Standard Risk Pts Research Articles

CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m 2 as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials. The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%. Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms. 477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible. In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34). Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13). The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population. We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms. The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.

Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients

Background. The current standard treatment for transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation. The phase III IsKia trial assessed efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd. Methods. TE NDMM pts aged <70 years were enrolled and randomized. IsaKRd pts received 4 28-day cycles of Isa: 10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2-4; K: 20 mg/m 2 IV day 1 cycle 1, followed by 56 mg/m 2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2-4; R: 25 mg PO daily days 1-21; d: 40 mg PO days 1, 8, 15, 22; MEL200-ASCT and 4 consolidation cycles with IsaKRd at the same schedule. KRd pts received 4 KRd induction cycles; MEL200-ASCT and 4 KRd consolidation cycles (K, R and d at the same schedule as in the IsaKRd arm). The primary endpoint was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10 -5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all pts who achieved at least a very good partial response (≥VGPR). Key secondary endpoints were the rate of NGS MRD negativity (10 -5) after induction and PFS. MRD rates were evaluated in an ITT analysis (pts with missing MRD data or who achieved ≤PR were considered as MRD positive). The data cut-off for the analysis was May 22, 2023. Results. 302 pts were enrolled and randomized (151 in both the IsaKRd and KRd arms). Pt characteristics were well balanced between the two arms: median age was 61 vs 60 years, respectively; 18% vs 19% of pts had high-risk (HiR) cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)]; 9% vs 8% had ≥2 HiR CA [double hit; including del(17p), t(4;14), t(14;16) and gain/amp(1q)]. In ITT analysis, the rates of MRD negativity at the 10 -5 cut-off after consolidation (primary endpoint) were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd; the respective rates of MRD negativity at the 10 -6 cut-off were 67% vs 48% (OR 2.29; p<0.001); consistent MRD results were detected by next-generation flow. ≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms. The MRD negativity advantage, both at 10 -5 and 10 -6, was retained in all subgroups analyzed ( Figure), with similar benefit in pts with standard-risk (SR) and HiR features. In particular, the 10 -5 MRD negativity rates with IsaKRd were 76% in HiR and 77% in double-hit pts, comparable to the one in SR pts (79%). In the KRd arm, the 10 -5 MRD negativity rates were 58% in HiR and 53% in double-hit pts, inferior to the one in SR pts (70%). The 10 -6 MRD negativity rates with IsaKRd were 72% in HiR, 77% in double-hit pts and 67% in SR pts. The MRD negativity rate after induction (first key secondary endpoint) was also significantly higher with IsaKRd vs KRd (10 -5: 45% vs 26%, OR 2.34, p<0.001; 10 -6: 27% vs 14%, OR 2.36, p=0.004), with a consistent benefit in all subgroups. After induction, the MRD negativity rates in HiR and double-hit pts treated with IsaKRd were: 10 -5, HiR 60%, double-hit 54%; 10 -6, HiR 40%, double-hit 31%. The MRD negativity rates after ASCT were also significantly better with IsaKRd vs KRd (10 -5: 64% vs 49%, OR 1.93, p=0.006; 10 -6: 52% vs 27%, OR 3.01, p<0.001), with a consistent advantage in all subgroups. At the current follow-up (median, 20 months, IQR 18-23), there was no difference in PFS (95% at 1 year in both arms). 55% of pts had ≥1 hematologic adverse events (AEs) with IsaKRd vs 43% with KRd; main grade 3-4 hematologic AEs in IsaKRd vs KRd were neutropenia (37% vs 22%) and thrombocytopenia (15% vs 17%). 41% of pts had ≥1 non-hematologic AEs with IsaKRd vs 37% with KRd, including infections (16% vs 12%), gastrointestinal (7% vs 5%), vascular (2% vs 7%) and cardiac events (1% vs 4%). Discontinuation for toxicity was 6% in IsaKRd vs 5% in KRd arms; treatment-related deaths were 4 with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and 1 with KRd (septic shock). Conclusion. In TE NDMM pts, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase as compared to KRd, with no new safety concerns. This benefit was retained in HiR pts.

