MRD-negative Rates Research Articles

Phase II study of the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone as salvage therapy in relapsed/refractory multiple myeloma

The combination of daratumumab, pomalidomide and dexamethasone (DPd) has previously demonstrated deep and durable responses, including high rates of MRD negativity, in a heavily pretreated patient population. Quadruplet regimens offer an opportunity to further improve upon these results. We report preliminary findings from an ongoing phase 2 multicenter trial of the addition of ixazomib to the combination of DPd in patients with relapsed/refractory multiple myeloma. The primary objective is to determine overall response rate and the safety and tolerability of this novel regimen.

Profound MRD negativity rates after frontline tandem autologous-allogeneic stem cell transplantation followed by bortezomib maintenance in high-risk or young myeloma patients

Prior studies suggest that allogeneic (allo) stem cell transplant (SCT) can overcome high-risk (HR) cytogenetics associated with poor outcome in multiple myeloma (MM). Despite being the only potentially curative therapy for MM, the use of allo SCT remains controversial due to unacceptably high nonrelapse mortality (NRM; 10-15%), morbid extensive chronic graft-versus-host disease (cGVHD; 50-80%) and high relapse rates (50-60%). We hypothesized that bortezomib (BTZ) after allo SCT might decrease both relapse and cGVHD in HR disease and young MM patients (pts) who have the greatest loss in years of life from MM.

Post-transplant minimal residual disease assessment in Multiple myeloma

MRD status was assessed in MM patients undergoing high-dose Melphalan and autologous stem cell transplantation (ASCT). The primary objective of this study was to determine the MRD negativity rate in this population.

Abstract 561: Discovery of a potential best-in-class anti-CD38 therapeutic utilizing Fc multimerization

Abstract CD38 targeting antibodies are at different phases of clinical development, with daratumumab already approved as monotherapy and in combination with standards of care in multiple myeloma (MM). Anti-CD38 monoclonal antibodies (mAbs) induce tumor cell depletion in part by Fc-dependent effector mechanisms such as antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). However, not all MM patients achieve minimal residual disease (MRD)-negativity and similar clinical response. In addition, some patients on daratumumab develop resistance due to reduced cell surface CD38 and high levels of complement inhibitors (CD55 and CD59). We have leveraged Fc multimerization technology (Ortiz et al Sci Transl Med. 2016; 8: 365) to generate an optimized platform (SIF; selective immunomodulator of Fc receptors) that utilizes the valency effect of Fc multimerization to enhance binding to the Fcγ receptors and complement. We combined the Fab-region of CD38 targeting mAb to SIF platform to generate an anti-CD38 SIFbody to enhance immune and complement mediated cytotoxicity against tumor cells. In several human tumor cell line-based cytotoxic assays using primary human effector cells (NK cells and macrophages) and complement, the anti-CD38 SIFbody demonstrates up to 10-fold increase in efficacy and ≥16-fold increase in potency compared to daratumumab and the surrogate therapeutic anti-CD38 mAb (TAK-079). In isolated whole human blood incubated with tumor cells, the anti-CD38 SIFbody demonstrated 40-100 fold increase in potency and 2-3 fold increase in efficacy. In bone marrow cells isolated from MM patients with >80% plasma cells anti-CD38 SIFbody showed better potency and a 3-5 fold increased efficacy (with 100% plasma cell elimination) than daratumumab, suggesting the SIFbody may be more suitable molecule for achieving greater MRD-negativity rates in MM patients. Daratumumab fails to induce CDC against tumor cell lines with low CD38 and high CD55 and CD59, however the SIFbody achieves 100% efficacy in such settings, suggesting this molecule may be effective in patients who are developing resistance to treatment. In single dose pharmacodynamic and tolerability studies in cynomolgus monkeys SIFbody demonstrated up to 5-fold increase in B cell depletion from peripheral blood compared to TAK-079 across all dose ranges (0.3, 1, & 3 mg/kg) tested without any adverse events. Therefore, by leveraging our Fc multimerization technology we have generated a differentiated potential best-in-class anti-CD38 therapeutic. Citation Format: Amit Choudhury, Daniel F. Ortiz, Shannon Argueta, Kevin Garofalo, Jonathan C. Lansing, Utsav Jetley, Danice Wilkins, Carlos Bosques, Edward Cochran, Naveen Bhatnagar, Jay Duffner, Abhinav Gupta, Stan Lee, Karunya Srinivasan, Viraj Parge, Radouane Zouaoui, Jason Wang, Anthony M. Manning. Discovery of a potential best-in-class anti-CD38 therapeutic utilizing Fc multimerization [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 561.

