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Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.

Adobe PDF - Supplementary_Data.pdf from Homozygous Deletion Mapping in Myeloma Samples Identifies Genes and an Expression Signature Relevant to Pathogenesis and Outcome

Purpose: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes.Experimental Design: Using single nucleotide polymorphism–based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome.Results: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the “cell death” network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets.Conclusions: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma. Clin Cancer Res; 16(6); 1856–64

Introduction Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling. Methods Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia’s formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted. Results Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5–12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF. Conclusion Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab. Trial Registration ClinicalTrials.gov Identifier: NCT02316106. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01601-w.

Autologous stem cell transplant (ASCT) remains the standard of care for consolidation after induction therapy for eligible patients with newly diagnosed myeloma. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on a patient’s fitness rather than a strict age cut-off. Data from the UK NCRI Myeloma XI trial, a large phase III randomized controlled trial with pathways for transplant-eligible and -ineligible patients, were used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including an analysis using an age-matched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the transplant-eligible pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in progression-free survival associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged

Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine >500umol/L, urine output =60 ml/min/1.73m2, moderately impaired 30-59 or severely impaired =500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of ≥25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high (>=500) or low ( Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC>=500 68.6% v dFLC Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. Disclosures Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies:Celgene, Amgen, Merck: Research Funding. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cook:Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory:Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner:Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones:Celgene: Honoraria, Research Funding. Kaiser:Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma

PURPOSE Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P < .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P < .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate >15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI], 0.014–0.096), 0.102 (80% CI, 0.044–0.160), and 0.206 (80% CI, 0.118–0.295), respectively, translating to a median PFS ≥24 months in all arms (P < 0.0001, P < 0.0001 for all arms). Twenty-four–month PFS rates were 89.9% (90% CI, 78.5–95.4%), 82.0% (90% CI, 69.0–89.9%), and 75.3% (90% CI, 61.1–85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ≥3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ≥75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

IntroductionMultiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and disseminationEthics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN16847817, May 2017; Pre-results.

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (

Background Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored. Patients and Methods We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Results Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population. Conclusion Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes.

Infection with the novel coronavirus SARS‐CoV‐2 virus resulting in an acute respiratory disease (COVID‐19 disease) is the cause of the current pneumonia pandemic, with a rapid rise in cases being reported in the European Union and UK (1, 2). The UK index case was identified on the 31st of January, 2020 and given the rapid spread and high mortality rate of COVID‐19, it is imperative to define the impact on patients with co‐existing medical conditions(3).

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1–7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3–4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses; some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654; The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca); serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding; Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Cook: Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy.

Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts >20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare ( Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation ( 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associated exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. Figure 1 Figure 1. Disclosures Cook: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Royle: BMS: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees; Celgene: Other: Attending fees; Takeda: Other: Attending fees; Jannsen: Other: Attending fees. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Best: BMS/Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding; Meck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Henderson: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty-score adapted dosing strategies

Introduction Despite efficacious modern induction combination therapies a subset of myeloma patients have high-risk disease which manifests as either primary refractory disease or early relapse following initial response. The presence of known molecular high-risk lesions explain the majority of these cases but understanding the factors influencing the poor phenotypic outcome for the remainder will help us improve outcomes further. This exploratory analysis of the Myeloma XI+ trial aimed to understand the population of patients with phenotypic high-disease in the context of carfilzomib and lenalidomide induction therapy. Methods The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design. Induction therapy was planned for a minimum of 4 cycles or to maximum response prior to autologous stem cell transplant (ASCT). There was a subsequent randomisation to lenalidomide maintenance or observation at 3 months post ASCT. Primary refractory disease was defined as not achieving at least a minimal response (MR) at maximum response after at least 4 cycles of induction therapy or progression at any time during induction regardless of initial response. Early relapse (ER) after ASCT was defined as progression within 12 months of ASCT. Molecular risk was defined as the presence of one (high risk) or more than one (ultra-high risk) of the following lesions: del(17p), gain(1q), t(4,14), t(14;16) or t(14;20). Results The incidence of primary refractory disease with the KRdc combination was very low. Only 8/526 (1.5%) patients were primary refractory, all having progression during induction therapy with a median progression free survival of only 126 days. The number of patients is too small to draw any firm conclusions regarding the characteristics associated with primary refractory disease. 401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction. Those that did not proceed to ASCT on trial were either ineligible, mostly due to not completing the minimum required induction therapy, or were deemed not fit to undergo the procedure based on patient/clinician decision. Of those patients who underwent ASCT, 36/401 (9.0%) relapsed within 12 months (ER). These ER patients had both a shorter PFS2 and second PFS suggesting a continued association with adverse outcome beyond first line therapy. Patients in the ER group were compared with those patients not relapsing until beyond 12 months after ASCT (nER). There was no difference in the sex, age or paraprotein or light chain sub-type of patients. There was evidence of a greater impact of bone marrow disease burden in the ER group with a lower haemoglobin (median 99 g/L vs 115, p = 0.0216), lymphocyte count (1.3 x10^9/L vs 1.8, p = 0.0012) and platelet count (187 x10^9/L vs 252, p = 0.0049) at baseline. Median bone marrow aspirate plasma cell infiltration was ER 33% vs nER 23%. There were no significant differences in ISS stage (ER ISS I 19%, II 50%, III 22%, nER ISS I 35%, II 36%, III 22%, p = 0.1434), lactate dehydrogenase, albumin or beta-2 microglobulin. Patients in the ER group were less likely to have received lenalidomide maintenance (ER 12/36 [33%] vs nER 222/365 [61%]). For some (4/36) not receiving lenalidomide was due to relapse occurring prior to reaching the maintenance randomisation point (100 days post-ASCT). For those with available data 75% of patients in the ER group had molecular high (50%) or ultra-high (25%) risk disease, whilst 25% had standard risk using the trial definition. The individual lesions accounting for high-risk status were: gain(1q) in ER 42% vs nER 35%; t(4;14) ER 50% vs nER 10%; del(17p) ER 8% vs nER 7%. Discussion The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features. Disclosures Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davies: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Menzies: Celgene / BMS: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding. Henderson: BMS / Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Cook: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Kaiser: AbbVie: Consultancy; Takeda: Consultancy, Other: Educational support; Seattle Genetics: Consultancy; Amgen: Honoraria; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: The KRdc combination is off label