Molecular Analysis at Relapse of Patients Treated on the Ibrutinib and Rituximab Arm of the National Multi-Centre Phase III FLAIR Study in Previously Untreated CLL Patients

Background The NCRI FLAIR trial confirmed ibrutinib + rituximab (IR) improved progression free survival (PFS) over FCR in untreated CLL. Durable responses are achieved on continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy, but acquired resistance mutations in BTK, and PLCG2 are reported in up to 80% of relapsed/refractory patients (pts) failing BTKi often detected at low variant allele frequencies (VAF) several months before relapse. Their frequency, evolutionary dynamics, and relevance to progression in the upfront-treatment setting are poorly characterised. We present the observed clonal evolution in standard risk pts with disease progression (DP) on IR, integrating next generation sequencing (NGS) with serial measurable disease monitoring by flow cytometry, and tracking individual BTK mutations ( BTKmt) by digital droplet PCR (ddPCR) from initial detection to DP. Methods 771 randomised pts to FCR (n=385) or IR (n=386). Pts treated with IR received rituximab at 375 mg/m 2 on D1/C1 and 500 mg/m 2 on D1/C 2-6 of every 28-days. I was given orally at 420 mg/day for up to 72 mo. All 61 DP pts on IR were included in the analysis. DNA from baseline and progression peripheral blood (PB) samples were processed for sequencing of 33 genes recurrently mutated in lymphoid malignancies including BTK (exon 15) and PLCG2 (exons 19-20) with an Illumina MiSeq. Variants were reported down to minimum VAF of 3-5% and coverage of 100X. Low VAF (3-6%) BTKmt were validated by ddPCR using the QX200 ddPCR protocol (sensitivity 1-0.1%). ddPCR was used for the individual serial analysis at baseline and 6 monthly in pts with confirmed BTKhot spot mutations (p.C481S (c.1441T>A, c.1442G>C)), p.C481R (c.1441T>C), p.T474I (c.1421C>T) and presented with concurrent PB MRD monitoring using highly sensitive flow cytometry with a detection limit of one CLL cell in 100,000leukocytes (0·001%). Results 61/386 pts progressed after a median follow up of 44 mo. on I with 50/61 pts progressing after >24 mo. No deaths were recorded before DP. 47/61 IR DP samples were sequenced by MiSeq, 10 further samples with low disease burden were only analysed by ddPCR for hotspot BTKmt. 7/47 sequenced at baseline and DP, developed new isolated mutations in ATM, SF3B1, NOTCH1, BIRC3, BRAF, KLF2, CDKNB1 or TRAF2. The most frequently mutated gene at DP was BTK. From 57/61 sequenced samples at DP, 7 were found to have hotspot BTKmt most with multiple mutations (Fig/Table). No BTKmt detected at DP were detected at baseline by NGS or ddPCR. One pt had a PLCG2 mutation at DP (VAF 33.3%). The 8 BTKmt/ PLCG2 mt IR progressions were mostly in late DP pts (median 60.3 mo.) compared to a median time to DP of 54.3 mo in BTKwt/ PLCG2wt pts. The majority of BTKmt IR DP (5/7) were reported after stopping therapy at 72 mo. 6 monthly samples during I were studied for BTKmt. Evolution of BTKmt in the context of increasing disease burden on I, shows a steady rise in the VAF preceding frank DP (Fig). 148/386 (38.3%) IR pts were 100% homologous to germline IGHV unmutated and 31/148 (20.9%) progressed. 12/15 pts, who acquired additional mutations at DP were IGHV unmutated and 9/12 were 100% homologous to germline including 6/8 with acquired BTK/PLCG2 mutations. Conclusion In upfront IR treated standard risk CLL pts 15.8% progressed (61/386), the majority late. Only 13% of the IR DP cohort (8/61) had a BTK/PLCG2 mutation, suggesting other non- BTK/PLCG2 mutations or disease related factors as contributors to DP after initial response in the upfront setting. Interestingly, the background mutation profile did not change from baseline in those who acquired BTK/PLCG2 mutations at DP, but 7/15 acquired non- BTK/ PLCG2mutations at DP. The majority of IR DP with BTK/PLCG2 mutations (6/8), were 100% homologous to germline IGHV unmutated, suggesting an inherent higher risk disease profile as a risk factor for acquiring BTKmt with prolonged BTKi therapy. BTK/PLCG2 mutations were enriched amongst very late progressors with 6/8 pts progressing shortly after stopping therapy at 72 mo., which is later than previously reported for relapsed/refractory CLL pts.