A High-Sensitivity 10-Color Flow Cytometric Minimal Residual Disease Assay in B-Lymphoblastic Leukemia/Lymphoma Can Easily Achieve the Sensitivity of 2-in-106 and Is Superior to Standard Minimal Residual Disease Assay: A Study of 622 Patients.

Flow-cytometric minimal residual disease (FC-MRD) monitoring is a well-established risk-stratification factor in B-lymphoblastic leukemia/lymphoma (-B-ALL) and is being considered as a basis for deintensification or escalation in treatment protocols. However, currently practiced standard FC-MRD has limited sensitivity (up to 0.01%) and higher false MRD-negative rate. Hence, a highly sensitive, widely applicable, and easily reproducible FC-MRD assay is needed, which can provide a reliable basis for therapeutic modifications. A 10-color high-event analysis FC-MRD assay was studied for the evaluation of MRD status at postinduction, (PI; day-35), postconsolidation, (PC; day-78), and subsequent follow-up time-points (SFU) in bone marrow samples from pediatric B-ALL. One-thousand MRD samples (PI-62.2%; PC-26.5%; and SFU-11.3%) from 622 childhood B-ALL patients were studied. High-event analysis was performed with median 4,452,000 events (range, 839,000 to 8,866,000 events) and >4 million events in 71% samples. MRD was measurable in 43.2% of PI-samples, in 29.4% PC-samples, and in 32.7% SFU-samples. To simulate comparison with standard FC-MRD, we reanalyzed MRD results gating only first 500,000 and first 1000,000 events in 122 PI-MRD positive samples with MRD levels <0.02%. Of these samples gated for 500,000 events and 1000,000 events, 32% and 21.3% were found to be falsely MRD-negative, respectively. We report an easily reproducible high-sensitivity 10-color FC-MRD assay with the sensitivity of 2-in-106 (0.0002%). It allowed the detection of low-level MRD in samples, which could have been reported negative using the standard FC-MRD with limited event analysis. Thus, this high-sensitivity MRD-methodology can provide a reliable basis for therapeutic modifications in B-ALL. © 2019 International Clinical Cytometry Society.

PS950 EFFICACY AND SAFETY OF INOTUZUMAB OZOGAMICIN IN PATIENTS WITH RELAPSED/REFRACTORY B‐CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED IN THE INO‐VATE TRIAL: OUTCOMES BY SALVAGE‐TREATMENT PHASE