Introduction: Molecular diagnostic testing for lymphoproliferative disorders (LPDs) includes detection of clonal immunoglobulin (IG) and/or T cell receptor (TCR) rearrangements, translocations, copy number alterations (CNA) and somatic mutations. To date, laboratories still rely on subjective and labour-intensive technologies, e.g. karyotyping/FISH to detect complex genomic alterations. Whole Genome Sequencing (WGS) can detect all genomic alterations, but factors such as cost, computation/storage, DNA requirements and poor detection of clinically relevant subclonal mutations limits the routine implementation of WGS in clinical diagnostics. We have developed "KaryoSequencing" (KS), a novel approach that combines targeted deep-sequencing, using a targeted hybridisation capture NGS panel, for rare mutation and translocation detection with shallow WGS (sWGS) for genome wide copy number analysis, in a single test. Methods: KS was validated using 138 clinical samples from patients with acute lymphoblastic leukaemia (ALL) (n=46), chronic lymphocytic leukaemia (CLL) (n=46) and plasma cell myeloma (PCM) (n=46) samples from 3 UK laboratories. Samples underwent library preparation and hybridisation using the EuroClonality-NDC assay. A KS library for each sample was prepared by combining the pre-capture and post-capture libraries at an optimised ratio to enable high coverage (>500 x) at regions covered by the targeted panel while providing 0.5-1x coverage genome-wide. Forty-six KS libraries were pooled and sequenced per NovaSeq 6000 run, using a 200-cycle SP flow cell and a 100bp paired-end strategy. For analysis of targeted regions, somatic mutation calling was performed using VarDict and structural variants (rearrangements and translocations) were detected using ARResT/Interrogate. For analysis of large chromosomal copy number variation using sWGS, a modified version of QDNASeq/ACE with a window size of 50kb was performed. For sWGS analysis, bioinformatic exclusion of all target capture regions and panel-specific off-target regions was performed using a panel of 48 DNA samples from healthy individuals ran on the same KS protocol. Results: Analysis of genome-wide copy number by sWGS was concordant in 477 of 503 (95%) evaluable FISH tests, including precise detection of hyper and hypo-diploidy and other complex karyotypes. The performance of the targeted deep-sequencing component of the KS approach was assessed to ensure comparable performance to previously validated results for the EuroClonality-NDC. The EuroClonality-NDC detected a clonal IG rearrangement in 46/46 (100%) CLL cases and in 42/46 (91.3%) PCM cases. Clonality was detected in 43/46 (93.5%) and 44/46 (95.7%) cases at an IG and TCR locus respectively in ALL, a disease entity known to exhibit cross-lineage rearrangements. Overall, 44 translocations were detected in the 138 samples by the EuroClonality-NDC. FISH results were available for 32 of the 44 translocations detected by NGS and were concordant in 29/32 (91%). In two PCM samples NGS and FISH reported a different translocation; in the ALL sample, the FISH pattern showed an additional copy but not a split signal. Across the entire cohort of 138 samples, KaryoSequencing detected 190 mutations with a variant allele frequency ranging from 4.0 - 97.6%. Of the detected mutations, 69/190 (36.3%) had a VAF Conclusions: KaryoSequencing demonstrated >95% sensitivity and specificity for detection of gross genome-wide copy number alterations while retaining the analytical performance for detection of rearrangements, translocations, and mutations for the lymphoid-specific targeted regions of the EuroClonality-NDC assay. KS is a cost-effective and high-throughput integrated alternative to current diagnostic strategies in haematological malignancies and can be implemented in routine clinical practice. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Gonzalez: Univ8 Genomics Ltd: Current holder of individual stocks in a privately-held company.

Introduction In traditional analysis of cancer clinical trials, key endpoints such as progression-free survival (PFS) and overall survival (OS) are often analysed separately. Using multistate models (MSMs) we can model these events simultaneously to holistically analyse the disease-treatment pathway. This provides meaningful estimates for the probability of disease progression and death at any point in the disease course, incorporating treatment and prognostic factors of interest. MSMs are also a useful tool to assess the relationship between how the time spent in one state affects the risk of transitioning to future states. In the context of myeloma (MM), this can be used to determine patient prognosis based on the time for which they remain in 1 st remission after initial treatment. Methods In the largest randomised trial of MM patients undertaken to date (NCRI Myeloma XI), newly diagnosed MM patients eligible for ASCT (NDMM TE) were randomised to induction, intensification and maintenance treatments. Maintenance randomisation, at ASCT+3 months, was to lenalidomide (R), lenalidomide plus vorinostat (RZ) or observation. Co-primary endpoints were PFS and OS analysed by Cox regression. An MSM was used for exploratory analysis of 1074 TE patients randomised to maintenance. Patients transitioned irreversibly between 4 states: 1 st remission, alive and in remission after 1 st progressive disease (PD1), alive and in remission after 2 nd PD (PD2) and dead (Figure 1). Time in 1 st remission was included as a covariate to assess the effect of early disease progression on subsequent state transitions ( Results The median follow-up from randomisation was 57m (interquartile range: 43-72m). MSM analysis found that a 1 st remission of At a snapshot at 5 years post-randomisation, those with a 1 st remission ≥18m had a 24.9% chance of being in the PD1 state, compared to just 6.4% and 1.1% in those with 1 st remissions of 12-18m and MSM analysis also found R and RZ were associated with a reduced risk of transition from 1 st remission to PD1 vs. observation (R HR 0.51, 95%CI 0.42-0.60; RZ HR 0.68, 95%CI 0.55-0.88), reflecting the results of the primary trial analysis of PFS. Primary trial analysis of OS found that R was associated with significantly longer OS than observation. However, MSM analysis found R was associated with an increased risk of death following both PD1 (HR 1.60, 95%CI 1.06-2.41) and PD2 (HR 1.46, 95%CI 1.03-2.07) vs. observation. This suggests that the OS benefit of R is gained by extending the time in 1 st remission. RZ was associated with increased risk of death without PD (HR 3.07, 95%CI 1.05-9.03) and death following PD2 (HR 1.49, 95%CI 0.99-2.26) vs. observation. The MSM also found that the expected duration in 1 st remission was longest for R and shortest for observation (R 56.7m, RZ 47.7m and obs. 38.6m). However, in the PD1 state (R 12.8m, RZ 15.7m and obs. 21.9m) and PD2 state (R 5.4m, RZ 7.3m and obs. 11.0m) this order was reversed, although the difference between the groups was reduced for later states. Discussion MSMs are a powerful tool for exploring the myeloma disease pathway, identifying associations between states and providing transition probabilities which can be easily interpreted to gain further insights to those obtained via traditional methods. MSMs are an effective method to visualise data, clearly demonstrating the association between early relapse post-ASCT and poor prognosis in NDMM. This work has expanded on the primary analysis of the maintenance randomised treatments in Myeloma XI, corroborating results previously observed and highlighting the potential effects of maintenance treatment on each stage of the disease pathway. Figure 1 Figure 1. Disclosures Craig: Celgene: Research Funding; Merck Sharpe & Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kaiser: AbbVie: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Other: Educational support; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy. Olivier: Celgene / BMS: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Merck Sharpe and Dohme: Research Funding. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Takeda: Consultancy; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Cook: Amgen: Consultancy; BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy. Davies: BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cairns: Celgene / BMS: Other: travel support, Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding.