Bortezomib-Melphalan-Prednisone (VMP) Vs. Lenalidomide-Dexamethasone (Rd) in Transplant-Ineligible Real-Life Multiple Myeloma Patients: Updated Results of the Randomized Phase IV Real MM Trial

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for del(17p), t(14;16), or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Upfront Autologous Stem Cell Transplantation (ASCT) Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Consolidation in Transplant-Eligible, Newly Diagnosed (NDTE) Multiple Myeloma (MM): Results of the Cardamon Study According to Cytogenetic Risk

Upfront Autologous Stem Cell Transplantation (ASCT) Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Consolidation in Transplant-Eligible, Newly Diagnosed (NDTE) Multiple Myeloma (MM): Results of the Cardamon Study According to Cytogenetic Risk

Inferior Outcomes for Multiple Myeloma (MM) Patients (pts) Harbouring t(11;14) and the Promise of Venetoclax, Real-World Australian Retrospective

Introduction/ BackgroundTraditionally, MM harbouring t(11;14) is considered standard risk disease. In the era of novel therapies, however, pts with t(11;14) are reported to have inferior outcomes to other standard risk pts. Evidence of response to the BCL-2 inhibitor, Venetoclax (Ven), has further increased interest in understanding outcomes of t(11;14) pts. In this study, we aimed to describe the historical outcomes of t(11;14) MM and response to Ven in a real-world cohort of Australian pts.MethodsThis was a retrospective, multicentre study conducted by members of the Australasian Leukaemia and Lymphoma Group, Myeloma Working Party. Cases were identified by interrogation of cytogenetics/FISH database from 2010 to 2019 inclusive. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate.ResultsSeventy-four pts [median age 65 years (yrs), range (43-85)] were identified across seven centres. 43% pts had ISS Stage III MM with 88% harbouring additional cytogenetic abnormalities, incl. 13% with gain in 1q and 12% with del(17p). The majority (81%) of pts received proteasome inhibitor (PI)-based 1 st line therapy with 60% having an upfront autologous stem cell transplant (ASCT) and 54% having immunomodulatory drug (IMiD)-based maintenance therapy. Two patients received an allogeneic stem cell transplant after ASCT. The overall response rate (ORR) was 86% with 38% achieving very good partial response (VGPR) or better. The median progression free survival-1 (PFS-1) was 1.91 yrs (95% CI 1.73-2.56) [PI-based, n=60, PFS 1.84yrs (95% CI 1.61-2.41) vs IMiD-based, n=5, PFS 4.58yrs (95% CI 1.16-5.51), HR 0.68 p=0.45] The median overall survival (OS) was 5.35 yrs (95% CI 4.12-6.56). Second and third line therapy was predominantly IMiD-based (see Table 1) with recent introduction of anti-CD38 monoclonal antibodies (mAbs). Median PFS-2 was 0.77 yrs (95% CI 0.39-0.98) while median PFS-3 was 0.65 yrs (95% CI 0.34-1.16). Eleven pts (median 3 prior lines of therapy) were given Ven [Six pts in combination with PI, three with PI and mAbs and two with dexamethasone]. ORR to Ven was 55% with 45% achieving VGPR or better. Median PFS with Ven was 0.54 yrs (85% CI 0.05-2.17). Median PFS for patients with 1-4 lines (n=6) was 1.22 years and median PFS for patients with 5 lines or more (n=5) was 0.54 years, HR 0.56 (95% CI 0.12-2.5).ConclusionFor pts harbouring t(11;14), the duration of response to PI-based 1 st line therapy is suboptimal even with the use of ASCT consolidation in the majority of patients. Despite multiple prior lines of therapy, Venetoclax shows promising results and every effort should be made for early identification of this cytogenetic lesion. Further studies are required to examine the impact of novel triplet and quadruplet combination therapy and use of venetoclax early in the disease course of this sub-group of patients. [Display omitted] DisclosuresTalaulikar: Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Roche: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Gibbs: Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria; AbbVie: Consultancy.

