all grade of Infusion‐Related Reactions–IRRs‐ has been described (up to 50% of cases), including 5% of at least grade 3 IRRs. In some cases IRRs can induce infusion delayed or interruption and need of patient hospitalization. It is known that highest risk of reaction is during the first or second exposure to DARA.Aims:To describe DARA‐related IRR in real life clinical setting, particularly management of first infusion.MethodsStarting from April 2017, 13 RRMM patients received DARA intravenously (i.v.) according to the manufacture schedule. To reduce IRRs, only the first dose was split in 2 administrations within 24 hours. One hour after standard premedication the first 250 ml were given starting at infusion rate of 50 mL/hour as schedule. After 24 hours, premedication was given and the remaining 750 mL were infused as schedule.Results:Our cohort included 13 heavily pre‐treated patients (n = 76 M/F), most of them double refractory (n = 11) with a median of 4 previous lines (range 1‐13). Median age was 61 years (range 46‐74). At least 3 treatment cycles were given to 11 (84%) patients, two cycles to 12 patients.At the first day of infusion, 10/13 patients had a grade 1‐2 IRR treated with suspension of infusion for about 20‐30 minutes followed by infusion of antipyretics or antihistamine. Restarting DARA infusion was safe and comfortable. IRRs were cough in 4 patients, congestion and runny nose in 4 patients, throat tightness and dyspnea in 3 patients and chills in 1 patient. Rarely, a second manifestation of IRRs occurred again. Symptoms were treated in the same way and resolved promptly.None of our patients discontinued treatment for IRR, and up to now 5 patients are completing the third cycle, six patients died for disease progression (2 after the first cycle, 1 after the second cycle, 1 after the third cycle) while for the remaining 6 treatment is ongoing. 6/13 patients had severe adverse events (anemia and neutropenia ≥ grade 3, NCCN) and 2/13 pneumonia grade 3, requiring hospitalization.Clinical benefit was evident for 7/13 patients, with 53% of overall response rate (after 8 infusions): 1 patient achieved a CR, 2 achieved a very good partial remission (VGPR), 4 patients achieved partial response (PR), a patient achieved stable disease (SD).Progression occurred in 2 patients after 1 cycle, 2 patients after 2 cycles and two other after 3 cycles. Overall median PFS was 13 months, median OS was not reached.Summary/Conclusion:In line with published clinical trials in the setting of RRMM, DARA monotherapy is efficacious in RRMM patients with an overall response rate of 53%. According to our schedule, IRRs are weakly and occur only the first day, when the infusion rate is increased from 50 to 100 mL/hour and it can be reduced by splitting the infusion over 24 hours.

S1603 FIRST CLINICAL (PHASE 1B/2A) STUDY OF IBERDOMIDE (CC‐220; IBER), A CELMOD, IN COMBINATION WITH DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background:IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and dexamethasone (DEX).Aims:This phase 1b/2a multicenter, open‐label, dose‐escalation study (NCT02773030) was conducted to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary efficacy of IBER in combination with DEX, in patients with relapsed/refractory multiple myeloma (RRMM).Methods:Eligible patients had RRMM and must have received ≥2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All patients had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in patients aged >75 years) on days 1, 8, 15, and 22, of each 28‐day cycle. Dose escalation was reviewed by a dose escalation committee.Results:As of January 2019, 58 patients had received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplantation (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) patients and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% patients, respectively. Three patients discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table 1); 20 of 51 patients remain on treatment (2–27+ cycles).Summary/Conclusion:IBER + DEX showed favorable efficacy and safety in heavily pretreated patients with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT.image

S874 EFFICACY OF DARATUMUMAB + BORTEZOMIB/THALIDOMIDE/DEXAMETHASONE (D‐VTD) IN TRANSPLANT‐ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA BASED ON MINIMAL RESIDUAL DISEASE STATUS: ANALYSIS OF CASSIOPEIA