Background:Inotuzumab ozogamicin (InO) is a humanized anti‐CD22 antibody conjugated to calicheamicin. Upon binding to CD22 on acute lymphoblastic leukemia (ALL) cells, InO is internalized and calicheamicin is released, resulting in DNA double‐strand cleavage and apoptosis. Single agent InO is highly effective in relapsed/refractory (R/R) ALL, having shown clinical activity in a Phase II study. In a Phase III randomized study (INO‐VATE), InO induced a higher response rate and better overall survival than standard of care (SoC).Aims:To assess outcomes by salvage line, for patients (pts) receiving InO vs SoC in the INO‐VATE study.Methods:In this global, open‐label, randomized trial, pts aged ≥18 years with R/R, CD22‐positive, and Philadelphia chromosome (Ph)+ or Ph‐ B‐cell ALL due to receive first (S1) or second salvage (S2) therapy were eligible for enrolment. Pts were randomized 1:1 to receive InO or the investigator's choice of SoC. Pts enrolled were stratified by age (&lt;55 years vs ≥55 years), salvage‐treatment phase (S1 vs S2), and duration of first remission (&lt;12 months vs ≥12 months). A total of 326 pts (InO: 164; SoC: 162) were randomized (intention‐to‐treat population). As per the case report form, pts received either S1 (InO: 111 pts; SoC: 102 pts) or S2 (InO: 51 pts; SoC: 59 pts) treatment. Data as of January 4, 2017 are presented.Results:Baseline characteristics were well balanced between InO and SoC (for both S1 and S2), with some exceptions for S2: compared with InO, a higher proportion of SoC pts were Ph+(17.6% vs 25.4%) and a lower proportion of SoC pts had complex cytogenetics (33.3% vs 16.9%). Responses stratified by S1 vs S2 are presented (Table). Rates of complete remission (CR)/CR with incomplete hematologic recovery (CRi) and rates of MRD negativity (among pts with CR/CRi) were significantly higher for InO compared with SoC, for both S1 and S2 (all P &lt; 0.02). The difference in rates of CR/CRi and MRD negativity between InO and SoC tended to be larger for S1 but these differences were not statistically significant. PFS was significantly longer for InO compared with SoC, for both S1 and S2 (both P &lt; 0.001). OS was longer for InO compared with SoC for S1 and S2; this difference was statistically significant for S1 (P = 0.035) but not S2 (P = 0.353). The proportion of patients proceeding to allogeneic stem cell transplantation (SCT) was significantly higher for InO compared with SoC, for both S1 and S2 (both P &lt; 0.005). In each treatment arm, the proportion of patients proceeding to SCT was higher for S1 than for S2; the differences between S1 and S2 were not statistically significant in either treatment arm.The incidences of several classes of AEs were similar for S1 vs S2, for both InO and SoC; these included grade ≥3 AEs (InO: 91.0% vs 90.2%; SoC: 95.7% vs 98.0%), grade ≥3 thrombocytopenias (InO: 41.4% vs 39.2%; SoC: 60.2% vs 57.1%), and grade ≥3 febrile neutropenias (InO:24.3% vs 29.4%; SoC: 57.0% vs 49.0%). Hepatobiliary disorders (grade ≥3) were less common in S1 vs S2, for both the InO (12.6% vs 25.5%) and SoC (7.5% vs 10.2%) arms. Veno‐occlusive disease (VOD) was less common in S1 than S2 for the InO (9.9% vs 15.7%) arm but not for the SoC arm (2.2% vs 2.0%).Summary/Conclusion:InO is highly effective and provides significant clinical benefit compared with SoC in patients with R/R ALL. Analysis by salvage status indicates that InO provided higher efficacy and better outcomes when utilized as first salvage therapy. Hepatotoxicity was more common in S2 than S1 for both InO and SoC.image

How to approach CLL in clinical practice.

How to approach CLL in clinical practice.

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 &amp; 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.

PF594 BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE VS BORTEZOMIB-THALIDOMIDE-DEXAMETHASONE INDUCTION: INTEGRATED ANALYSIS OF RANDOMIZED CONTROLLED TRIALS IN TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA

Background: European and US guidelines recommend VRD and VTD for pts with TE NDMM. However, no RCTs have directly compared VRD vs VTD to date. Aims: To evaluate efficacy and safety of VRD vs VTD in TE NDMM via integrated analysis. Methods: Prospective, phase 3 RCTs evaluating VRD or VTD induction (every 3 or 4 wks) in TE NDMM before ASCT were included if they met pre-defined eligibility criteria (including access to pt-level data). Primary endpoint was noninferiority of ≥ VGPR rate post induction. Secondary endpoints included safety and ≥ VGPR rate during induction and post ASCT. Exploratory endpoints were PFS and MRD negativity. Statistical methods were based on propensity score (PS). Pts with missing baseline values for the variables used for the PS analyses were excluded. Results: Four studies met the eligibility criteria: VRD, PETHEMA GEM (GEM)2012 and IFM 2009; VTD, GEM2005 and IFM 2013–04. GEM2005 and GEM2012, used for the primary analysis, had a symmetrical induction design (six 4-wk cycles then ASCT). IFM studies were considered supportive due to their variable number of cycles (3 VRD cycles before ASCT vs 8 VRD cycles in IFM 2009 and 4 VTD cycles before ASCT in IFM 2013–04). IFM analyses compared the IFM 2009 VRD non-ASCT of vs IFM 2013–04 VTD arm. The VRD and VTD PS-stratified cohorts of the GEM and IFM studies had no clinically meaningful differences in baseline characteristics. The integrated analysis met its primary endpoint (non-inferiority) and demonstrated a statistically significant and clinically relevant ≥ VGPR rate improvement after 6 cycles of induction with VRD vs VTD (66.3% vs 51.2%; P = .00281; Figure) in the GEM studies. IFM non-inferiority results had similar ≥ VGPR rates for VRD vs VTD by 4 cycles (12 wks; 57.1% vs 56.5%). Responses deepened during induction in the GEM studies. Among the 378 VRD pts who started cycle 6, ≥ VGPR rate increased from 54.5% by 3 cycles of induction to 62.7% by 4 cycles, and to 70.1% by 6 cycles and post induction. Of the 111 VTD pts, these rates were 35.1%, 40.5%, and 55.9%, respectively. The ≥ VGPR rate post-ASCT (74.4% vs 53.5%) and MRD negativity (10–4) rates post induction (46.7% vs 34.9%) and post ASCT (62.4% vs 47.3%) support the benefit of VRD vs VTD. Safety was as previously reported for these studies. Peripheral neuropathy (PN) can limit VRD and VTD Tx duration. In GEM studies, SC vs IV administration of BORT may have contributed to lower rates of PN (grouped term) with VRD vs VTD (grade 3/4, 5.5% vs 15.4%; grade ≥ 2, 20.7% vs 44.6%). TEAEs led to dose reduction (21.6% vs 35.4%) and study or Tx discontinuation (3.1% vs 9.2%) less frequently in the VRD vs VTD cohorts. In IFM studies, TEAEs led to dose reduction more frequently (32.9% vs 18.3%) and Tx discontinuation less frequently (6.5% vs 11.2%) with VRD vs VTD. Grade 3/4 PN (grouped term) was 5.9% vs 15.4%, whereas grade ≥ 2 events were similar (30.3% vs 27.2%), which may reflect BORT administration in these IFM studies (IV for VRD vs SC for VTD, respectively).Summary/Conclusion: Six cycles of VRD induction led to a significantly higher ≥ VGPR rate than VTD in TE NDMM. Deepening responses and MRD negativity further support the benefit of VRD over VTD. TEAEs in the GEM and IFM studies were generally consistent with the known safety profiles of the individual agents. TEAEs with the VRD regimen were manageable, and the overall tolerability profile compared well with VTD, with lower rates of TEAEs leading to discontinuation. This analysis supports the favorable benefit-risk profile with VRD over VTD as induction Tx in TE pts with NDMM.

PF596 EFFICACY AND SAFETY OF DARATUMUMAB, BORTEZOMIB, AND DEXAMETHASONE (D‐VD) IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED SUBGROUP ANALYSIS OF CASTOR BASED ON CYTOGENETIC RISK

Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P &lt;0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P &lt;0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P &lt;0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P &lt;0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P &lt;0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

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]

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]

Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA.

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts &lt;75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (&lt;75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for &lt;75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both &lt;75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (&lt;75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in &lt;75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [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 and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk: Updated subgroup analysis of CASTOR.