OAB-004: Carfilzomib-based induction/consolidation with or without autologous transplant and Lenalidomide (R) or Carfilzomib-Lenalidomide (KR) maintenance: efficacy in high-risk patients of the FORTE study

<h3>Introduction</h3> Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. <h3>Methods</h3> Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. <h3>Results</h3> 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). <h3>Conclusion</h3> KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.

P-051: Inferior outcomes for Multiple Myeloma (MM) patients (pts) harbouring t(11;14) and the promise of venetoclax, real-world Australian retrospective

<h3>Background</h3> Traditionally, MM harbouring t(11;14) is considered standard risk disease. In the era of novel therapies however, pts with t(11;14) are reported to have inferior outcomes to other standard risk pts. Evidence of response to the BCL-2 inhibitor, Venetoclax (Ven), has further increased interest in understanding outcomes of t(11;14) pts. Here we aim to describe the historical outcomes of t(11;14) MM and response to Ven in a real-world cohort of Australian pts. <h3>Methods</h3> This was a retrospective, multicentre study conducted by members of the Australasian Leukaemia and Lymphoma Group, Myeloma Working Party. Cases were identified by interrogation of cytogenetics/FISH database from 2010 to 2019 inclusive. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate. <h3>Results</h3> Seventy-four pts [median age 65 years (yrs), range (43-85)] were identified across seven centres. 43% pts had ISS Stage III MM with 88% harbouring additional cytogenetic abnormalities, incl. 13% with gain in 1q and 12% with del(17p). The majority (81%) of pts received proteasome inhibitor (PI)-based 1st line therapy with 60% having an upfront autologous stem cell transplant (ASCT) and 54% having immunomodulatory drug (IMiD)-based maintenance therapy. Two patients received an allogeneic stem cell transplant after ASCT. The overall response rate (ORR) was 86% with 38% achieving very good partial response (VGPR) or better. The median progression free survival-1 (PFS1) was 1.91 yrs (95% CI 1.73-2.56) [PI-based, n=60, PFS 1.84yrs (95% CI 1.61-2.41) vs IMiD-based, n=5, PFS 4.58yrs (95% CI 1.16-5.51), HR 0.68 p=0.45] The median overall survival (OS) was 5.35 yrs (95% CI 4.12-6.56). Second and third line therapy was predominantly IMiD-based with recent introduction of anti-CD38 monoclonal antibodies (mAbs). Median PFS-2 was 0.77 yrs (95% CI 0.39-0.98) while median PFS-3 was 0.65 yrs (95% CI 0.34-1.16). Eleven pts (median 3 prior lines of therapy) were given Ven [Six pts in combination with PI, three with PI and mAbs and two with dexamethasone]. ORR to Ven was 55% with 45% ≥ VGPR. Median PFS with Ven was 0.54 yrs (85% CI 0.05-2.17). Median PFS for patients with 1-4 lines (n=6) was 1.22 years and median PFS for patients with 5 lines or more (n=5) was 0.54 years, HR 0.56 (95% CI 0.12-2.5). <h3>Conclusion</h3> For pts harbouring t(11;14), the duration of response to PI-based 1st line therapy is suboptimal even with the use of ASCT consolidation in the majority of patients. Despite multiple prior lines of therapy, Venetoclax shows promising results and every effort should be made for early identification of this cytogenetic lesion. Further studies are required to examine the impact of novel triplet and quadruplet combination therapy and use of venetoclax early in the disease course of this sub-group of patients.