8001 Background: Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts > 20%) were included in OPTIMUM across 39 UK hospitals. Patients received up to 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference. Results: Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention to treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (TNR; withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% TNR. MRD status was 41% MRDneg, 40% MRDpos and 19% not evaluable post induction and 64% MRDneg, 14% MRDpos and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% TNR. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was 3.7%. Conclusions: This is to our knowledge the first report on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM. Clinical trial information: NCT03188172.

BACKGROUND Lenalidomide (LEN), an established treatment (Tx) for newly diagnosed multiple myeloma, is routinely administered until disease progression. Therefore, patients (pts) for whom LEN is no longer an option at first relapse, including LEN-refractory pts, are a clinically relevant and growing population. Tx of these pts remains challenging, as they have been poorly represented in phase 3 clinical trials. OPTIMISMM (NCT01734928), a phase 3 trial specifically designed to address this population, demonstrated significantly improved progression-free survival (PFS) with pomalidomide (POM), bortezomib (BORT), and low-dose dexamethasone (PVd) compared with BORT and low-dose dexamethasone (Vd) in pts who received 1-3 prior regimens and were 100% LEN pretreated (70% LEN refractory) (Richardson PG, et al. Lancet Oncol. 2019;20:781-794). Here, we report the efficacy and safety of PVd in pts treated after 1 prior line of therapy (LOT) according to age, prior stem cell transplant (SCT), and in pts with high-risk cytogenetic abnormalities (HR CAs). METHODS Pts were randomized 1:1 to receive PVd or Vd in 21-day cycles. POM 4 mg/day was given on days 1-14 (PVd arm only); bortezomib (BORT) 1.3 mg/m2 was given on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9+; and dexamethasone 20 mg/day (10 mg/day for pts aged > 75 yrs) was given on the days of and after BORT. Key eligibility criteria included ≥ 2 cycles of prior LEN, including LEN-refractory pts. The primary endpoint was PFS. RESULTS As of October 26, 2017, 226 of 559 pts enrolled in OPTIMISMM had 1 prior LOT; 100 pts were aged ≤ 65 yrs (49 PVd, 51 Vd) and 126 were aged > 65 yrs (62 PVd, 64 Vd). In pts aged ≤ 65 yrs (PVd vs Vd), the median age was 58.0 vs 59.0 yrs, 63.3% vs 47.1% were male, 55.1% vs 51.0% were LEN refractory, and 83.7% vs 72.5% had prior BORT. In pts aged > 65 yrs, the median age was 73.0 vs 71.5 yrs, 58.1% vs 51.6% were male, 59.7% vs 60.9% were LEN refractory, and 41.9% vs 46.9% had prior BORT. After 1 prior LOT, PVd vs Vd significantly improved PFS in pts aged ≤ 65 yrs (median, 22.0 vs 13.1 mos; P = .0305) and those > 65 yrs (median, 17.6 vs 9.9 mos; P = .0348) (Figure). The overall response rate (ORR) was significantly higher with PVd vs Vd across the age groups (Table). The rate of ≥ very good partial response (VGPR) was 65.3% vs 17.6% in pts aged ≤ 65 yrs and 58.1% vs 26.6% in pts aged > 65 yrs. Comparable PFS and ORR outcomes were noted for an age cutoff of ≤ 70 yrs (median PFS, 17.8 vs 13.1 mos with PVd [n = 71] vs Vd [n = 78]; ORR, 88.7% [≥ VGPR, 62.0%] vs 55.1% [≥ VGPR, 21.8%], respectively) vs > 70 yrs (median PFS, 16.5 vs 9.5 mos with PVd [n = 40] vs Vd [n = 37]; ORR, 92.5% [≥ VGPR, 60.0%] vs 54.1% [≥ VGPR, 24.3%], respectively). These PFS and ORR findings were similar to those reported in pts with and pts without prior SCT (Table). Median PFS was 22.0 mos with PVd vs 13.8 mos with Vd in pts with prior SCT (P = .0241) and 16.5 vs 9.5 mos, respectively, in pts without prior SCT (P = .0454). Pts with HR CAs (n = 32 [18 PVd, 14 Vd]), defined as having a del(17p), t(4;14), or t(14;16), had a median PFS of 14.7 mos with PVd and 9.9 mos with Vd. The most common grade 3/4 treatment-emergent adverse events (TEAEs) with PVd vs Vd were neutropenia (49.0% vs 6.3%), infections (30.6% vs 14.6%), and thrombocytopenia (26.5% vs 18.8%) in pts aged ≤ 65 yrs and neutropenia (25.8% vs 12.9%), infections (27.4% vs 16.1%), and thrombocytopenia (14.5% vs 22.6%) in pts aged > 65 yrs. CONCLUSIONS In pts with LEN-pretreated relapsed or refractory multiple myeloma at first relapse, PVd reduced the risk of progression or death by 50% in pts aged ≤ 65 yrs and by 43% in pts aged > 65 yrs vs Vd. Additionally, across age subgroups, second-line Tx with PVd vs Vd significantly improved ORR and led to deeper responses. Similar findings were observed in pts with and pts without prior SCT. PVd also benefited pts with HR CAs vs Vd. Overall, TEAEs with PVd were generally consistent with the known profiles of the constituent agents. These data in pts at first relapse continue to demonstrate that PVd is effective and safe as a second-line Tx following LEN, regardless of age, prior SCT status, and presence of HR CAs. Disclosures Dimopoulos: Sanofi Oncology: Research Funding. Weisel:GSK: Honoraria; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. White:Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Pavic:Celgene, Janssen, Takeda, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Casal:Celgene Corporation: Employment. Srinivasan:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment, Equity Ownership. Biyukov:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Yes. The triplet combination is not currently approved in the US for the treatment of multiple myeloma.

Introduction Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone. Patients and Methods Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m2 days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle). Results Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability. Conclusion Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor–based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.

