BACKGROUND:High-risk multiple myeloma, defined by two or more high-risk cytogenetic abnormalities (HRCAs), high-risk gene expression profiling (GEP), or plasma cell leukaemia, remains associated with poor long-term outcomes despite quadruplet induction therapy. OPTIMUM showed that intensified induction, extended consolidation, and maintenance therapy after autologous stem-cell transplantation (ASCT) improved progression-free survival for patients with high-risk multiple myeloma. Here we report the 5-year follow-up of survival outcomes across molecular subgroups. METHODS:The multicentre, externally controlled, phase 2 OPTIMUM trial was conducted at 22 centres in the UK and enrolled patients aged 18 or older with newly diagnosed high-risk multiple myeloma or plasma cell leukaemia, measurable disease according to IMWG criteria, up to two previous induction cycles, and an Eastern Cooperative Oncology Group Performance Status of 2 or less. Participants received intravenous or subcutaneous daratumumab, oral cyclophosphamide, subcutaneous bortezomib, oral lenalidomide, and oral or intravenous dexamethasone induction at protocol specified doses before and after ASCT; melphalan-bortezomib during ASCT; consolidation part 1: daratumumab, bortezomib, lenalidomide, and dexamethasone; consolidation part 2: bortezomib, lenalidomide, and daratumumab; and maintenance lenalidomide and daratumumab until disease progression, unacceptable toxicity, or withdrawal. The trial used a Bayesian design and activity of treatment was compared with a molecularly matched external control cohort from the Myeloma XI trial. The primary endpoint was 18-month progression-free survival and has been previously reported. In this analysis, we report progression-free survival, progression-free survival 2 (time from registration until second disease progression or death, whichever occurred first), and overall survival at 5 years follow-up; and subgroup analyses by high-risk multiple myeloma features at entry (≥2 HRCAs, high-risk GEP, ≥2 HRCAs and high-risk GEP; and plasma cell leukaemia; subgroups selected post-hoc). OPTIMUM was registered with ClinicalTrials.gov (NCT03188172; active [not recruiting], with ongoing follow-up and maintenance). FINDINGS:Between Sept 29, 2017, and Sept 24, 2019, 108 participants with high-risk multiple myeloma were recruited to OPTIMUM and 107 were included in the analysis, with 120 genetically matched patients from the Myeloma XI trial (external control). Median follow-up was 71·1 months (IQR 66·9-77·7) for OPTIMUM and 117·8 months (98·3-128·6) for Myeloma XI. Progression-free survival (not reached [NR; 70·6-NR] vs 24·4 months [19·7-30·4]; HR 0·32 [95% CI 0·22-0·45]; p<0·0001) and overall survival (NR [NR-NR] vs 57·4 months [47·3-74·2]; HR 0·43 [95% CI 0·28-0·65]; p<0·0001) was longer in OPTIMUM than in Myeloma XI. Median progression-free survival 2 was NR (NR-NR) in OPTIMUM and 43·9 months (38·3-51·5) in Myeloma XI (HR 0·26 [95% CI 0·17-0·41]; p<0·0001). The survival benefit was consistent across high-risk multiple myeloma subgroups, except for patients with three or more HRCAs. INTERPRETATION:OPTIMUM shows sustained progression-free survival and overall survival improvement with risk-stratified extended therapy, supporting implementation of molecular diagnostics and tailored treatment in patients with newly diagnosed high-risk multiple myeloma. FUNDING:Myeloma UK, BMS, and Johnson & Johnson.

ABSTRACT:Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG- and GEP-standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.

Early intervention in smoldering multiple myeloma (SMM) may delay progression to MM. Here, we present the final analysis of the phase 2 CENTAURUS study. In total, 123 patients with intermediate/high-risk SMM were randomized to IV daratumumab 16 mg/kg after a long-intense (n = 41), intermediate (n = 41), or short-intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the long-intense, intermediate, and short-intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P < .0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the long-intense or intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per-protocol treatment. The median duration of study treatment was 44.0 (range, 1.0-91.6), 35.2 (range, 1.9-90.6), and 1.6 (range, 0.1-1.9) months in the long-intense, intermediate, and short-intense arms, respectively. No new safety signals were observed. With extended follow-up (median,-7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. This trial was registered at www. ClinicalTrials.gov as #NCT02316106.

ABSTRACT:Early intervention in smoldering multiple myeloma (SMM) may delay progression to MM. Here, we present the final analysis of the phase 2 CENTAURUS study. In total, 123 patients with intermediate/high-risk SMM were randomized to IV daratumumab 16 mg/kg after a long-intense (n = 41), intermediate (n = 41), or short-intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the long-intense, intermediate, and short-intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P < .0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the long-intense or intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per-protocol treatment. The median duration of study treatment was 44.0 (range, 1.0-91.6), 35.2 (range, 1.9-90.6), and 1.6 (range, 0.1-1.9) months in the long-intense, intermediate, and short-intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ∼7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. This trial was registered at www.ClinicalTrials.gov as #NCT02316106.