Daratumumab, Bortezomib, and Dexamethasone (DVd) Versus Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of Castor

Daratumumab, Bortezomib, and Dexamethasone (DVd) Versus Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of Castor

A Randomized Study of Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Cyclophosphamide-Dexamethasone Induction in Newly Diagnosed Myeloma Patients Eligible for Transplant: High Efficacy in High- and Standard-Risk Patients

Background :Proteasome inhibitor-based induction is currently considered standard of care in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for high-dose therapy and transplant (MEL200-ASCT). The second-generation proteasome inhibitor Carfilzomib proved to be effective, either in combination with Lenalidomide-Dexamethasone (KRd) or with Cyclophosphamide-Dexamethasone (KCd) (Jakubowiak, Blood 2012; Bringhen, Blood 2014). Aim : The primary objective of this analysis was to compare the efficacy of KRd vs KCd induction in pts eligible for transplantation. The secondary aim was to evaluate the efficacy of KRd vs KCd in different subgroups of pts according to prognostic features, focusing specifically on high-risk pts. Methods : NDMM pts Results : At data cut-off, 309 pts were randomized to KRd vs 154 pts to KCd. Pts characteristics were well balanced: median age was 57 years in both groups, ISS Stage II/III was reported in 48% of pts in KRd and KCd, high-risk chromosomal abnormalities (del(17p) or t(4;14) or t(14;16)) were present in 30% of KRd pts and 34% of KCd pts. After 4 cycles of induction, the rate of ≥partial response (PR) was 96% with KRd vs 92% with KCd; ≥VGPR was 74% with KRd vs 61% with KCd (P=0.01), with 31% vs 20% of pts (P=0.03) achieving ≥near complete response (nCR) and 15% vs 6% (P=0.02) ≥complete response (CR) respectively in KRd and KCd; stable disease was reported in 3% of KRd vs 7% of KCd pts, with only 1% of pts in each group being primary refractory. Subgroup analysis of response rates showed the superiority of KRd vs KCd in terms of ≥VGPR in all the subgroups analyzed (Figure 1 - Panel A). Of interest, the rates of ≥VGPR, ≥nCR and ≥CR were comparable in high- and standard-risk pts treated with KRd (Figure 1 - Panel B). Six-month MRD results were available in a subset of pts (122 KRd and 53 KCd pts): MRD was negative in 66/122 (54%) KRd pts vs 16/53 (30%) KCd pts (P=0.005). Regarding safety, the rate of ≥1 grade 3-4 hematologic adverse events (AEs) was comparable between KRd and KCd (7% vs 6%), the most frequent being neutropenia (KRd 6% vs KCd 5%). The rate of ≥1 Grade 3-4 non-hematologic AEs was higher with KRd (32% vs 16%, P Conclusions :KRd induction showed a higher efficacy of KCd in terms of ≥VGPR, ≥nCR and ≥CR rates, with an acceptable safety profile. The superiority of KRd vs KCd was confirmed in high- and standard-risk groups, with response rates in high-risk pts treated with KRd comparable to the ones in standard-risk, suggesting the high efficacy of this regimen even in this subset of pts representing a current unmet medical need. Updated data will be presented at the meeting. Disclosures Gay: Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Offidani: celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Oliva: Takeda: Honoraria; Celgene: Honoraria. Mancuso: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Palumbo: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding. Musto: Janssen: Honoraria; Celgene: Honoraria. Boccadoro: Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Carfilzomib-based induction/consolidation with or without autologous transplant (ASCT) followed by lenalidomide (R) or carfilzomib-lenalidomide (KR) maintenance: Efficacy in high-risk patients.

8002 Background: Cytogenetic abnormalities (CA) are one of the most powerful prognostic factors in multiple myeloma (MM). In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd_ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12, HR 0.64) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd_ASCT, HR 0.53). KR maintenance significantly improved PFS vs R (HR 0.63). Methods: MM patients (pts) were randomized to KRd_ASCT vs KCd_ASCT vs KRd12 and, thereafter, to KR vs R maintenance. Subgroup analyses according to FISH evaluated the impact of each single high-risk (HiR) CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)] and that of combined CA, defining HiR by the presence of ≥1 HiR CA and double-hit (DH) by the presence of ≥2 HiR CA. Pts negative for all the HiR CA were considered at standard risk (SR). The primary objective was the impact of treatment on PFS according to pt risk. Results: 396 out of 474 enrolled pts were included in the analysis with complete FISH data: 243 HiR, 105 DH and 153 SR. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd_ASCT vs KRd12 (HR 0.47, p = 0.05) and KCd_ASCT (HR 0.38, p = 0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd_ASCT improved PFS vs KRd12 (HR 0.6, p = 0.04) and KCd_ASCT (HR 0.57, p = 0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd_ASCT vs KRd12 (HR 0.53, p = 0.07) and KCd_ASCT (HR 0.49; p = 0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Analyses by single CA were limited by the small number of pts in each subgroup, but a trend towards a PFS benefit from KRd_ASCT vs KRd12 was seen in pts with del17p (HR 0.61, p = 0.3), t(4;14) (HR 0.59, p = 0.2) and 1q gain (HR 0.45, p = 0.02). In pts with del1p, KRd_ASCT (HR 0.24, p = 0.06) and KRd12 (HR 0.33, p = 0.09) showed superiority over KCd_ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd_ASCT vs KCd_ASCT, HR 1.16, p = 0.73; KRd12 vs KCd_ASCT, HR 1.34, p = 0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p = 0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p = 0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p = 0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p = 0.37), t(4;14) (HR 0.59, p = 0.3), 1q gain (HR 0.54, p = 0.07) and del1p (HR 0.23, p = 0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p = 0.7). Conclusions: KRd_ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd_ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus supporting their use in HiR pts, who represent an unmet medical need. Clinical trial information: NCT02203643.