Background Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. Methods and findings The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10−5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. Conclusions The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. Trial registration ClinicalTrials.gov ISRCTN49407852., Graham Jackson and co-workers study a combination induction treatment including carfilzomib for patients with transplant-eligible myeloma., Author summary Why was this study done? Although outcomes for myeloma patients have improved over recent decades, many patients will eventually relapse, and finding new treatment regimens that keep patients in first remission for longer is imperative. Treatment combinations aim to target myeloma using different mechanisms of action. This aims to prevent resistant cells remaining and leading to relapse. Carfilzomib has been shown to be effective in the treatment of relapsed myeloma when given in combination with lenalidomide. We performed this study to compare the outcomes of newly diagnosed myeloma patients treated with the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) to those of patients treated with immunomodulatory-agent-based triplet control combinations. What did the researchers do and find? A total of 1,056 patients with newly diagnosed myeloma were randomised between KRdc and control. Patients receiving the quadruplet KRdc combination were more likely to achieve at least a very good partial response and had longer progression-free survival than patients receiving control treatments. Side effects were not significantly increased with the quadruplet combination compared to control. What do the findings mean? The results suggest that KRdc can elicit deep responses and long periods of progression-free survival with tolerable side effects in newly diagnosed myeloma patients. Further studies are needed to compare KRdc to combinations of other new agents for the treatment of newly diagnosed myeloma patients.

Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancy (SPM), particularly AML and MDS. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Myeloma XI is a large phase III randomised trial in-which len is used as an induction and maintenance therapy. We have previously reported on early SPM incidence in the context of this trial and shown that haematological SPM (hSPM) incidence was not increased in association with len (Cumulative incidence 0.7% at 3 years). We have also published data showing that maintenance len is associated with improved survival in post-transplant patients. Here we present for the first time, a long-term analysis of SPM incidence in 4358 patients who have received maintenance therapy versus observation in the context of the Myeloma XI trial. Methods Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, len, carfilzomib and bortezomib combinations and len as maintenance treatment in NDMM patients. The trial includes transplant eligible (TE) and transplant non-eligible (TNE) pathways. TE patients received high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Since May 2010, 4358 patients have been treated and assigned to induction. Median follow up is now 68 months (IQ range 49-83), with over 1100 patients enrolled for more than 5 years. A total of 1971 patients have entered maintenance with 1137 randomised to len and 834 observation (median 24 cycles (range 1-97)). Results The median time to SPM development from induction is 41.6 months (range 1.4 - 97.1). Cumulative incidence of all SPMs is 4.1% (95% CI 3.5, 4.7), 7.4% (6.6, 8.3) and 10.8% (9.5, 12.1) at three, five and seven years respectively (figure 1). 378 SPMs have been reported in 318 patients, 180 (57%) treated in the TNE pathway (IR 9.9%) and 138 (43%) in the TE pathway (IR 5.5%). The average age at the time of SPM is 78 and 68 for the TNE and TE pathways, respectively. Of the patients who developed an SPM 195 (61%) did so following maintenance randomisation. The incidence was highest in those receiving len based maintenance (n=145, IR 10.8%). In the observation arm 50 patients developed an SPM (IR 5.6%). The median time to SPM development from maintenance randomisation was 43 months in those receiving len and 40 months in the observation only group. One hundred and ten of the patients who developed an SPM following maintenance randomisation were in the TNE pathway with 77 patients receiving len. The overall incidence of SPM development in TNE patients receiving len maintenance is 15.4% and 9.9% for observation. Within the TE arm 85 SPM cases developed following maintenance randomisation with 68 patients receiving len. The overall incidence of SPM development in the TE patients treated with len maintenance is 7.7% and 3.1% for observation. Of the remaining patients 98, (31%) developed an SPM during induction and twenty five (8%) following induction but prior to maintenance. Forty eight patients developed a hSPM (IR 1.1%), MDS (n=20), AML (n=13), BLCBL (n=6), B-ALL (n=4), CML (n=1), mixed phenotype leukaemia (n=1), T-ALL (n=1), Burkitt lymphoma (n=1) and Hodgkin's Lymphoma (n=1). Of these cases, 35 patients were TE pathway treated, with 25 receiving lenlidomide maintenance (IR 2.8%). The median time to hSPM development in the TE patients was 51.8 months. The remaining 13 cases occurred in the TNE treated patients with 7 receiving lenalidomide maintenance (IR 1.4%). The median time to hSPM development in the TNE patients was 42.3 months. Of the remaining cases, 107 patients developed non-melanoma skin cancers (NMSC) (TE n34, IR 1.3% / TNE n73, IR 4.0%) and 181 patients developed solid tumours (TE n78, IR 3.1% / TNE n103, IR 5.6%). Forty one patients developed >1 SPM. Outcome analysis is underway and will be presented at the meeting. Conclusions The overall incidence of SPM is highest in TNE patients receiving lenalidomide maintenance but hSPM rates remain low. This suggests that advanced age is a considerable risk factor for the development of second cancers, particularly NMSC. Second haematological cancers were low in all groups, irrespective of maintenance allocation. Disclosures Jones: Celgene: Honoraria, Research Funding. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. Gregory:Amgen, Merck: Research Funding; Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Boyd:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses.

Background: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (>=VGPR 65.3%, PR 24.5%) than CTD (>=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P Optimum outcomes were seen in those receiving Len as both induction and maintenance therapy (Figure 1C). Patients receiving CRD induction followed by Len maintenance (CRD-R) had a median PFS of 77 months [56, 86] compared to CTD-R 64 [49, 74], CRD-Obs 37 [33, 42] and CTD-Obs 44 [38, 51]. Conclusions: In this study the use of Len as both induction and maintenance was associated with the best outcomes irrespective of cytogenetic risk group. With long term follow up CRD induction for newly diagnosed transplant eligible myeloma patients was associated with both a PFS and OS benefit compared to CTD and was better tolerated. The PFS impact of CRD was particularly notable in patients with high and ultra-high risk disease. Lenalidomide maintenance was associated with significantly longer PFS than observation across all risk groups. on behalf of the NCRI Haematological Oncology Clinical Studies Group Disclosures Jackson: Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jones:Celgene: Honoraria, Research Funding. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria; Novartis, Janssen: Research Funding. Lindsay:Celgene: Other: personal fees and non-financial support ; Takeda: Other: personal fees and non-financial support ; Amgen: Other: non-financial support. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding. Gregory:Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding; Amgen, Merck: Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. OffLabel Disclosure: CTD/CRD induction therapy and Lenalidomide maintenance 10mg 21/28 days