Introduction: Older and frailer patients with multiple myeloma (MM) are less able to tolerate some therapies which may explain the inferior health outcomes they experience. The UK Myeloma Research Alliance Myeloma XIV FiTNEss trial (NCT0372004) is a phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not eligible for stem cell transplant that compares a standard (reactive) therapeutic dosing strategy (RT) to a pre-emptive frailty-adjusted dosing strategy (FA). FA uses IMWG-based scores to determine patients' level of frailty and adapts the dosing strategy accordingly in an effort to reduce toxicity and early treatment cessation. We conducted an economic evaluation alongside the FiTNEss clinical trial to determine the value of FA vs RT in Unfit/Frail patients over 12 months. Methods: The FiTNEss trial randomised newly diagnosed MM patients to either standard reactive dose modification in light of toxicity (RT) vs upfront pre-emptive dose-modification according to IMWG FS (FA), of induction therapy comprising the oral triplet ixazomib, lenalidomide and dexamethasone (IRd). The primary end point of the first randomisation was to compare early treatment cessation of induction therapy delivery with the triplet IRd between patient cohorts. The primary endpoint of the second randomisation was to compare progression free survival for maintenance lenalidomide (R) plus placebo and lenalidomide plus ixazomib (IR). The economic evaluation adopted the cost-utility framework and presents cost per quality-adjusted life year (QALY). Health-related quality of life (HRQoL) was captured on the EQ-5D-3L measure at baseline, 2, 6 and 12 months. Health care resource use was captured using patient reported forms at the same time points, supplemented by hospital incident forms. Costs included resources required for the frailty assessment, medication costs (including second line therapies for those progressing or stopping first line therapy), primary care costs (e.g. GP visits) and secondary care costs (e.g. hospital visits and stays). We conducted a complete case (CC) analysis, using cases who had provided full cost and HRQoL follow-up data, and an intention-to-treat (ITT) analysis using multiple imputation to deal with missing data. Estimates were adjusted for trial minimisation factors. We present cost and QALYs per trial arm and incremental cost-effectiveness ratios (ICERs). Sampling uncertainty is characterised in the probability of cost-effectiveness given the UK willingness to pay for QALY gains (£20,000-£30,000). Results: The FiTNEss trial recruited 733 patients from 04/08/2020 until 01/03/2024 from 84 sites in the UK; 535 patients were Unfit/Frail. The cost of the frailty assessment was modest (£28.50 based on an assumed 30 minutes of research nurse time). A total of 163 patients were included in the CC sample. The number of treatment cycles completed was slightly higher among Unfit/Frail in the FA arm (7.84 [95%CI 7.3:8.39] vs 7.73 [95%CI 7.19:8.27], p=0.78). Mean per patient primary care costs were lower in the FA arm (£107 [95%CI £75:£138] vs £194 [95%CI £112:£276], p=0.05); but mean secondary care costs were higher in the FA arm (£3,582 [95%CI £2324:£4841] vs £2,036 [95%CI £1295:£2777], p=0.04), driven by higher unplanned hospital admitted days. The adjusted differences in costs and QALYs between trial arms for the CC analysis were £7,431 [95%CI £-3532:£18394, p=0.14] and 0.072 ([95%CI 0.022:0.141], p=0.07) (ICER = £103,208), respectively; and for the ITT analysis were £250 [95%CI £-6841:£7340, p=0.95] and 0.02 ([95%CI -0.021:0.06], p=0.35) (ICER = £12,943), respectively. Thus, FA was more costly on average when considering medication and health care use costs but offered QALY gains over RT. At the UK cost-effectiveness threshold of £20,000-30,000 FA has a 52-54% probability of cost-effectiveness. Conclusions: This preliminary analysis suggests that frailty-adjustment of induction therapy in newly diagnosed TNE MM is likely to lead to non-trivial benefits in QALYs over 12 months, but higher levels of secondary care use and medication costs compared to standard dosing. Based on the ITT analysis, the FA strategy is likely to be considered cost-effective in Unfit/Frail patients. Future planned research extrapolating HRQoL benefits over a longer time horizon, where cheaper maintenance therapies are used, may give a more accurate estimate of the value of FA.