8040 Background: MM patients (pts) with high cytogenetic risk have poor outcomes. In CASTOR, D-Vd prolonged progression-free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited tolerability in RRMM pts. We conducted a subgroup analysis of D-Vd vs Vd in CASTOR, based on cytogenetic risk. Methods: Pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next-generation sequencing (NGS) and fluorescence in situ hybridization/karyotype testing. High-risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)-risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ assay V2.0. Results: In CASTOR (D-Vd, n = 251; Vd, n = 247), high-risk was confirmed in 26.7% and 25.9% of pts in the D-Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D-Vd prolonged PFS vs Vd in pts with high- (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24-0.65]; P = 0.0002) or std-risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20-0.37]; P &lt; 0.0001). Higher rates of ORR, MRD negativity, and sustained MRD negativity were seen with D-Vd vs Vd (Table). D-Vd prolonged PFS in first relapse pts (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14-0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11-0.29]; P &lt; 0.0001) and PFS2 vs Vd (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37-0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32-0.59]; P &lt; 0.0001) regardless of risk. Additional data will be presented. Conclusions: Adding daratumumab to Vd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Vd. These findings support use of D-Vd for high-risk RRMM. Clinical trial information: NCT02136134. [Table: see text]

Phase II results of mitoxantrone in combination with clofarabine in children with relapsed/refractory acute leukemia.

7036 Background: Despite improved outcomes in pediatric acute leukemia, those who relapse or are refractory do poorly. Mitoxantrone and clofarabine as single agents have proven efficacy in pediatric leukemia. Our previously reported phase I results demonstrated the MTD of this combination to be clofarabine 35 mg/m2 x 5 days and mitoxantrone 12 mg/m2 x 4 days. Here, we present our phase II data utilizing the RP2D. Methods: Prospective, open label safety and efficacy study (NCT01842672). Patients 0-30.99 yr old with ALL or AML with relapse OR induction failure were given 1 to 3 cycles of clofarabine (RP2D 35 mg/m2/day) Day 1-5, in combination with mitoxantrone 12 mg/m2/day on Day 3-6. Dexrazoxane was given prior to mitoxantrone. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total 21 patients have enrolled at the RP2D clofarabine. Median age 8 yrs (0.5-22 yrs). Patient characteristics include 13 ALL (8=Induction Failure, 4=Relapse 1, 1=Relapse 2) and 8 AML (4=Induction Failure, 4=Relapse 1). Overall regimen was well tolerated. One patient with grade IV prolonged myelosuppression. Median time to neutrophil recovery was 24 days. Eighteen of 21 (85.7%) patients achieved an MRD negative CR. Three patients died of progressive disease. All 18 patients achieving CR went on to receive an allogeneic HSCT with no documented transplant associated toxicities attributed to prior MITCL therapy. One patient developed MRD (2.6%) at Day +270 post HSCT and underwent subsequent therapy. The remaining 17 patients continue to demonstrate MRD negativity. Two patients died of transplant associated complications. The overall and event free survival for patients who responded to therapy are 89% (CI95 0.64-0.98) and 83% (CI95 0.58-0.96), respectively at a median follow up time of 24 months (range 2-58). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35 mg/m2 clofarabine in children with poor risk acute leukemias. Phase II data is encouraging with 85.7% MRD negative CR rate in leukemic patients allowing patients to safely proceed to AlloHSCT with a 2 year survival rate of 89%. Longer follow up and a larger cohort is planned and ongoing. Clinical trial information: NCT01842672.

Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): Updated subgroup analysis of POLLUX based on cytogenetic risk.

8038 Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P &lt;0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66]; P &lt;0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72]; P &lt;0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]

Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (&lt;18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

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.