Introduction: Systemic AL amyloidosis is a rare multisystem disease caused by an underlying plasma cell dyscrasia with amyloid fibril deposition causing progressive organ failure. Treatment of the underlying plasma cell disorder underpins the management of AL amyloidosis with bortezomib-based regimes as standard first line treatment. Thalidomide has activity in AL amyloidosis used in low doses in combination with cyclophosphamide and dexamethasone. Carfilzomib (Kyprolis), a second generation irreversible inhibitor of the proteasome, is licenced for treatment of relapsed refractory myeloma. This prospective phase 1 multicentre study was designed to define the maximum tolerated dose (MTD) and recommended dose (RD) of one weekly dose of carfilzomib in combination with a fixed dose of thalidomide and dexamethasone (KTD) in patients with relapsed refractory amyloidosis. Methods and Patients Patients were recruited for treatment with carfilzomib in escalating dose cohorts using a 3+3 dose escalation design at three planned dose levels (Table 1) - all participants received carfilzomib 20mg/m2 on cycle 1 day 1. The primary endpoint was to define the MTD, RD and assess the safety and tolerability of KTD. The key secondary endpoint was a preliminary assessment of the activity of KTD. Results A total of 10 patients were recruited (6 male, 4 female) with a median age of 64 years (30% >70 years). The mean time from AL amyloidosis diagnosis for Dose levels 0 and 1 was 7.8 years (SD ±3.87 yrs.) and 3.2 years (SD ± 1.80) respectively. All non-refractory patients had received at least two previous lines of therapy, with a maximum of four previous lines of therapy. The median creatinine was 77.0µmol/L, the median NT-proBNP was 53.3pmol/L and dFLC at the time of treatment was 77.0mg/L. Three evaluable patients were recruited to Dose Level 0 with no dose limiting toxicities (DLTs) observed. A further 3 evaluable patients were recruited to Dose Level 1 - one patient experienced a DLT (acute kidney injury). Hence, 3 further patients were recruited at this dose level. One participant had a serious adverse event (SAE) following day 1 dosing at 20mg/m2 - deemed not evaluable for DLT assessment as received no further treatment. Three further patients were recruited at Dose level 1 with no further DLT's. The data monitoring committee decided that it was not in the patients' best interest to proceed to Dose level 2, as significant evidence of activity at dose level 1 and concern about potential toxicity. As of June 2019, 7 participants have completed 3 cycles and 4 participants (40%) have completed 6 cycles. Responses were determined centrally according to amyloidosis consensus criteria 2005. The overall hematologic response rate at end of 3 cycles was 70%. This included: complete response - 1 (10%); very good partial response - 3 (30%) and partial response 3 (30%). Of the 3 participants at Dose level 1, 1 participant had a VGPR, 1 had PR and 1 had no response (discontinued at the end of cycle 2). One patient had no response by the end of cycle 2 (discontinued due to toxicity) and 2 patients with DLT's were not assessable for response. A total of 3 participants had SAE's: 1. At dose level 1, grade 3 acute kidney injury which was deemed to be DLT, which recovered with supportive care. 2. At dose level 1, pyrexia, hypotension and hypoxia requiring intensive care admission after day 1 dose of 20mg/m2. There was no clear evidence of infection and this was deemed to be a SAE due to carfilzomib (but not DLT). 3. At dose level 1, grade 3 abdominal pain deemed unrelated to study medication. There were 66 other grade 1 or 2 adverse events reported from 9 participants from the first 3 cycles. There were no SUSARs or deaths in the study reported to date. None of the patients had worsening cardiac function. Results here are preliminary with further endpoints and detail to be presented when all participants have completed therapy. Conclusion This study defined, in combination with thalidomide and dexamethasone, the recommended dose of carfilzomib was 45mg/m2 on days 1, 8 and 15. The MTD of carfilzomib was not reached. Three participants experienced a SAE and a number of participants had grade 1-2 AE's. At the end of 3 cycles, 70% of participants achieved a hematologic response with 40% VGPR or better which appears comparable to other studies in relapsed AL amyloidosis. KTD is a potentially effective regime that can be considered for further study in relapsed refractory systemic AL amyloidosis. Disclosures Garg: Novartis: Consultancy, Honoraria. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kishore:Celgene, Jazz, Takeda: Other: Travel expenses; Celgene, Takeda, Janssen: Honoraria, Speakers Bureau. Pitchford:Amgen: Other: Research funding to institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Oughton:Amgen: Other: Research funding to institution. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Wechalekar:Amgen: Research Funding; GSK: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria.

Background Transplant non-eligible (TNE) myeloma patients are a very heterogeneous group that is not well-defined on the basis of age alone, but rather by the interplay of age, physical function, cognitive function and comorbidity better defined as 'frailty'. The International Myeloma Working Group (IMWG) has published a scoring system for myeloma patient frailty that predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). It has been proposed to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but has not been validated prospectively. We hypothesize that by defining subgroups of patients based on the IMWG frailty score, and guiding up-front dose adjustments we can personalize therapy to improve treatment tolerability and therefore short-term outcomes, along with quality of life. In addition we plan to compare the use of single agent immunomodulatory (IMiD) based maintenance therapy with an IMiD and proteasome inhibitor maintenance doublet to try and improve long-term outcomes for patients. Study Design and Methods Myeloma XIV (NCT03720041) is a phase III, multi-center, randomized controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRd), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (IR) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. The trial outline is shown in Figure 1. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomized (R1) on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomization (R2) on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians are blinded to maintenance allocation. The primary objectives of the study are to determine: Early treatment cessation (within 60 days of randomization) for standard versus frailty-adjusted up-front dosingProgression-free survival (PFS, from maintenance randomization) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (IR) The secondary objectives of the study include determining: progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, overall survival (OS), overall response rate (ORR), treatment compliance and total amount of therapy delivered, toxicity & safety including the incidence of Second Primary Malignancies (SPMs), Quality of Life (QoL), cost-effectiveness of standard versus frailty-adjusted up-front dosing of IRd and cost-effectiveness of IR versus R. Exploratory analyses include the association of molecular subgroups with response, PFS and OS. Seven hundred and forty participants will be enrolled into the trial at R1 to give 80% power to demonstrate a difference in early cessation and ensure that at least 478 participants remain and are randomized at R2 (based on attrition rates in our previous study Myeloma XI). At R2 478 patients will give us 80% power to detect an eight month difference in PFS between R and IR. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Best:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Bowcock:Takeda: Honoraria, Research Funding. Boyd:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Drayson:Abingdon Health: Consultancy, Equity Ownership. Henderson:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty adjusted dosing. Ixazomib and lenalidomide combination as maintenance.