Introduction The UKMRA/NCRI Myeloma XI+ phase III randomized trial for NDMM patients compared intensified induction with a carfilzomib containing quadruplet (KRdc) vs a response-adapted approach of sequential triplet therapies. An interim analysis at a median of 35 months follow-up demonstrated a significant improvement in progression-free survival in the KRdc group (HR 0.63, 95% CI 0.51, 0.76, p <0.001). Here we present updated analysis after a median 102 months of follow up, including analysis of the co-primary endpoint overall survival. Methods Using an adaptive trial design the Myeloma XI trial, which initially randomized patients between CRd and CTd, was amended to randomly assign patients 2:1:1 between KRdc, CRd and CTd (Myeloma XI+). KRdc was given in 28 day cycles (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, cyclophosphamide (C) 500mg PO d1,8), CRd (28d, C 500mg PO d1,8, R 25mg PO d1-21, D 40mg PO d1-4, 12-15) and CTd (21d, C 500mg PO d1,8,15 thalidomide 100-200mg PO daily, D 40mg PO d1-4,12-15). Induction regimens were continued for a minimum of 4 cycles and to maximum response. Suboptimal responders (MR/PR) to CTd/CRd were randomized between pre-transplant intensification with a proteasome inhibitor (bortezomib, CVD) containing triplet or no further therapy prior to ASCT, patients with refractory disease (SD/PD) all received CVD. For all patients a maintenance randomization post ASCT compared lenalidomide to observation. Centrally analysed cytogenetic data was available for a representative subset of patients. High-risk (HiR) was defined as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk (UHiR) the presence of more than one lesion. MRD assessment was performed using next generation flow with a median sensitivity of 2x10-5. Results 1056 patients underwent induction randomization, allocated to KRdc n=526, CTd n=265 and CRd n=265. The groups were well matched for baseline variables with median age 61 (range 33-75). No change in the toxicity profile emerged with long-term follow up. KRdc was associated with a significantly longer median PFS than triplet therapy, KRdc 56 vs CTd/CRd 37 months (HR 0.69, 95%CI 0.60, 0.80, p<0.001). Improved PFS was seen in all cytogenetic risk groups: SR median KRdc 64 vs CTd/CRd 42m (HR 0.71, 95%CI 0.51, 1.00), HiR 45 vs 36m (HR 0.70, 95%CI 0.47, 1.03), UHiR 34 vs 20m (HR 0.49, 95%CI 0.21, 1.12). MRD negativity was achieved in 26.9% of those tested at the end of induction (KRdc 38.5% vs CRd 16.3% vs CTd 10.8%) and in 47.7% after ASCT (KRdc 57.0%, CRd 36.7%, CTd 37.7%). MRD negative status was associated with improved PFS with all regimens and KRdc was associated with improved outcomes compared to CRd/CTd even in those achieving MRD negativity. Early achievement of MRD negativity with KRdc (after induction) was associated with improved PFS compared to those who achieved MRD- after ASCT. Analysis of OS for contemporaneously randomised patients was numerically longer with KRdc vs CTd/CRd (OS at 60 months 76% vs 71%, HR 0.87, 95%CI 0.72, 1.06, p=0.168). As the trial closed prior to the planned event-driven analysis (419/466 of required contemporary deaths) due to funding constraints, resulting in some loss of power for the OS analysis, an additional OS analysis was performed incorporating all patients randomised across the study (KRdc n=526, CTd n=1021, CRd n=1021) with appropriate adjustment for temporal changes in the control group. These data suggested KRdc significantly prolonged OS compared to CTd/CRd (OS at 60 months 76% vs 68%; HR 0.80, 95%CI 0.67, 0.95, p=0.011). The greatest OS benefit was seen in patient with ISS stage 3 and HiR/UHiR disease. PFS and OS results were consistent when an optimal control group (i.e. excluding those randomised to no CVD if PR/MR) was used. Conclusions The addition of carfilzomib to an immunomodulatory agent, dexamethasone and cyclophosphamide triplet was associated with deeper responses and a significantly longer PFS. OS was significantly improved when including non-contemporaneous controls, adjusted for temporal trends. This suggests a clinically significant improvement in overall survival and emphasises the importance of early combination of PI and IMID therapy rather than a response adapted approach, with particular benefit in patients with aggressive disease defined as HiR or UHiR.

Introduction In the phase III UKMRA/NCRI Myeloma XI trial 1248 patients were randomised between lenalidomide maintenance and observation after induction therapy and ASCT. At a median of 31 months (m) follow-up there was a significant improvement in progression free survival (PFS) and overall survival (OS). Median PFS was 57m (95%CI 50-not reached) in the lenalidomide group and 30m (25-32) in the observation group (HR 0·48 [95%CI 0·40, 0·58]; p<0·0001 and 3-year OS was 87·5% [95%Cl 84·3-90·7] with lenalidomide and 80·2% [95%CI 76·0, 84·4] with observation; HR 0·69 [95% CI 0·52-0·93]; p=0·014. Here we present updated analysis after a median of 101 months follow up and explore outcomes by subgroups including transplant eligibility, MRD status, cytogenetic risk and duration of therapy. Methods Myeloma XI was a phase III trial with a pathway for transplant eligible (TE) newly diagnosed myeloma patients who, after immunomodulatory agent-based induction therapy and autologous stem cell transplant, were randomised between lenalidomide maintenance (Len, 10mg 21/28 days planned to continue till disease progression) or observation (Obs). Centrally analysed cytogenetic data was available for a representative subset of patients. High-risk was defined as presence of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) and ultra-high risk the presence of more than one lesion. MRD assessment was performed using next generation flow cytometry with a median sensitivity of 2x10-5. Results After a median of 101m of follow up lenalidomide maintenance was associated with a significantly prolonged median PFS 33 vs 66m, HR 0.57 [95% CI 0.50, 0.65], p<0.001. This improvement in PFS was consistent across cytogenetic risk groups (SR median PFS 37 vs 83m, HR 0.49 [95%CI 0.37, 0.66], p<0.001, HiR 29 vs 59m, HR 0.45 [95%CI 0.31, 0.66], p<0.001, UHiR 11 vs 23m, HR 0.50 [95%CI 0.28, 0.88]), p=0.017. Median overall survival was not significantly different in the overall population (116 vs 130m, HR 0.91 [95%CI 0.77, 1.09], p=0.316) but there was evidence of heterogeneity by genetic risk status with those patients having only one cytogenetic lesion having a significant OS benefit (SR OS at 7 years 67% vs 72%, HR 0.90 [95% CI 0.61, 1.34], HiR 42 vs 64%, HR 0.58 [95% CI 0.37, 0.90], UHiR 25 vs 25%, HR 0.91 [95% CI 0.46, 1.79]). MRD negative status at both ASCT+3m and ASCT+9m timepoints was strongly associated with improved PFS (ASCT+3m HR 0.55 [95%CI 0.46, 0.65], ASCT+9m HR 0.41 [95%CI 0.31, 0.54]) and OS (ASCT+3m HR 0.72 [95%CI 0.58, 0.89], ASCT+9m HR 0.52 [0.36, 0.75]). There was evidence of benefit of lenalidomide maintenance over observation in the MRD positive group for both PFS and OS and in the MRD negative group for PFS but not OS. Patients converting to MRD negativity by 9m appeared to have similar long outcomes to those achieving MRD negativity at the earlier time point. Multiple cut-point analysis confirmed previous findings suggesting a benefit for lenalidomide maintenance beyond 4-5 years in the overall population. There was no evidence of an adverse impact on overall survival with longer duration therapy. For patients MRD negative at the start of maintenance the benefit of ongoing maintenance appeared to lose significance earlier, after 3 years. With extended follow-up the median duration of maintenance is 36 cycles [range 1-146]. Around half of patients stopping maintenance did so due to disease progression (51.5%). In the remainder, the most common reason cited was toxicity (19.6%). 79% of patients required a lenalidomide dose modification during their maintenance course. No new specific toxicity signals were identified with longer-term follow up. Cumulative incidence of second primary malignancies at 8 years was 7.0% (95%CI 4.79%, 9.12%) in the observation arm and 12.4% (95%CI 10.13%, 14.71%) in the lenalidomide arm. Conclusions Taken together these data can help define the optimal maintenance strategy for different patient groups. For patients with standard risk disease who become MRD negative after ASCT, limited duration maintenance approaches could be considered and should be evaluated in randomised studies. Patients with single high-risk lesions appear to have the greatest benefit, with an overall survival benefit from maintenance continued to progression. Patients with UHiR disease and those MRD positive at 9 months after ASCT have poor long-term outcomes and should be considered for combination maintenance approaches.