The MRD-Negativity Rate Measured By Flow Cytometry after the 1st and the 2nd Induction Course Among CR AML Patients from Different Cytogenetic Subgroups Does Not Differ Though the Morphological CR Achievement Does

Background. The recent ELN recommendations (2017) have introduced new criteria of response in AML - complete remission with MRD-negativity (CR/MRD-neg). It's a well-known fact that AML with different cytogenetics has different chemosensitivity, and so - CR rate in patients with favorable, intermediate or poor cytogenetic markers substantially differs. MRD negativity corresponds to more favorable long-term results in CR patients, but it's not clear whether the MRD-negativity rate is the same in favorable, intermediate or poor risk AML pts. As it is still poorly understood whether the high risk AML patients need classical «7+3» induction, we introduced a new approach for this cohort of patients - prolonged low-dose cytostatic exposure after hypomethylating priming.Aim. To evaluate the MRD-negativity in CR AML patients from different cytogenetic subgroups after the first classical non-intensive induction: «7+3», «Aza+7+3», «Aza-Ida-Ara-C», and the second induction differed by intensity.Materials and patients. 83 AML patients with a median age of 37 y.o. (17-59), m/f 31/52, after achieving CR (69 pts) were included in the MRD study in the National Research Center for Hematology. From March 2016 till Dec 2017, 49 pts disregarding cytogenetic risk were treated with «7+3» as the first induction course (Dauno 60 mg/m2 1-3 days, Ara-C 100 mg/m2 bid 1-7 days). The second induction course for these pts was «7+3» with continuous Ara-C infusion (200 mg/m2 1-7 days). Since Dec 2017 till July 2018 in all patients epigenetic priming with 3 days of Azacitidine (75 mg/m2) was applied additionally in order to obtain the cytogenetic results prior to cytostatic exposure. All patients were tested by molecular markers (FLT3, CEBPa, mNPM1) but this data did not influence the treatment choice. 8 pts from favorable/intermediate cytogenetic risk group after Aza-prephase have got «7+3» (Dauno 60 mg/m2 4-6 days, Ara-C 200 mg/m2 by continuous infusion, 4-10 days), and 13 pts from poor cytogenetic risk group (complex, -7,-5, inv3, monosomy) after Aza-priming received prolonged low-dose schedule (Ida 3 mg/m2 4-10 days, Ara-C 10 mg/m2 bid sc 4-17 days). The second induction course for favorable/intermediate risk group was FLAG-Ida, for poor risk group - the same as the 1st induction. MRD testing was performed by 6-color flow cуtometry with FACS Canto II (BD) machine after 1st and 2nd chemotherapy courses. The rate of MRD-negativity was calculated among CR patients.Results. Totally among 83 patients CR was achieved in 83%, early death was registered in 6% and refractory AML was diagnosed in 11%. The induction and MRD testing results after the 1st and the 2nd induction course according to prognostic group and treatment arm are demonstrated in the Table.1. Morphological CR rate differs substantially in patients from favorable/intermediate and poor risk by any treatment approach (p=0,04). The prolonged low-dose induction with Aza-prephase induced the same numbers of CRs as the classical «7+3»: 69% vs 46% (p=0,42). Epigenetic priming provided identical MRD-negative CRs in all treatment and cytogenetic groups: 75% vs 62% in favorable/intermediate risk group (p=0,29), 67% vs 50% in poor risk (p=0,62). The second intensive induction with Flag-Ida in favorable/intermediate risk group did not increase the portion of MRD-neg CR pts in comparison with «7+3»: 88% vs 71% (р=0,14). Early relapse rate through all groups showed comparable results.Conclusion. Though the morphological CR achievement is highly influenced by cytogenetic subgroup in AML, the MRD-negativity rate among CR pts by flow cytometry after the 1st and the 2nd induction course is similar. The de-intensification of induction for poor risk group did not lead to the deterioration of therapy efficacy and provided the same rate of MRD-negativity. The 2nd intensified induction after «7+3» did not increase the MRD-negativity in CR pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.