Background:VTd is considered a standard of care for patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible. The CD38‐targeted monoclonal antibody daratumumab (DARA) demonstrated a significant reduction in the risk of progression or death and improvement in stringent complete response (sCR), CR or better (≥CR), and minimal residual disease (MRD)‐negative rates when added to VTd in transplant‐eligible NDMM patients in the phase 3 CASSIOPEIA study.Aims:Determine MRD status and its association with progression‐free survival (PFS) in transplant‐eligible NDMM patients receiving D‐VTd versus VTd as pre‐transplant induction and post‐transplant consolidation in CASSIOPEIA.Methods:Transplant‐eligible NDMM patients were randomized 1:1 to 4 cycles of pre‐autologous stem‐cell transplant (ASCT) induction and 2 cycles of post‐ASCT consolidation with DARA + VTd or VTd. Analyses of MRD were performed on bone marrow aspirates after induction and after consolidation (at Day 100 post‐ASCT) for all patients, regardless of response. MRD was assessed primarily by EuroFlow‐based multiparametric flow cytometry (MFC) and, based on sample yield, secondarily with next‐generation sequencing (NGS; Adaptive clonoSEQ® Assay). Here, we report post‐induction and post‐consolidation MFC results (10−5 sensitivity threshold) and post‐consolidation NGS results (10−6).Results:A cohort of 1,085 patients received D‐VTd (n = 543) or VTd (n = 542). The post‐induction MRD‐negative rate (MFC, 10−5) was significantly higher for the D‐VTd arm versus the VTd arm (34.6% vs 23.1%; P < 0.0001; Table). Similarly, post‐consolidation MRD‐negative rates by MFC (10−5) and NGS (10−6) were significantly higher for patients receiving D‐VTd versus VTd (63.7% vs 43.5% and 39.1% vs 22.8%, respectively; P < 0.0001 for both analyses; Table). Post‐consolidation MRD‐negative rates (MFC, 10−5) were consistent across patient subgroups, including ISS stage III or high‐risk cytogenetics.Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in patients reaching MRD negativity (HR, 0.31; 95% CI, 0.20–0.50; P < 0.0001), and D‐VTd showed additional PFS benefit versus VTd alone (HR, 0.48; 95% CI, 0.30–0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented.Summary/Conclusion:The addition of DARA to VTd during induction and consolidation deepened responses, as demonstrated by significant increases in MRD‐negative rates. Deepened post‐consolidation responses with D‐VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in patients with NDMM who were transplant eligible.image

S145 PHASE 3 RANDOMIZED STUDY OF DARATUMUMAB + BORTEZOMIB/THALIDOMIDE/DEXAMETHASONE (D-VTD) VERSUS VTD IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: PART 1 CASSIOPEIA RESULTS

Background: VTd is a standard of care for transplant-eligible newly diagnosed multiple myeloma (NDMM) patients. Daratumumab (DARA), a CD38 mAb, significantly reduced the risk of progression or death and improved complete response (CR) and minimal residual disease (MRD)-negative rates in relapsed refractory multiple myeloma or transplant-ineligible NDMM in phase 3 studies. Aims: We report the primary and final analysis of Part 1 of the CASSIOPEIA trial for NDMM. Methods: In Part 1, transplant-eligible NDMM patients 18–65 years old were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-autologous stem cell transplantation {ASCT} induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1–2; T 100 mg PO QD; d 40–80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT therapy. The primary endpoint was the rate of post-consolidation stringent complete response (sCR) assessed at Day 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 patients (D-VTd, 543; VTd, 542) was randomized. The Day 100 post-ASCT sCR rate was significantly higher for the D-VTd arm versus the VTd arm (28.9% vs 20.3%; P = 0.0010; Table). With 18.8-months median follow-up, progression-free survival (PFS) from first randomization favored D-VTd with a hazard ratio (HR) of 0.47 (95% CI, 0.33-0.67; P < 0.0001; Figure). With median PFS not reached in either arm, 18-month PFS rates were 92.7% versus 84.6% for D-VTd versus VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). Overall survival is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23–0.80). The most common (≥10%) grade 3/4 treatment-emergent adverse events (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of patients.Summary/Conclusion: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in transplant-eligible NDMM. CASSIOPEIA is the first study to demonstrate the clinical benefit of daratumumab plus standard of care in transplant-eligible NDMM patients.