Background: Outcome for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (MM) remains unsatisfactory. Recently, we showed promising early results with stratified treatment for UHiR MM; however, maintaining responses is most challenging in UHiR, but also most relevant for patients, and efficacy beyond the initial 36 months has not yet been reported for any of the novel risk-stratified MM trials. We present here the 5-year PFS and OS follow-up for the risk stratified OPTIMUM/MUKnine trial (NCT03188172), in which treatment was specifically tailored to address UHiR MM relapse patterns. Methods: In OPTIMUM, NDMM patients with UHiR by ≥2 HRCA: t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) or gene expression risk (GEP; SKY92 signature), identified through central genomic screening of all-comers, or with PCL, received up to 6 cycles of Dara-CVRd induction, V-ASCT, 6 cycles Dara-VRd (Cons1) and 12 cycles Dara-VR (Cons2), before moving to monthly Dara-R maintenance until progression. OPTIMUM recruited 107 UHiR participants, including 9 PCL, from 472 all-comer patients screened at 39 UK NHS hospitals between Sep 2017 and Jul 2019. We report here results of the pre-planned 5-year PFS and OS analysis for the overall group, and for pre-defined sub-groups by genetics and GEP. Results are contextualised with UHiR patient outcomes from the digital comparator Myeloma XI (MyXI) trial, in which patients received carfilzomib/cyclophosphamide-Rd (KCRd) or CRd induction, ASCT and lenalidomide maintenance or observation. Median follow-up for OPTIMUM was 61.2 months, and 60.3 months for MyXI. Results: With more than 5 years of follow-up, the median PFS and OS for OPTIMUM UHiR patients were not reached. A continuous improvement in PFS outcomes was noted over the digital MyXI UHiR comparator, with a hazard ratio (HR) of 0.325 (95% CI: 0.220, 0.480; p<0.0001). PFS estimates for OPTIMUM at 36, 48 and 60 months were 75.2% (95% CI: 66.9, 83.4), 70.1% (95% CI: 61.3, 78.9) and 61.4% (95% CI: 51.8, 71.0), compared to MyXI with 32.1% (95% CI: 23.1, 41), 25.3% (95% CI: 16.4, 34.2) and 23% (95% CI: 13.9, 32.1), respectively. PFS estimates for patients who received KCRd in MyXI were 40.8% (95% CI: 23.1, 58.5), 23.8% (95% CI: 1.3, 46.3) and 23.8% (95% CI: 1.3, 46.3), respectively. Importantly, a continuous improvement in OS for OPTIMUM compared to MyXI also emerged with longer follow-up, with a hazard ratio of 0.467 (95% CI: 0.302, 0.723; p=0.0006). OS estimates at 60 months were 71.1% (95% CI: 62.1, 80) for OPTIMUM, versus 43.5% (95% CI: 33.4, 53.6) for MyXI. We further analyzed outcome of clinical and molecular sub-groups of interest. OPTIMUM included 9 PCL patients, who experienced inferior outcome compared to UHiR MM (HR 4.01), with PFS at 36, 48 and 60 months of 44.4%, 33.3% and 16.7%, respectively, highlighting an ongoing unmet need of this population. We found a strong association between genetic characteristics and outcome for the remaining 98 UHiR MM patients (excluding PCL), who were included in the trial based on ≥2 HRCA, ≥2 HRCA+GEP risk, or GEP risk alone. Patients with 3 HRCA (n=7) had markedly shorter 60 mo PFS with 14.3% (95% CI: 0, 40.2) than patients with 2 HRCA (n=50) with 66.9% (95% CI: 53.6, 80.3). Of the 50 patients with 2 HRCA, 21 had no GEP risk signature, and nearly all were still progression free and alive at 60 mo with a PFS of 95% (95% CI: 85.4, 100), suggesting exceptional benefit from OPTIMUM treatment, versus PFS 46.9% (95% CI: 28.4, 65.5) for those with 2 HRCA+GEP risk. Furthermore, UHiR MM patients identified by GEP only (n=49) had 60 mo PFS of 64.2% (95% CI: 49.9, 78.4) with OPTIMUM treatment, confirming their need for intensified treatment. Further sub-group analyses are underway and will be presented at the meeting. Conclusions: Our results demonstrate extended PFS beyond 5 years for the majority of UHiR MM treated with OPTIMUM treatment, and markedly improved overall survival over the MyXI UHiR digital comparator. Results exceed recently reported outcomes for patients with ≥2 HRCA, even from quadruplet induction trials, supporting OPTIMUM tailored treatment for UHiR with quintuplet induction, extended 18 mo Dara-VR consolidation, with permissive bortezomib dose reduction, and ongoing Dara-R maintenance. Furthermore, results reveal exceptional responders and ongoing unmet need groups and highlight, like for other lymphoid malignancies, the strength of integrating GEP with genetic testing in MM.