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis.

8042 Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P= 0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts with high-risk cytogenetics [t(4;14), del(17p), and t(14;16)] and/or gain(1q21). Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n = 179) or Kd (n = 123). High-risk cytogenetics was assessed by central laboratory analysis and defined as ≥1 of the following: del(17p): 50% cutoff; t(4;14) or t(14;16): 30% cutoff. Assessment of gain(1q21) was prespecified as ≥3 copies: 30% cutoff. Results: Of the randomized pts, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk cytogenetic abnormality (CA); 26.3% (Isa-Kd) and 25.2% (Kd) had isolated gain(1q21). The addition of Isa to Kd improved PFS for pts with ≥1 high-risk CA and standard-risk pts (Table); pts with t(4;14) (HR 0.549; 95% CI, 0.232–1.301) had a more pronounced treatment effect than pts with del(17p) (HR 0.837; 95% CI, 0.281–2.496). A clear PFS benefit with Isa-Kd was also seen for pts with isolated gain(1q21) and gain(1q21) combined with other high-risk CA (Table). The trend toward improved CR, ≥very good partial response (VGPR), and MRD- rates with the addition of Isa was more pronounced in pts with gain(1q21) than in pts with high-risk CA alone. Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd vs Kd, but the incidence of serious and fatal TEAEs was similar with both arms for high-risk pts (Table). Conclusions: The addition of Isa to Kd improved PFS in pts with high-risk CA and disease response in pts with gain(1q21) isolated or combined with high-risk CA, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA population. Isa-Kd is a potential new treatment option for the difficult-to-treat subgroup of pts with RMM and high-risk cytogenetics. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]

Is There an Unequal Benefit of Autologous Stem Cell Transplant in Different Cytogenetic Groups of High Risk Patients with Multiple Myeloma: The University of Miami Experience