S826 IMPROVED EFFICACY AND SAFETY OF A DUAL‐TARGET CAR‐T CELL THERAPY TARGETING BCMA AND CD38 FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM A PHASE I STUDY

Background:Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy for relapsed/refractory (RR) multiple myeloma (MM), including anti‐B cell maturation antigen (BCMA) CAR‐T cell therapy and anti‐CD38 daratumumab (DARA) monotherapy. We conducted an anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in order to avoid negative relapse of single‐target loss. Here we report a promising results on 12 patients about the efficacy and safety in the ongoing phase I study.Aims:1.To evaluate the safety of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including cytokine release syndrome (CRS), neurotoxicity and other adverse events. 2.To assess the efficacy of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including the overall response rate(ORR),duration of remission and Progression‐free survival(PFS). 3.To estimate the proliferation and persistence of the dual‐target CAR‐T cell in the blood of RRMM patients.Methods:A phase I clinical trial (ChiCTR1800018143) has been launched to evaluate the efficacy and safety of the dual‐target CAR‐T cell product for RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double‐relapsed or relapse after autologous hematopoietic stem cell transplantation(ASCT). Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2,d‐5 to d‐3) and Flu(25 mg/m2,d‐5 to d‐3) daily prior to the CAR‐T infusion (d0).The median number of infused cells was 2.17(0.5∼4.0) × 106 CAR+ cells/kg. The median follow‐up times is 21.5(6∼33)weeks and 66.7%(8/12) are more than 5 months. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma(2016), and the toxicity was graded by CTCAE 5.0.Results:As of January 31, 2019, 12 patients consisting of 66.67%(8/12) with genetic abnormalities,16.7%(2/12) with ASCT and 16.7%(2/12) with extrandal disease, have been infused with thedual‐target CAR‐T cell product. The overall response rate(ORR) is 83.3%(10/12), including 5 sCR, 2 VGPR and 3 PR. the shortest duration of sCR is 8 weeks and the longest one is over 26 weeks and 60%(3/5) have still maintained sCR more than 2 month. More encouragingly, 60%(6/10) have still kept sustained remission and allextramedullary lesions have been eliminated.The 8‐week Progression‐free survival(PFS) is 0.90 and 12‐week PFS is 0.77. Up to now, the CAR‐T cells still exists in the patients’ peripheral blood by flow cytometry and q‐PCR. The peak time of CAR‐T cells proliferation of sCR patients is about the 2nd week after infusion, which is earlier than other patients. 83.3%(10/12) were observed with cytokine release syndrome (CRS) and severe CRS(≥ Grade 3) accounted for 33.33%(4/12). No neurotoxicity was observed. Almost all the patients were observed with hematological toxicities. 16.7%(2/12) of patients was observed with hepatotoxicity and one patient with nephrotoxicity, which were relieved after symptomatic treatment.Summary/Conclusion:Our study demonstrates an improved efficacy with dual‐target CAR‐T therapy targeting BCMA and CD38 for RRMM with a high ORR, especially a higher rate and a longer duration of sCR. CRS and hematological toxicities are observed but manageable. Other toxicity is rare. These initial data provide strong evidence to support the further development of the dual‐target CAR‐T therapy for RRMM.ChiCTR1800018143 image