Introduction Ongoing therapy to progression has become a standard of care for newly diagnosed myeloma (NDMM) patients but this carries with it an increased burden of treatment administration and potential side effects. This may be of particular importance in the older, frailer, patient group due to increased co-morbidities and polypharmacy. Optimum duration may also differ in subgroups of patients, for example those at different levels of frailty. In a novel analysis, updated data for the transplant ineligible (TNE) pathway of the UKMRA/NCRI Myeloma XI trial after more than 8 years follow up were used to explore this question. Methods Myeloma XI was a phase III trial with a pathway for TNE NDMM patients who, after immunomodulatory agent-based induction therapy, were randomised between lenalidomide maintenance (Len, 10mg, 21/28 days planned to continue to disease progression) or observation (Obs). Progression-free survival (PFS) and overall survival (OS) data were analysed landmarked from multiple time points (2, 3, and 4 years) after the time of maintenance randomisation, including all patients who had not had an event prior to that time point. Data were analysed for all patients, and within UK-Myeloma Risk Profile groups (UK-MRP: based on WHO performance status, age, ISS and CRP, used as a surrogate for frailty), defined as MRP-low, med and high. Results In the TNE pathway 723 patients entered the maintenance randomisation and were allocated to observation (n=316) or lenalidomide (n=407). After a median of 101 months (m) of follow up lenalidomide maintenance was associated with a significantly prolonged median PFS in the TNE pathway (11 vs 26m, hazard ratio [HR] 0.49 [95%CI 0.42, 0.58], p<0.001). PFS benefit was seen across all MRP groups (MRP-low 13 vs 32m, HR 0.47 [0.37, 0.60], MRP-med 11 vs 25m, HR 0.51 [0.39, 0.66], MRP-high 10 vs 17m, HR 0.58 [0.43, 0.78]). There was no significant difference in OS with median 59 and 56m respectively, HR 0.98 [95%CI 0.83, 1.15], p=0.813). The magnitude of the PFS benefit was consistent when landmarked from 2y after randomisation (HR 0.65 [95%CI 0.49, 0.86], p=0.003) but the benefit appeared to diminish at later time points, from the 3y landmark (HR 0.84, [95%CI 0.57, 1.25], p=0.391) and 4y (HR 0.77 [95%CI 0.47, 1.27], p=0.313). OS remained equivalent from all landmarks with no evidence of an OS detriment from continuing lenalidomide (from 2y HR 1.01 [95%CI 0.84, 1.22], from 3y HR 0.95 [0.77, 1.16] and from 4y HR 0.95 [0.76, 1.20]. This did not appear to differ across MRP groups. When landmarked from 2yr after randomisation all groups had an ongoing benefit from lenalidomide maintenance (MRP-low HR 0.64 [95% CI 0.43, 0.94], MRP-med HR 0.80 [95% CI 0.45, 1.41], MRP-high HR 0.48 [95% CI 0.26, 0.87]). Analogous to the overall population, this benefit appeared lost at later landmarks and there was no evidence of OS detriment from any landmark in any MRP group. Median duration of maintenance was 19 cycles, range 1, 145, (MRP-low 28 [1,138], MRP-med 15 [1, 128] and MRP-high 11 [1, 145]). More than half of all patients stopping maintenance did so due to disease progression (58.5%). In the remainder the most common reason cited was toxicity (17.1%), and it was cited more for those in the MRP-med/high groups (21.7% and 18.2% respectively) vs MRP-low (12.7%). 72.5% of all patients required a lenalidomide dose modification during their maintenance course (MRP-low 75.4%, MRP-med 68.1%, MRP-high 73.3%). No new specific toxicity signals were identified with longer-term follow up. Cumulative incidence of second primary malignancies at 8 years was 10.4% (95%CI 7.06%, 13.83%) in the observation arm and 16.3% (95%CI 12.81%, 19.71%) in the lenalidomide arm. Conclusions Long-term follow up of the Myeloma XI trial demonstrates a persistent progression free survival benefit associated with lenalidomide maintenance compared to observation for TNE patients. Exploratory analysis suggests that the benefit of ongoing therapy beyond 2-3 years may be limited, irrespective of MRP subgroup, and randomised studies of limited duration therapy are therefore warranted.