BACKGROUND: Stratification using cytogenetics (CG), either metaphase karyotyping or fluorescence in situ hybridization (FISH) is used to identify patients (pts) with multiple myeloma (MM) who are at higher risk of relapse and tend to have poorer survival. It is largely unknown if autologous stem cell transplantation (auto-HCT) after high dose melphalan (200 mg/m2) is able to modify the survival of some of these high-risk MM pts and to make it comparable to standard risk. METHODS: Pts were classified as high risk (HR) if either conventional cytogenetics or FISH demonstrated at least one of the following 1q+, 1p-, 17p-, 13q-, t(4;14), or t(14;16), realizing that the inclusion of 13q- by FISH alone and 1p- in the HR MM definition is controversial. Pts with normal chromosomes or those with trisomies and hyperdiploidy were considered standard-risk (SR). We compared progression-free survival (PFS) and overall survival (OS) via a retrospective analysis of pts at the University of Miami Sylvester Comprehensive Cancer Center who underwent auto-HCT between January 2014 and December 2017 for MM. Survival analyses were performed using the log-rank test, with significance at p-value &amp;lt; 0.05. RESULTS: Male pts comprised 56% of the population, and 40% of pts were of Hispanic ethnicity. Of 205 pts undergoing auto-HCT, 108 (53%) had at least one HR cytogenetic abnormality. Interestingly, the depth of response to pre-transplant induction was higher in pts classified as HR, with 71% (77 of 108) achieving at least a very good partial response (VGPR), while 24% (23 of 96) SR pts achieved VGPR. While OS remained largely unaffected in HR pts (34.0 m vs. 35.1 m, p = 0.27); HR pts had an inferior PFS compared to SR pts (21.9 m vs. 25.7 m, p = 0.041). The presence of trisomies did not negate the poorer PFS of HR pts. When we evaluated specific HR CG abnormalities, OS and PFS in patients with 1q+ or t(4;14) were surprisingly comparable to SR pts, indicating a significant benefit from auto-HCT. On the other hand, OS was significantly decreased in pts with 1p- when compared to standard risk (16.5 m vs. 35.1 m, p = 0.004) or other high-risk patients (16.5 m vs. 35.4 m, p = 0.01), implying that 1p- group derive no benefit from auto-HCT. Similarly, OS was shorter in pts with t(14;16) (16.5 m vs. 34.4 m, p = 0.025) and with 17p- (26.6 m vs. 35.1 m, p=0.01), however the PFS was not affected in these populations. In pts with 13q-, PFS was significantly shorter (20.3 m vs. 25.7 m, p=0.023) compared to SR pts without affecting OS. CONCLUSION: At our center in a retrospective analysis of 205 pts: a) patients with HR MM responded better and faster than SR pts to induction, b) those with 1p- did not derive any benefit from transplant and c) pts with 17p- and t(14;16) had some short term benefit (similar PFS to SR group) but at the end their OS remained inferior. Nevertheless, we consider a very important finding the fact that, by having auto-HCT, pts with 1q+ and t(4;14), equalized their PFS and OS to those of SR pts. Based on these findings, patients with 1q+ and t(4;14) should still have a transplant in CR1 even after optimal induction. Whether 17p- and t(14;16) pts can extend PFS benefit after transplant into OS benefit with maintenance regimens stronger than lenalidomide alone remains to be determined. Disclosures Hoffman: Celgene: Honoraria, Speakers Bureau; Loxo: Current equity holder in publicly-traded company; Seattle Genetics: Research Funding.

Efficacy and tolerability of elotuzumab-based three-drug regimens for high-risk multiple myeloma: A meta-analysis.

e20550 Background: Efficacy of elotuzumab (E) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p) has not been thoroughly investigated. The aim of this study was to assess the efficacy of E based 3-drug regimens compared to non-E based regimens in high risk MM. Methods: A systematic review of literature was done to identify randomized controlled trials (RCTs) which reported overall response rates (ORR), progression free survival (PFS) and overall survival (OS) of MM patients (pts) with E based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS and OS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of E based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( &gt; 40%, as assessed by I-squared). Results: After screening 604 studies, 04 RCTs were included (n = 986 patients). E was evaluated with lenalidomide (L), pomalidomide (P), bortezomib (B) and dexamethasone (d). ELd regimen was studied in 359, EPd in 60 and EBd in 77 pts. Total 496 pts were evaluated with E. Pooled analysis of E based 3-drug regimens showed improved PFS (HR 0.69, 95% CI 0.59-0.81; p &lt; 0.00001, I2 = 0%) and ORR (OR 1.92, 95% CI 1.33-2.78; p = 0.0005; I2 = 25%) as compared to non-E 2-drug regimens. Relapsed/refractory MM pts (n = 456) also showed improved ORR in E vs non-E groups (OR 1.88, 95% CI 1.19-2.97; p = 0.007; I2 = 47%). Sub-group analysis showed 30% reduction in progression in high risk MM pts (HR 0.70, 95% CI 0.53-0.94; p = 0.02; I2 = 0%) and 31% in standard risk pts (HR 0.69, 95% CI 0.53-0.88; p = 0.003, I2 = 0%). OS showed 25% reduction in risk of death with E based regimens (HR 0.75, 95% CI 0.62-0.91; p = 0.004, I2 = 0%). E proved to be clinically safe across all patients (OR 1.10, 95% CI 0.78-1.57; p = 0.58; I2 = 71%). Conclusions: Elotuzumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.