PF556 PRECLINICAL EVALUATION OF THE NEW GPRC5DXCD3 (JNJ‐7564) BISPECIFIC ANTIBODY FOR THE TREATMENT OF MULTIPLE MYELOMA

Background:The prognosis of multiple myeloma (MM) patients who are refractory to all currently available therapies, including anti‐CD38 monoclonal antibodies, remains poor, indicating that there is an unmet need for novel treatment strategies. Although data on G‐protein coupled receptor 5D (GPRC5D) protein expression is scarce, GPRC5D RNA levels are selectively elevated in MM cell lines and primary MM cells. This makes GPRC5D an attractive target for the novel anti‐MM JNJ‐7564 bispecific antibody.Aims:We determined GPRC5D protein expression levels on bone marrow (BM) mononuclear cells (MNCs) and MM cell lines. We also analyzed the impact of differential GPRC5D gene expression on overall survival (OS) and progression free survival (PFS) in MM patients. Furthermore, the preclinical activity of a new GPRC5DxCD3 bispecific antibody (JNJ‐7564) in development for the treatment of MM was evaluated, as well as biomarkers for in vitro JNJ‐7564 response.Methods:GPRC5D protein expression was assessed by flow cytometry on BM MNCs derived from healthy donors (HD) and MM patients. GPRC5D gene expression levels were analyzed in purified CD138+ MM cells derived from patients who participated in 5 large randomized clinical trials (HOVON65, MRC‐IX, TT2, TT3 and APEX). MM cell lysis by JNJ‐7564 (0.00064–4 μg/ml; 48 hour‐incubation) was evaluated in MM cell lines and whole BM samples from newly diagnosed (ND) and relapsed/refractory (RR) MM patients. At baseline, the MNCs were characterized for the composition of T‐cell subsets. T‐cell activation and degranulation were measured by flow cytometry based on expression of CD25 and CD107a, respectively.Results:GPRC5D protein expression was significantly higher on MM cells compared to other BM cells, including HD plasma cells (fig 1A). GPRC5D protein expression was positively correlated with BCMA expression (r = 0.44; P = 0.02), but was independent of tumor load, and CD38 or PD‐L1 expression on MM cells. Gene expression levels of GPRC5D were highly variable in MM, and independent of age and ISS stage, but were significantly higher in patients with t(4;14) or gain 1q. There was no association with OS or PFS in the 5 clinical trials (n = 1421). JNJ‐7564 effectively killed GPRC5D+ MM cell lines (MM1.S, UM9 (fig 1B) and RPMI8226) in a dose‐dependent manner using HD peripheral blood MNCs as effector cells. Co‐incubation with patient‐derived BM stromal cells resulted in a modest impairment of killing capacity in MM1.S and RPMI8226 cells. In MM patient samples (n = 20), the mean lysis of MM cells with 4.0 μg/mL JNJ‐7564 was 62% (range: −8–97%; fig 1C), while NK‐cell and T‐cell frequencies were not affected. JNJ‐7564 was also effective in samples from extensively pretreated daratumumab (DARA)‐refractory patients (DRMM; n = 6; median of 6 prior lines; mean lysis with 4.0 μg/mL: 70%; range: 44–97%). Maximal lysis of primary MM cells was not associated with the level of GPRC5D expression on MM cells, effector:target ratio, or frequency of regulatory T‐cells. JNJ‐7564‐mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T‐cells (fig 1D).Summary/Conclusion:GPRC5D is highly and selectively expressed on MM cells, which makes it an attractive therapeutic target. The GPRC5DxCD3 bispecific antibody, JNJ‐7564, effectively lysed GPRC5D+ MM cell lines and primary MM cells in samples derived from both newly diagnosed and heavily pre‐treated patients, including DARA‐refractory patients. Altogether, this strengthens the preclinical rationale for an ongoing phase 1 study with JNJ‐7564 in RRMM.image

Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.

8005 Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P&lt;0.0001). Median duration of injection was 5 mins for DARA SC and median duration of infusion was 421/255/205 mins for the first/second/subsequent DARA IV infusions. Median PFS was 5.6 mos DARA SC vs 6.1 mos DARA IV (HR, 0.99; 95% CI, 0.78-1.26). Most common TEAEs (≥15%) were anemia, neutropenia, thrombocytopenia, and diarrhea. Primary reasons for treatment discontinuation included progressive disease (43% SC vs 44% IV) and AEs (7% SC vs 8% IV). Conclusions: Efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to IV. DARA SC significantly decreased IRR rate and administration time, with a comparable safety profile to DARA IV. Clinical trial information: NCT03277105.

Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): A multicenter, randomized, phase III study (PERSEUS).

TPS8055 Background: DARA, a human, CD38-targeting, IgGκ monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory MM (RRMM), and in combination with standard-of-care regimens in RRMM and transplant-ineligible NDMM. Given the initial safety and efficacy observed with DARA plus VRd (D-VRd) in the safety run-in cohort of the ongoing phase 2 GRIFFIN study in TE NDMM pts, the phase 3 PERSEUS study will evaluate the efficacy and safety of D-VRd versus VRd alone in TE NDMM. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd versus VRd alone in TE NDMM pts. Approximately 690 pts across Europe will be stratified by ISS stage and cytogenetic risk (high risk defined as presence of del17p, t[4;14], or t[14;16]) and randomized in a 1:1 ratio. All pts will receive VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-21; d: 40 mg PO Days 1-4, 9-12) for 4 pre-transplant induction and 2 post-transplant consolidation cycles (all 28-d cycles), followed by R (10 mg PO Days 1-28) maintenance until progressive disease (PD). Pts in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W in maintenance Cycles 7+ until PD. After induction, pts will undergo melphalan 200 mg/m2 conditioning and autologous stem cell transplantation (ASCT). Pts in the DARA group who achieve sustained minimal residual disease (MRD) negativity (10–5 threshold; assessed by NGS) for 12 months after ≥24 months of maintenance will stop DARA but continue R maintenance until PD; upon loss of CR or MRD-negative status, pts will restart DARA treatment. All pts will receive preinfusion medications. The primary endpoint is progression-free survival (PFS). Secondary endpoints include MRD-negative rate, overall response rate, PFS on next line of therapy, overall survival, time to and duration of response, health-related quality of life, pharmacokinetics, immunogenicity, stem cell yield after mobilization, time to engraftment post-ASCT, and safety. Clinical trial information: NCT03710603.

Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results.

8003 Background: VTd is a standard of care (SoC) for TE NDMM. CD38 mAb DARA significantly reduced the risk of progression/death and improved CR and MRD-negative rates in relapsed refractory MM or transplant-ineligible NDMM in phase 3 studies. We report the primary and final analysis of Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts 18-65 y were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-ASCT induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1-2; T 100 mg PO QD; d 40-80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT HDT. The primary endpoint, post-consolidation sCR rate, was assessed at Day [D] 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 pts (D-VTd, 543; VTd, 542) was randomized. The D 100 post-ASCT sCR rate was significantly higher for D-VTd vs VTd (28.9% vs 20.3%; P = 0.0010; Table). At 18.8-mo median follow-up, PFS from first randomization favored D-VTd with HR 0.47 (95% CI, 0.33-0.67; P &lt;0.0001). With median PFS NR in either arm, 18-mo PFS rates were 92.7% vs 84.6% for D-VTd vs VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). OS is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23-0.80). The most common (≥10%) grade 3/4 TEAEs (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of pts. Conclusions: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in TE NDMM. CASSIOPEIA is the first study to demonstrate clinical benefit of DARA + SoC in TE NDMM. Clinical trial information: NCT02541383. [Table: see text]

Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with newly diagnosed multiple myeloma (NDMM) for whom transplant is not planned as initial therapy: A multicenter, randomized, phase III study (CEPHEUS).

TPS8056 Background: DARA is a human, anti-CD38 IgGκ monoclonal antibody that significantly reduced the risk of progression/death with a manageable safety profile across several phase 3 studies in relapsed/refractory MM and NDMM. DARA + VRd (D-VRd) demonstrated efficacy and tolerability in the safety run-in cohort of the ongoing phase 2 GRIFFIN study that included transplant-eligible NDMM pts. To determine whether D-VRd demonstrates efficacy and tolerability in NDMM pts for whom transplant is not intended as initial therapy, the phase 3 CEPHEUS study will evaluate the efficacy and safety of D-VRd vs VRd alone in this pt population. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd vs VRd alone in pts with NDMM for whom transplant is not intended as initial therapy. Approximately 360 pts will be stratified by ISS stage and age/transplant eligibility (age &lt; 70 years and transplant-ineligible, or age &lt; 70 years and refusal to transplant, or age ≥70 years) and will be randomized in a 1:1 ratio. All pts will receive eight 21-day cycles of VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO/IV Days 1, 2, 4, 5, 8, 9, 11, 12), followed by 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg PO/IV Days 1, 8, 15, 22) until progressive disease (PD). Patients in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks in Cycles 9+ until PD. All pts will receive preinfusion medications. Minimal residual disease (MRD)-negative rate at 10–5 sensitivity threshold by NGS is the primary endpoint. MRD will be evaluated at suspected complete response or better. Secondary endpoints include progression-free survival (PFS), MRD-negative rate at 1-year, durable MRD negativity, overall response rate, time to and duration of response, PFS on next line of therapy, overall survival, clinical efficacy in high-risk molecular subgroups, health-related quality of life, pharmacokinetics, immunogenicity, and safety. Clinical trial information: NCT03652064.

Efficacy of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in transplant-eligible newly diagnosed multiple myeloma (TE NDMM) based on minimal residual disease (MRD) status: Analysis of the CASSIOPEIA trial.