Background Multiple myeloma (MM) predominates in the older adult with significant morbidity and mortality. Frailty (F) is increasingly recognized as a predictor for long- and short-term outcomes, with frailer patients at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for older/frail patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker, but no evidence exists for it as a predictive biomarker, and hence its capability to direct therapy decision-making. This is key to its impact on clinical practice. Study Design and Methods The UK-MRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for stem cell transplant. The primary objectives of the study are 1) to compare in unfit/frail patients early treatment cessation (within 60 days of randomisation) randomised to standard (RT: reactive) and frailty-adjusted (FA: F based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Here we report the final analysis of the first primary objective. Results The FiTNEss trial recruited patients between 04/08/2020 and 01/03/2024 from 84 UK sites. 733 patients were randomised. Median (range) age at randomisation was 77 years (62-93) with 35.2% aged 76-80 and 23.6% over 80. 55.7% were male sex. ISS was I in 20.7%, II in 46.4% and III in 32.6% with standard risk CA in 41.3%, high risk in 19.0% and unavailable in 39.7%. WHO performance status was 0-1 in 76.5%, 2 in 15.6% and 3+ in 7.2%. IMWG FS was FIT in 27.0%, UNFIT in 32.6% and FRAIL in 40.4%. In the R1 ITT population (UNFIT and FRAIL; n=535) 115 patients stopped therapy in the first 60 days: 61/265 (23.0%) in the RT arm vs 54/270 (20%) in the FA arm (adjusted Odds Ratio [OR]: 1.21; 95%CI 0.80-1.84; p=0.368). Reasons for stopping therapy were: death (RT 29.5%, 18/61 vs FA 27.8%, 15/54), patient choice (RT 26.2%, 16/61 vs FA 25.9%, 14/54), clinician choice (RT 13.1%, 8/61 vs FA 20.4%, 11/54) and toxicity (RT 24.6%, 15/61 vs FA 20.4%, 11/54). There was a significant difference in early treatment cessation in the FRAIL (26.1%, n=295) versus the UNFIT (15.8%, n=240) group (adj. OR: 1.85; 95%CI 1.19-2.88; p=0.0061). Across all induction cycles delivered (n=5890 in 733 participants) dose modifications were higher in the RT arm vs FA (I 6.9% vs 5.8%, R 11.9% vs 10.0% and d 9.5% vs 7.2%). In the safety population (n=722), the total number of treatment emergent adverse events was similar between the arms. However, for treatment-emergent serious adverse reactions there were more infections in the RT arm (17%, 60/359 vs 13%, 47/363) and more GI toxicity in the FA arm (8%, 29/359 vs 10%, 36/363). There was no clinically significant difference in the local response rate between the arms, >=VGPR in 42.2% of RT vs 37.8% in FA. Similarly, the 6- and 12-month MRD negative rate was similar (RT 9.9% and 9.3% vs FA 6.8% and 8.2%). 1-year PFS was 73.4% (95%CI 68.1-77.9) in the RT and 76.4% (95%CI 71.3-80.7) in the FA arms (Hazard Ratio [HR] 0.95, 95%CI 0.74-1.20; p=0.657). 136 patients have died, 81 (22.2%) in the RT and 55 (14.9%) in the FA arms. Causes of death were: PD (RT 30.9%, 25/81 vs FA 38.2%, 21/55), infection (RT 19.8%, 16/81 vs FA 9.1%, 5/55), cardiac (RT 7.4%, 6/81 vs FA 12.7%, 7/55) and respiratory (RT 9.9%, 8/81 vs FA 9.1%, 5/55). The 1-year OS was 83.2% (95%CI 78.5-86.9) in RT and 88.7% (95%CI 84.7-91.7) in FA arm (HR 1.45 95%CI 1.03-2.04; p=0.035). Conclusion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The delivery of a frailty-adjusted dosing schedule whilst not improving early treatment cessation rate, did not compromise depth or durability of response and did reduce early mortality (1-year). Subgroup analysis will investigate where the greatest benefit is achieved. This analysis highlights the potential of the IMWG FS to be both a prognostic and predictive biomarker for early mortality in newly diagnosed TNE MM patients.

Chromosomal copy number aberrations (CNAs) are common in multiple myeloma (MM) and play a major role in patient prognosis and treatment outcome. Detection of CNAs is possible using targeted region sequencing (TRS), however, accurate detection and quantification of the total copy number and the subclonal fraction of each targeted genomic region is challenging, especially in low-purity samples. Using the Myeloma Genome Project (MGP) Panel [PMID:35522533], we have developed a segmentation-based CNA calling approach for TRS to (a) identify copy number breakpoints, (b) estimate total copy number and its subclonal fraction (defined as significant deviation from expected clonal state), based on tumor coverage ratio (LogR) normalized by its paired germline sample and (c) adjust for the purity of the tumor sample as estimated from the TRS panel single nucleotide variant (SNV) data. We initially used a set of 27 longitudinal samples from 14 MM patients with both TRS and whole-genome sequencing (WGS) data to optimize the method for accuracy. Results showed a high concordance (96.3%) in total copy number in the targeted regions between WGS (by using Battenberg) and TRS. Cohen's Kappa between the two was 0.93 (95%CI 0.84-1), showing strong agreement between TRS and gold-standard WGS calls. In addition to standard calling of gain and deletion events even in tumors with purity as low as 17%, the method could also differentiate different total copy number states (e.g. distinguishing between Gain1q and Amp1q). We could detect subclonal events with CCF > 0.3 in tumors with a minimum purity of 50%. The ability to detect CCF depended on sample sequencing evenness as quantified by mean absolute difference of LogR across the genomic regions of the panel (MAD(LogR)<0.3). Our method also allowed the detection of biallelic (e.g., Del17p-TP53) and combinatorial (e.g., Gain1q-Del1p) events in myeloma. To validate this method, the same analysis was then undertaken on two independent, recently generated TRS datasets (Oxford dataset, N=48 and the UK RADAR clinical trial, N=80), albeit with single time-point samples. Similar frequencies of high-risk CNAs were identified in the validation datasets (Del1p32-p12, Gain1q21, Amp1q21 and Del17p at 23%, 23%, 4% and 15% in the Oxford dataset and 19%, 28%, 6% and 20% in the RADAR dataset respectively) which also match well with previous reports, corroborating the utility of the developed CNA calling method. Altogether, these results demonstrate that this computational method accurately detects CNAs with prognostic value. Also, with the increasing use of subclone size to define high-risk myeloma in new myeloma high-risk guidelines, our method may enable better risk stratification from TRS data at diagnosis. This method has the potential to be applied to other hematological cancer targeted panels to call accurate CNA in the regions targeted by NGS panels.