Background High-risk myeloma patients have unsatisfactory outcomes with current treatments and are in urgent need of improved diagnostic and therapeutic strategies. We have recently validated specific markers predicting high-risk disease in newly diagnosed MM (NDMM), in particular double-hit with presence of ≥2 consensus high-risk markers t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) (Shah V, et al., Leukemia 2018) and diagnostic GEP SKY92 high risk signature (Sherborne A, et al., IMW 2017). Diagnostic tests for these markers were implemented in the UK multi-center OPTIMUM: MUK9 trial to prospectively stratify therapy for high-risk NDMM. Trial design OPTIMUM: MUK9 is a phase 2 trial for transplant eligible NDMM, consisting of two inter-related protocols: a molecular screening protocol (MUK9A) and an interventional trial (MUK9B) for high-risk MM identified in MUK9A. Patients with suspected or confirmed MM fit for intensive therapy enrolled in MUK9A have central molecular profiling at ICR, London, of CD138-selected BM MM cells for translocations, copy number aberrations (qRT-PCR; MLPA P425, MRC Holland) and SKY92 signature status (MMprofiler; SkylineDx). If clinically indicated SOC therapy (VTD, max. 2 cycles) can be given whilst central results are generated. Patients found to have high-risk MM by double-hit and/or SKY92 are offered enrolment into MUK9B. All other patients receive SOC (VTD, HD-MEL+ASCT) for which clinical data is collected. Patients diagnosed with plasma cell leukemia (PCL) can be enrolled directly in MUK9B. MUK9B treatment consists of quintuplet daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction (up to 6 cycles), bortezomib-augmented single HD-MEL+ASCT, Dara-VRd consolidation 1 (6 cycles), Dara-VR consolidation 2 (12 cycles) and Dara-R maintenance (until PD). Dose adjustments are permitted in order to maximize tolerability of long-term therapy. Patient reported outcomes (PRO) are recorded at baseline and throughout treatment. Response and MRD are centrally assessed (Birmingham, Leeds). Primary endpoint for MUK9A is feasibility of central molecular testing within 56 days turnaround time, which we report on here. Primary endpoint of MUK9B is treatment efficacy, comparing MUK9B PFS to near-concurrent molecularly matched high-risk patient outcomes from UK NCRI Myeloma XI using a Bayesian design. Secondary endpoints include safety, PFS2, MRD and OS and study of molecular evolution in high-risk disease. Results The protocol recruited 29/Sep/17 - 31/Jul/19 at 39 UK sites, achieving the recruitment target of 105 high-risk patients treated on MUK9B ahead of projections. At the time of analysis (12/Jul/19), 430 patients with suspected or confirmed NDMM have been recruited to MUK9A across 39 UK NHS hospitals. Of these, 376 (87%) patients were confirmed to have symptomatic MM (60.9% male; median age 61y (range 29-79)) as per updated IMWG diagnostic criteria (2014), including 9 (2%) PCL patients, with the remainder diagnosed as SMM/MGUS (31; 7%) or other (14; 3%). For 371 of the 376 symptomatic MM patients BM was received by the central laboratory and was of sufficient quality for profiling in 331 (89%) patients. Repeat samples were requested for all others and a sufficient sample received for 20/45 (44%). Central results were successfully reported within the pre-specified 56 day interval for all patients (median 17 days; IQR 13-22). Of 346 patients with a reported result, 128 (37.0%) have high-risk MM, with molecular characteristics mirroring Myeloma XI patients (Figure 1). PCL patients show expected characteristics as listed in Table 1. Basic demographics were not different between high-risk vs. non-high-risk. 101 high-risk patients have or are planning to enter MUK9B, 10 pending decision; 17 high-risk patients did not enter MUK9B, the majority due to ineligibility. 92 patients have started Dara-CVRD therapy. There are currently no safety concerns, the majority of patients are completing induction successfully; 1 patient stopped induction therapy due to adverse events. Updated results will be presented. Discussion Our data demonstrate feasibility of multi-center molecular stratified trial delivery for high-risk NDMM patients. These early trial results strongly support accelerated trial strategies for MM patient groups with high unmet need and rational drug development specifically for high-risk MM. Disclosures Jenner: Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Croft:Celgene: Other: Travel expenses. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria. Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses.

Background Outcome varies considerably in newly diagnosed myeloma (NDMM), in particular in transplant eligible (TE) patients, ranging from a few years to decades. Autologous stem cell transplant (ASCT) remains the overall aim following induction therapy even with the advent of novel agents. Greater availability of novel treatments allows for complex combination induction and potentially maintenance therapies. Possible long-term unintended effects and affordability will likely make rational treatment stratification for populations in most need desirable, in particular for public health care systems. We report here an extended outcome analysis of 1,064 genetically and clinically characterised patients from the transplant treatment pathway of the NCRI Myeloma XI trial. Patients In Myeloma XI patients were randomised to induction therapy with CTD (cyclophosphamide, thalidomide and dexamethasone) or CRD (cyclophosphamide, lenalidomide and dexamethasone) and +/- CVD (cyclophosphamide, bortezomib, dexamethasone) intensification in patients with Genetic results for the high-risk markers t(4;14), t(14;16), t(14;20), gain(1q) and del(17p) were determined for all patients with sufficient material centrally by qRT-PCR and MLPA (MRC Holland). For a sub-set of patients with insufficient central material, local cytogenetic (FISH) reports were centrally reviewed and only those with a valid result for all risk markers included in this analysis. Differences in PFS, PFS2 and OS were assessed and compared using the log-rank test. Results Patient outcome was analysed by combining information on genetic risk defined as standard risk (SR) (no adverse lesions), high-risk (HR) (single adverse lesion: t(4;14), t(14;16), t(14;20), gain(1q) or del(17p)) or ultra-high risk (UHR) (≥2 adverse lesions) and International Staging System (ISS) 1 vs. ≥2. Genetic information was available for all 1064 patients. Baseline clinical characteristics (age, sex, race) were similar between groups, but 47.7% of UHR+ISS≥2 had an IgA paraprotein compared to 27.4% average across all groups. After a median follow up of 68 months (interquartile range 49-83) we found that the two most contrasting risk categories, UHR+ISS2/3 (10.1% patients) and SR+ISS1 (17.3%) were associated with the expected extreme clinical outcomes, with median PFS of 20 months vs. 50 months (P Across all genetic risk groups, fewer patients with ISS≥2 vs. those with ISS1 completed intention-to-treat HD-MEL and ASCT. For example, 65.4% of UHR+ISS≥2 completed ASCT vs. 76.1% of SR+ISS1 patients. The main reasons for patients not proceeding to ASCT were 'clinician decision/patient unfit' (43.5%), 'disease progression/death' (26.1%) or 'patient decision' (13%) for UHR+ISS≥2 patients, with fewer 'progression/death' (15%) and a more 'patient decision' in SR+ISS1. Across all groups, more patients were able to undergo ASCT following KCRD induction as opposed to CTD or CRD. This improvement was most notable in the UHR+ISS≥2 group: 82.4% KCRD vs. 58.9% CTD and 67.6% CRD. Differences in outcomes by risk group were comparable between PFS1 and PFS2. However, for UHR+ISS≥2, median PFS2 was 35 months and OS 43 months (delta=8 months), indicating limited efficacy of current treatments beyond 2nd line for this group. The difference between PFS2 and OS was markedly higher for HR+ISS≥2, with PFS2 52 months and OS 68 months. Conclusion Our results indicate the urgent need for improved treatment approaches for ultra-high risk patients, in particular those with UHR+ISS≥2. Our analysis demonstrates that fewer of these patients reach important therapeutic milestones such as ASCT if not effectively treated during induction. These patients are likely to derive the biggest benefit from early stratification and novel treatment approaches, as our data indicate that these patients obtain modest benefit from therapies beyond 2nd line. Disclosures Kaiser: Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Paterson:Celgene, Amgen, Merck, Takeda: Other: Research funding to institution. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria.