8017 Background: In TE NDMM patients (pts), the CD38 monoclonal antibody DARA significantly reduced the risk of progression/death and improved stringent CR, ≥CR, and MRD-negative rates when added to VTd in the phase 3 CASSIOPEIA study. MRD status and its association with progression-free survival (PFS) was evaluated in TE NDMM pts receiving D-VTd vs VTd as pre-transplant induction/post-transplant consolidation in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts were randomized 1:1 to 4 cycles of pre-ASCT induction and 2 cycles of post-ASCT consolidation with DARA + VTd or VTd. Landmark analyses of MRD were performed on bone marrow aspirates after induction by multiparametric flow cytometry (MFC; 10–5 sensitivity threshold) and after consolidation (at Day 100 post-ASCT) by MFC (10–5) and next-generation sequencing (NGS; 10–6) for all pts, regardless of response. Results: A cohort of 1085 pts was randomized (D-VTd, n = 543; VTd, n = 542). Post-induction and post-consolidation MRD-negative rates were significantly higher for D-VTd vs VTd (Table). Post-consolidation MRD-negative rates (MFC) were consistent across pt subgroups, including ISS stage III or high-risk cytogenetics. Multivariate analyses accounting for treatment arm and MRD negativity (MFC) showed a PFS benefit in pts reaching MRD negativity (HR, 0.31; 95% CI, 0.20-0.50; P &lt;0.0001). Based on these analyses, D-VTd showed additional PFS benefit vs VTd (HR, 0.48; 95% CI, 0.30-0.78; P = 0.0028). Analysis of MRD based on response (per IMWG criteria) will be presented. Conclusions: Adding DARA to VTd induction and consolidation deepened responses, as demonstrated by significant increases in MRD-negative rates. MRD negativity was associated with a PFS benefit regardless of treatment group. However, deepened responses with D-VTd led to improved outcomes, with MRD negativity associated with prolonged PFS, versus VTd in pts with TE NDMM. Clinical trial information: NCT02541383. [Table: see text]

Stem cell (SC) yield and transplantation results from transplant-eligible newly diagnosed multiple myeloma (TE NDMM) patients (pts) receiving daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) in the phase 3 CASSIOPEIA study.

8042 Background: High-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is the standard of care in TE NDMM. In the phase 3 CASSIOPEIA study, D-VTd significantly improved stringent complete response (sCR), ≥CR, and minimal residual disease (MRD)-negative rates and reduced the risk of progression/death vs VTd in TE NDMM pts. We assessed SC yield and transplantation results among pts receiving D-VTd vs VTd induction prior to HDT/ASCT in Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts ages 18-65 y were randomized 1:1 to 4 pre-transplant induction and 2 post-transplant consolidation cycles of DARA + VTd or VTd alone. After induction, pts underwent SC mobilization with cyclophosphamide 3 g/m2 (recommended dose) and GCSF. Peripheral blood SCs were harvested based on response to mobilization. Plerixafor was given if SC collection failed at first attempt and in accordance with institutional practice. Melphalan 200 mg/m2 IV was given as HDT prior to ASCT. Results: A total of 1085 pts were randomized (D-VTd, 543; VTd, 542). Among pts who completed mobilization (D-VTd, 506; VTd, 492), more pts receiving D-VTd vs VTd received plerixafor during mobilization (21.7% vs 7.9%). Pts underwent a median (range) of 2 (1-6) vs 1 (1-4) days of apheresis for D-VTd vs VTd. The median number of CD34+ cells collected was lower for D-VTd vs VTd (6.3×106/kg vs 8.9×106/kg). Nevertheless, a similar percentage of ITT pts receiving D-VTd vs VTd underwent ASCT (90.1% vs 89.3%). The median number of CD34+ cells transplanted for D-VTd vs VTd was 3.3×106/kg vs 4.3×106/kg. Hematopoietic reconstitution rates were high and similar for transplanted pts receiving D-VTd vs VTd (99.8% vs 99.6%). For D-VTd vs VTd, a median (range) of 13.0 (6-54) vs 13.0 (4-43) days was required to achieve sustained ANC &gt; 500 cells/mm3, and a median (range) of 14.0 (2-56) vs 12.0 (1-47) days was required to achieve sustained platelets &gt; 20,000 cells/mm3 without transfusion. Conclusions: SC mobilization and collection was feasible with D-VTd induction. Adding DARA to VTd allowed successful transplantation in pts with TE NDMM. Clinical trial information: NCT02541383.