Background. A subset of patients with multiple myeloma (MM), termed “high-risk”, have high rates of early relapse and short survival. The definition of high-risk (HR) has evolved with treatment advances and improved genetic characterisation of patient cohorts. New genetic insights require a test that can detect translocations, copy number alterations (CNA) and small variants for risk assignment. This test must correctly identify the HR cohort and be widely and sustainably deployable in healthcare systems. The Myeloma Genome Project (MGP) Panel is a targeted DNA panel developed to include loci for CNA, translocations and genetic variants (PMID:35522533). It incorporates key disease drivers, therapeutic targets and prognostic features, including detection of genomic double/triple hits and bi-allelic inactivation of tumour suppressor genes via structural change, CNA and somatic variation. The UK-MRA RADAR study is a national, multi-centre, risk-adapted, response-guided multi-arm, multi-stage phase II/III trial which will recruit 1400 patients with newly diagnosed MM eligible for autologous stem cell transplant. Genetic risk classification is performed as standard of care (SoC) testing using Fluorescence in situ hybridization test (FISH)/ multiplex ligation-dependent probe amplification (MLPA). HR is defined as two or more genetic abnormalities incorporating t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Participants who cannot be confirmed as standard risk (SR) or HR are classified as unable to determine (UTD) and treated as SR. The collection of central samples within RADAR affords a unique opportunity to compare the performance of FISH/MLPA to MGP in assigning risk status. We report the first results of this analysis, with more to follow. Methods. DNA was extracted from CD138-magnetic bead enriched MM cells in baseline bone marrow samples at a central lab. Paired germline DNA was obtained from peripheral blood. MGP libraries were prepared in an NHS clinical laboratory from samples that met QC metrics and sequenced as previously reported. SoC testing was done across 23 regional NHS labs using FISH/MLPA. Data were analysed to identify 20% Cancer Clonal Fraction (CCF) of high-risk features as per requirements for the SoC results used in RADAR. Genetic risk classification was derived as per the RADAR definition and agreement between the two methods assessed using Cohen's Kappa. Additional measures (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) were derived using SoC classification as the reference group, in a complete case analysis. Finally, a recently proposed revised IMWG HR definition was applied to the MGP results, and the classification of patients compared descriptively. Results. To 1st July 2024, 876 patients have been recruited to RADAR. Of the first 93 central samples received, we report comparison of the 83 who met QC criteria for performing MGP sequencing/analysis. This set was similar to the overall RADAR population in terms of age, ethnicity, paraprotein type and HR proportion, with numerically more females and ISS1 in the MGP set. In the reported set SoC risk assignment was 63/83 (75.9%) SR, 15/83 (18.1%) HR and 5/83 (6.0%) UTD. MGP-based risk assignment using the RADAR definition was 65/83 (78.3%) SR, 15/83 (18.1%) HR and 3/83 (3.6%) UTD. Cohen's Kappa between the two was 0.64 (95% CI: 0.46, 0.83), with MGP re-designating 2 HR cases to SR, and 3 SR cases to HR. 78/83 (94.0%) participants had confirmed classification (SR or HR) in the SoC method. In these 78 samples with SoC as the reference, the sensitivity of MGP was 80%, the specificity was 97%, the PPV 86% and NPV 95%. Risk assignment by MGP using the new IMWG definition was 48/83 (58%) SR, 32/83 (39%) HR and 3/83 (3.6%) UTD. TP53 variants were present in 8/83 (9.6%), co-existing with other HR events in 6/83 (7.2%). Discussion. These initial results suggest there is substantial agreement between the SoC and MGP methods when classifying HR according to the RADAR trial definition. RADAR's ‘2-hit’ HR definition predates the anticipated IMWG criteria, where single TP53/del(17p) events also define HR status, thus HR incidence by IMWG criteria is higher. MGP detects TP53 variants, but RADAR SoC tests do not. We continue to assess and develop MGP assay performance against SoC, in consideration of its deployment for clinical use.