BACKGROUND As lenalidomide (LEN) becomes increasingly established as a standard of care in the treatment (Tx) of newly diagnosed multiple myeloma (NDMM), patients (pts) for whom LEN is no longer a Tx option, including those who have become refractory to LEN, represent a clinical reality. These pts represent the largest population with MM at first relapse in the United States and a growing population globally. To date, they have been poorly studied and remain difficult to treat. Previous trials have demonstrated a clinical benefit with pomalidomide (POM) therapy in LEN-refractory pts with relapsed or refractory MM (RRMM), including those who were heavily pretreated (median of 5 prior regimens) (San Miguel et al. Lancet Oncol 2013; Richardson et al. Blood 2014; Dimopoulos et al. Blood 2016). These studies led to the approval of POM + low-dose dexamethasone (LoDEX) in RRMM. The pomalidomide, bortezomib, and low-dose dexamethasone (PVd) regimen has shown promising activity in early-phase clinical trials in LEN-refractory pts. In the phase 3 OPTIMISMM trial, PVd showed significantly improved progression-free survival (PFS) and a manageable safety profile compared with bortezomib and low-dose dexamethasone (Vd) in intent-to-treat population of pts who received 1-3 prior regimens and were 100% LEN pretreated; 70% of pts were LEN refractory (Richardson et al. ASCO 2018 abstract 8001). Here, we present efficacy and safety results in LEN-refractory and -nonrefractory pts treated at first relapse. METHODS Pts were randomized 1:1 to receive PVd or Vd in 21-day cycles: POM 4 mg/day on days 1-14 (PVd arm only); bortezomib (BORT) 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1-8 and on days 1 and 8 of cycles 9+; and DEX 20 mg/day (10 mg/day if aged > 75 yrs) on the days of and after BORT. Key eligibility criteria included ≥ 2 cycles of prior LEN therapy, including LEN-refractory pts. BORT-exposed pts were eligible to enroll, provided they did not have progressive disease during therapy or within 60 days of the last dose of a BORT-containing regimen with BORT dosed at 1.3 mg/m2 twice weekly. The primary endpoint was PFS. RESULTS Out of 559 pts enrolled patients, 226 were treated in the second line (2L), data cut off October 26, 2017: 111 with PVd and 115 with Vd. Median follow-up for 2L pts was 16.4 mos. Among 2L pts, 129 (57.1%) were LEN refractory (64 PVd; 65 Vd) and 97 (42.9%) were LEN nonrefractory (47 PVd; 50 Vd). In LEN-refractory pts (PVd vs Vd) median age was 68.0 vs 69.0 yrs, 57.8% vs 58.5% were male, and 56.3% vs 47.7% had prior BORT. In LEN-nonrefractory pts, median age was 66.0 vs 65.5 yrs, 63.8% vs 38% were male, and 66.0% vs 72.0% had prior BORT. Other key baseline characteristics were similar between Tx arms and subgroups. Median PFS was 17.8 mos with PVd vs 9.5 mos with Vd in LEN-refractory (HR 0.55; 95% CI, 0.33-0.94; Figure 1A) and 22.0 vs 12.0 mos in LEN-nonrefractory pts (HR 0.54; 95% CI, 0.29-1.01; Figure 1B). Response outcomes are shown in Figure 2. ORR was 85.9% with PVd vs 50.8% with Vd in LEN-refractory pts (P < .001) and 95.7% vs 60.0% in LEN-nonrefractory pts (P < .001). In 2L LEN-refractory pts, the most common grade 3 or 4 treatment-emergent adverse events (TEAEs) with PVd vs Vd were neutropenia (35.9% vs 12.9%), thrombocytopenia (17.2% vs 22.6%), and anemia (17.2% vs 8.1%). Grade 3 or 4 infections occurred in 29.7% vs 21.0% of pts. In 2L LEN-nonrefractory pts, the most common grade 3 or 4 TEAEs were neutropenia (36.2% vs 6.3%) and thrombocytopenia (23.4% vs 18.8%). Grade 3 or 4 infections occurred in 27.7% vs 8.3% of pts. In 2L LEN-refractory pts, median Tx duration of PVd vs Vd was 9.7 vs 6.1 mos. In 2L LEN-nonrefractory pts, median Tx duration of Pvd vs Vd was 13.6 vs 6.6 mos. CONCLUSIONS To date, OPTIMISMM is the only phase 3 trial to address Tx of pts with RRMM following LEN exposure in early lines and the first to report data in LEN-refractory pts after first relapse. PVd reduced the risk of progression and death by 45% and 46% vs Vd in LEN-refractory and -nonrefractory pts, respectively. Further, in both subgroups, 2L Tx with PVd significantly improved ORR and led to deeper responses compared with Vd. AEs with PVd therapy were generally consistent with the known AEs of POM, BORT, and DEX. These data further demonstrate that PVd is effective and tolerable in pts for whom LEN is no longer a Tx option, including LEN-refractory pts, supporting its use as 2L therapy in RRMM. Disclosures Dimopoulos: Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. White:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria; BMS: Honoraria; Novartis: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Jenner:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Pavic:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salomo:Cilag: Consultancy; Janssen: Consultancy. Yu:Celgene: Employment, Equity Ownership. Nguyen:Celgene Corporation: Employment. Bensmaine:Celgene: Equity Ownership. Peluso:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1: 1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m(2) on days 1 and 2 of cycle 1; 27 mg/m(2) thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n = 157) or control (n = 158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4-14.4) vs 10.0 months (95% CI 7.7-12.0) with carfilzomib vs control (hazard ratio = 0.975; 95% CI 0.760-1.249; P = 0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade >= 3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