Daratumumab-based three drug regimens for high-risk multiple myeloma: A meta-analysis.

e20549 Background: Efficacy of daratumumab (D) based regimens in high risk multiple myeloma (MM) (i.e, ISS stage II/III and t(4;14) or (del17p)) has not been thoroughly investigated. The aim of this study was to assess the efficacy of D based 3-drug regimens compared to non-D based regimens in high risk MM. Methods: A systematic review of literature was performed to identify randomized controlled trials (RCTs) which reported overall response rates (ORR) and progression free survival (PFS) of MM patients (pts) with D based 3-drug regimens. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using RevMan v.5.3 to report the efficacy of D based 3-drug regimens. A random effects model was employed only when there was significant heterogeneity among studies ( &gt; 40%, as assessed by I-squared). Results: Screening of 604 studies yielded 04 RCTs (n = 2,234 pts). D was evaluated with lenalidomide (L), carfilzomib (C), bortezomib (B) and dexamethasone (d). DLd regimen was studied in 649, DCd in 312 and DBd in 240 pts. Total 1201 pts were evaluated with D. D based 3-drug regimens proved to be of improved efficacy versus non-D 2-drug regimens in the pooled analysis i.e., PFS (HR 0.46, 95% CI 0.33-0.63; p &lt; 0.00001; I2 = 81%) and ORR (OR 2.83, 95% CI 2.06-3.88; p &lt; 0.00001; I2 = 44%). Relapsed/refractory MM (n = 833) also showed improved ORR (OR 2.79, 95% CI 1.78-4.36; p &lt; 0.00001; I2 = 62%). In high risk group, addition of D decreased the risk of progression to 42% (HR 0.58, 95% CI 0.39-0.85; p = 0.005; I2 = 3%). In standard risk pts, D decreased the risk of progression/death to 66% (HR 0.34, 95% CI 0.23-0.51; p &lt; 0.00001; I2 = 74%). D increased the risk of neutropenia (OR 1.88, 95% CI 1.54-2.31; p &lt; 0.00001; I2 = 0%), respiratory tract infections (OR 1.87, 95% CI 1.49-2.35; p &lt; 0.00001; I2 = 0%) and diarrhea (OR 1.83, 95% CI 1.46-2.29; p &lt; 0.00001; I2 = 23%) in the study population. Conclusions: Daratumumab based 3-drug regimens appear to abrogate high risk features in MM compared to 2 drug regimens.

Bortezomib-Based Induction, Augmented Conditioning with Busulfan and Melphalan + ASCT and Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma: Long-Term Results of the National Canadian Mcrn-001 Study

Bortezomib-Based Induction, Augmented Conditioning with Busulfan and Melphalan + ASCT and Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma: Long-Term Results of the National Canadian Mcrn-001 Study

High Risk Genomic Alterations Identified at the Time of Diagnosis Are Strongly Associated with MRD and Subsequent Poor Outcomes in AYA ALL Patients Treated on a Pediatric Inspired Chemotherapy Regimen

High Risk Genomic Alterations Identified at the Time of Diagnosis Are Strongly Associated with MRD and Subsequent Poor Outcomes in AYA ALL Patients Treated on a Pediatric Inspired Chemotherapy Regimen

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Efficacy and Safety of Ixazomib-Dexamethasone, Ixazomib-Cyclophosphamide-Dexamethasone, Ixazomib-Thalidomide-Dexamethasone and Ixazomib-Bendamustine-Dexamethasone for Elderly Newly Diagnosed Multiple Myeloma (NDMM) Patients: Analysis of the Phase II Randomized Unito-EMN10 Study

Treatment of Myeloma Patients Progressing on Lenalidomide-Based Maintenance after ASCT Performed As Part of 1st, 2nd or 3rd Line Therapy: Real-World Results from the National Myeloma Canada Research Network (MCRN) Database

Treatment of Myeloma Patients Progressing on Lenalidomide-Based Maintenance after ASCT Performed As Part of 1st, 2nd or 3rd Line Therapy: Real-World Results from the National Myeloma Canada Research Network (MCRN) Database

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)

Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)