Introduction: Belantamab Mafodotin (Belamaf) is a BCMA targeted antibody drug conjugate with a multi-modal mechanism of action including direct MMAF induced cellular cytotoxicity as well as immunogenic cell death. It has demonstrated superior progression free survival compared to standard of care when combined with either bortezomib (DREAMM-7) or pomalidomide (DREAMM-8) for patients with relapsed or refractory multiple myeloma (RRMM). However these trials dose Belamaf at either Q3W or Q4W which may lead to dose delays and interruptions. ProMMise is a platform trial investigating Belamaf combinations for RRMM using an extended dosing schedule of Q8W to improve tolerability. ProMMise B combines Belamaf with oral cyclophosphamide which at low doses may be synergistic through induction of T and NK cell anti myeloma immune responses by T regulatory cell depletion so may augment the single-agent efficacy of Belamaf. Additionally, cyclophosphamide is low cost, widely globally available and commonly used in combination with standard of care agents. Methods: This was a multi-centre Phase I/II clinical trial for patients with RRMM with 2-4 prior lines. The primary endpoint was to identify the recommended dose of Belamaf in combination with cyclophosphamide and dexamethasone, to estimate the ≥ VGPR rate and assess the safety and toxicity of the combination. Patients received Belamaf 1.9mg/kg (dose level 1) escalating to 2.5mg/kg (dose level 2) Q8W plus cyclophosphamide 500mg orally days 1,8,15 with dexamethasone 40mg weekly Q4W until disease progression/ intolerance. Dose limiting toxicities were evaluated during the dose escalation phases of both levels followed by cohort expansion at the recommended dose. Ocular exams were required at baseline and for at least the first 3 doses of Belamaf. The trial management group included a diversity officer who monitored enrolment monthly according to age, sex and self-identified ethnicity compared to UK cancer registry data. Results: 26 patients were registered with a median age of 63 years (range: 49-86); male:female 1.6; White (54%), Black (15%), Asian (4%), Unknown (27%). Patients had received a median of 3 prior lines (2-4). 7 patients were treated at dose level 1 and 6 into dose level 2 with1 DLT (G3 thrombocytopenia with bleeding) noted. Belamaf 2.5mg/kg was declared the recommended dose and 13 patients were enrolled into dose level 2 expansion. At the time of reporting, patients had completed a median of 6 (2-24) 28 day cycles (level1: 16, level 2: 5). The overall response rate for all patients was 68% (dose level 1: 88% (95% CI 47-100%); dose level 2: 59% (95% CI 33-82%)). The ≥VGPR rate was: 40% (dose level 1: 75% (95% CI 35-97%); dose level 2: 24% (95% CI 7-50%)). In interpreting response rates, it is relevant that responses were seen to deepen over time and follow-up is currently relatively shorter for dose level 2. At dose level 2, the most common all grade adverse events (AEs) reported were: thrombocytopenia (65%), fatigue (35%), nausea (29%) and pain (29%). ≥G3 AEs were thrombocytopenia (19%), fever (13%), neutropenia (6%). Serious AEs of infections were reported in 29%. ≥ G3 corneal events were reported in 38% for dose level 1 and 35% for dose level 2, although more cycles were completed for dose level 1 than 2. 63% of cycles were modified or delayed in dose level 1 vs 63% in dose level 2. Within the first 6 cycles, Belamaf was given at 67% of planned for dose level 1 and 60% of planned for dose level 2. Cyclophosphamide was given at 53% of planned dose at dose level 1 and 45% at dose level 2. Conclusions: Belamaf Q8W in combination with cyclophosphamide and dexamethasone was safe, tolerable and efficacious for patients with RRMM with an ORR of 59-88%. Whilst the initial recommended dose taken for expansion was Belamaf 2.5mg/ kg, the 1.9mg/kg dose has now been chosen for further evaluation due to improved treatment compliance, lower corneal adverse events and similar efficacy. Funding: GSK provided funding and Belamaf supply. This study was also supported by Myeloma UK through the UKMRA-MUK- concept and access research programme. Trial registration number: ISRCTN19869915

This Good Practice Paper provides recommendations for the diagnosis and initial management of transplant-eligible high-risk myeloma patients. It describes recent updates to the genetic diagnostics of high-risk myeloma and provides recommendations for treatment on the basis of recent prospective clinical trial evidence.

Background The Myeloma Response Assessment and Diagnosis System (MY-RADS) guidelines establish a standardised acquisition and analysis pipeline for whole-body MRI (WB-MRI) in patients with myeloma. This is the first study to assess image quality in a multi-centre prospective trial using MY-RADS. Methods The cohort consisted of 121 examinations acquired across ten sites with a range of prior WB-MRI experience, three scanner manufacturers and two field strengths. Image quality was evaluated qualitatively by a radiologist and quantitatively using a semi-automated pipeline to quantify common artefacts and image quality issues. The intra- and inter-rater repeatability of qualitative and quantitative scoring was also assessed. Results Qualitative radiological scoring found that the image quality was generally good, with 94% of examinations rated as good or excellent and only one examination rated as non-diagnostic. There was a significant correlation between radiological and quantitative scoring for most measures, and intra- and inter-rater repeatability were generally good. When the quality of an overall examination was low, this was often due to low quality diffusion-weighted imaging (DWI), where signal to noise ratio (SNR), anterior thoracic signal loss and brain geometric distortion were found as significant predictors of examination quality. Conclusions It is possible to successfully deliver a multi-centre WB-MRI study using the MY-RADS protocol involving scanners with a range of manufacturers, models and field strengths. Quantitative measures of image quality were developed and shown to be significantly correlated with radiological assessment. The SNR of DW images was identified as a significant factor affecting overall examination quality. Trial registration ClinicalTrials.gov, NCT03188172 , Registered on 15 June 2017. Critical relevance statement Good overall image quality, assessed both qualitatively and quantitatively, can be achieved in a multi-centre whole-body MRI study using the MY-RADS guidelines. Key points • A prospective multi-centre WB-MRI study using MY-RADS can be successfully delivered. • Quantitative image quality metrics were developed and correlated with radiological assessment. • SNR in DWI was identified as a significant predictor of quality, allowing for rapid quality adjustment. Graphical Abstract

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

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.