Background: Isatuximab (ISA) targets CD38-expressing tumor cells through a combination of activities, including antibody-dependent cellular cytotoxicity, direct pro-apoptotic activity, and complement-dependent cytotoxicity. A phase I study evaluating ISA monotherapy demonstrated promising clinical activity in 35 patients with relapsed/refractory multiple myeloma (RRMM) (Martin T et al, J Clin Oncol 2014; 32:8532). This is an ongoing phase II study (NCT01084252) with 2 stages: stage 1 to select the dose for stage 2 of the study, and stage 2 to assess efficacy and safety of ISA monotherapy or in combination with dexamethasone in RRMM. In stage 1, patients were randomized to 1 of 3 dose groups: ISA 3 mg/kg Q2W, 10 mg/kg Q2W × 2 cycles then Q4W, or 10 mg/kg Q2W. Based on pharmacokinetic data, a fourth dose of 20 mg/kg QW × 4 doses then Q2W was added. The overall response rates (ORRs) for the 4 dosing schemes were 4% (1/23), 20% (5/25), 29% (7/24), and 24% (6/25), respectively. Based on these results, a dose of 20 mg/kg QW for cycle 1 followed by 20 mg/kg Q2W in subsequent cycles was chosen for stage 2 of the study (Richter J et al, J Clin Oncol 2016;34:8005). Here, we report the baseline characteristics and demographic data from stage 2 at the selected dosing scheme from stage 1. Full safety and efficacy data will be presented at the meeting. Methods: This study enrolled patients with MM who had previously received an immunomodulatory drug and a proteasome inhibitor. Patients received ISA monotherapy (20 mg/kg on Day 1, 8, 15, and 22 [QW] of cycle 1 followed by 20 mg/kg on Day 1 and 15 [Q2W] of subsequent cycles) or ISA in combination with dexamethasone (40 mg/day [20 mg/day in patients ≥75 years old]). The primary objective was to evaluate the activity of ISA as monotherapy and in combination with dexamethasone in patients with RRMM in terms of ORR. Results: A total of 165 patients received at least 1 cycle of treatment. Median age was 67 (37-85) years. Median time from diagnosis to first dose was 5.35 (0.7-23.0) years. Median number of prior lines was 4 (2-11) and median number of prior regimens was 6 (2-17). Patients received a median of 5 (1-17) cycles of treatment, with a median duration of exposure of 22 (1-69) weeks. Discontinuation occurred in 106 (64.2%) patients due to adverse events (15 patients, 9.1%), disease progression (85 patients, 51.5%), or patient decision (6 patients, 3.6%). Conclusion: The full efficacy and safety data for this heavily pre-treated RRMM population will be available for presentation at the meeting. Funding: Sanofi Disclosures Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Research Funding; Sanofi: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cole:University of Michigan: Employment; Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria. Hungria:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Jenner:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vorobyev:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biocad: Consultancy; Takeda: Speakers Bureau; BMS: Speakers Bureau; Astellas: Speakers Bureau. Yanez Ruiz:Universidad de la Frontera: Employment. Yin:Sanofi: Employment. Hamlett:BDM Consulting Inc.: Employment; Sanofi: Consultancy. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Multi-agent induction chemotherapy followed by autologous stem cell transplant (ASCT) is a standard of care for younger patients with multiple myeloma, aimed at maximising the depth and duration of first response (PFS1). However, the duration of PFS1 is variable between patients. Improved understanding of how to identify high risk patients who relapse early and the ability to design strategies applicable to their biology represents the central aim of personalized medicine approaches for MM. This landmarked analysis of the Myeloma XI trial was designed to identify the characteristics of patients with PFS1 of less than a year after ASCT. Patients and methods In MXI patients were randomised to induction therapy with CTD (cyclophosphamide, thalidomide and dexamethasone) or RCD (lenalidomide, cyclophosphamide and dexamethasone) and +/- CVD (bortezomib, cyclophosphamide, dexamethasone) intensification in patients with Patients who completed ASCT were identified with very early relapse (PFS1 Results Of 1274 patients receiving ASCT: 178 (14%) relapsed within 12m and 1096 (86%) thereafter. There were higher rates of ≥VGPR in the PFS1≥12m group (70% vs 59%) and in both groups most patients responded at ≥PR (PFS1 Inferior outcomes continued for the PFS1 As PFS1 Discussion Nearly three quarters of those with PFS1 Disclosures Bygrave: Amgen: Honoraria; Takeda: Honoraria, Other: Travel Support; Janssen: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding. Pawlyn:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene Corporation: Consultancy, Honoraria, Other: Travel support; Takeda Oncology: Consultancy, Other: Travel support; Janssen: Honoraria, Other: Travel support. Davies:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; ASH: Honoraria; TRM Oncology: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Cairns:Merck Sharp and Dohme: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Striha:MSD: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Hockaday:Millenium: Research Funding; MSD: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Jones:Celgene: Honoraria, Other: Travel support, Research Funding. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Garg:Amgen: Honoraria, Other: Travel Support; Takeda: Other: Travel Grant; Novartis: Other: travel support, Research Funding; Janssen: Honoraria. Williams:Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel Support, Speakers Bureau; Takeda: Honoraria, Other: Travel support; Amgen: Honoraria, Speakers Bureau. Karunanithi:Janssen: Other: Travel support, Research Funding; Celgene: Other: Travel support, Research Funding. Lindsay:Celgene: Honoraria, Other: Travel support; BMS: Consultancy, Other: Travel support; Takeda: Other: Travel support; Janssen: Consultancy; Novartis: Other: Travel support. Jenner:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Gregory:Janssen: Honoraria; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Jackson:Amgen: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kaiser:Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Travel support; Takeda: Consultancy, Other: Travel Support; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.