Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

New developments in the diagnosis and characterization of Waldenström's macroglobulinemia.

INTRODUCTION: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) with immunoglobulin M (IgM) monoclonal gammopathy and morphologic evidence of bone marrow infiltration by LPL. Immunophenotyping and genotyping provide a firm pathological basis for diagnosis and are particularly valuable in differential diagnosis between WM and related diseases. Emerging technologies in mutational analysis present new opportunities, but challenges remain around standardization of methodologies and reporting of mutational data across centers. AREAS COVERED: The review provides an overview of the diagnosis of WM, with a particular focus on the role of immunophenotyping and genotyping. EXPERT OPINION: Demonstration of LPL with a bone marrow biopsy is essential to reach a definitive diagnosis of WM. However, MYD88L265P and a typical WM immunophenotypic profile are valuable for the differential diagnosis of WM and related diseases, such as marginal zone lymphoma, multiple myeloma, and chronic lymphocytic leukemia. These methodologies must be utilized across centers and with appropriate standards followed in the evaluation and reporting of sensitivities and specificities. The diagnostic and/or prognostic value of mutations in genes such as CXCR4 and TP53 that are currently not routinely evaluated in the diagnosis of WM should be explored.

Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial.

Background: Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. Methods: Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. Findings: In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. Interpretation: This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. Funding: Primary financial support was from Cancer Research UK [C1298/A10410].

Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study.

The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma.

PURPOSE: The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra-high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial. METHODS: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS. RESULTS: Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity. CONCLUSION: Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.

Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation.

Epstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation following B cell mitogen stimulation was shown to provide a potential model of polymorphic EBV-driven LPD. Here, we developed an in vitro model of plasma cell (PC) differentiation from peripheral blood memory B cells. To assess the frequency and phenotypes of EBV-associated populations derived during differentiation, we analysed eight differentiations during the PC stage with a targeted single-cell gene expression panel. We identified subpopulations of EBV-gene expressing cells with PC and/or B cell expression features in differentiations from all tested donors. EBV-associated cells varied in frequency, ranging from 3-28% of cells. Most EBV-associated cells expressed PC genes such as XBP1 or MZB1, and in all samples these included a quiescent PC fraction that lacked cell a cycle gene expression. With increasing EBV-associated cells, populations with B cell features became prominent, co-expressing a germinal centre (GC) and activating B cell gene patterns. The presence of highly proliferative EBV-associated cells was linked to retained MS4A1/CD20 expression and IGHM and IGHD co-expression, while IGHM class-switched cells were enriched in quiescent PC fractions. Thus, patterns of gene expression in primary EBV reactivation were shown to include features related to GC B cells, which was also observed in EBV-transformed lymphoblastoid cell lines. This suggests a particular association between spontaneously developing EBV-expansions and IgM+ IgD+ non-switched B cells.

Report of consensus Panel 4 from the 11th International Workshop on Waldenstrom's macroglobulinemia on diagnostic and response criteria.

Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.

Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.

Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM.

Upfront autologous haematopoietic stem-cell transplantation versus carfilzomib-cyclophosphamide-dexamethasone consolidation with carfilzomib maintenance in patients with newly diagnosed multiple myeloma in England and Wales (CARDAMON): a randomised, phase 2, non-inferiority trial.

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma is bortezomib-based induction followed by high-dose melphalan and autologous haematopoietic stem-cell transplantation (HSCT) and lenalidomide maintenance. We aimed to evaluate whether an immunomodulatory-free carfilzomib-based induction, consolidation, and maintenance protocol without autologous HSCT was non-inferior to the same induction regimen followed by autologous HSCT and maintenance. METHODS: CARDAMON is a randomised, open-label, phase 2 trial in 19 hospitals in England and Wales, UK. Newly diagnosed, transplantation-eligible patients with multiple myeloma aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 received four 28-day cycles of carfilzomib (56 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), cyclophosphamide (500 mg orally on days 1, 8, and 15), and dexamethasone (40 mg orally on days 1, 8, 15, and 22; KCd), followed by peripheral blood stem cell mobilisation. Patients with at least a partial response were randomly assigned (1:1) to either high-dose melphalan and autologous HSCT or four cycles of KCd. All randomised patients received 18 cycles of carfilzomib maintenance (56 mg/m2 intravenously on days 1, 8, and 15). The primary outcomes were the proportion of patients with at least a very good partial response after induction and difference in progression-free survival rate at 2 years from randomisation (non-inferiority margin 10%), both assessed by intention to treat. Safety was assessed in all patients who started treatment. The trial is registered with ClinicalTrials.gov (NCT02315716); recruitment is complete and all patients are in follow-up. FINDINGS: Between June 16, 2015, and July 8, 2019, 281 patients were enrolled, with 218 proceeding to randomisation (109 assigned to the KCd consolidation group [99 of whom completed consolidation] and 109 to the HSCT group [104 of whom underwent transplantation]). A further seven patients withdrew before initiation of carfilzomib maintenance (two in the KCd consolidation group vs five in the HSCT group). Median age was 59 years (IQR 52 to 64); 166 (59%) of 281 patients were male and 115 (41%) were female. 152 (71%) of 214 patients with known ethnicity were White, 37 (17%) were Black, 18 (8%) were Asian, 5 (2%) identified as Mixed, and 2 (1%) identified as other. Median follow-up from randomisation was 40·2 months (IQR 32·7 to 51·8). After induction, 162 (57·7%; 95% CI 51·6 to 63·5) of 281 patients had at least a very good partial response. The 2-year progression-free survival was 75% (95% CI 65 to 82) in the HSCT group versus 68% (95% CI 58 to 76) in the KCd group (difference -7·2%, 70% CI -11·1 to -2·8), exceeding the non-inferiority margin. The most common grade 3-4 events during KCd induction and consolidation were lymphocytopenia (72 [26%] of 278 patients who started induction; 15 [14%] of 109 patients who started consolidation) and infection (50 [18%] of 278 for induction; 15 [14%] of 109 for consolidation), and during carfilzomib maintenance were hypertension (20 [21%] of 97 patients in the KCd consolidation group vs 23 [23%] of 99 patients in the HSCT group) and infection (16 [16%] of 97 patients vs 25 [25%] of 99). Treatment-related serious adverse events at any point during the trial were reported in 109 (39%) of 278 patients who started induction, with infections (80 [29%]) being the most common. Treatment-emergent deaths were reported in five (2%) of 278 patients during induction (three from infection, one from cardiac event, and one from renal failure) and one of 99 patients during maintenance after autologous HSCT (oesophageal carcinoma). INTERPRETATION: KCd did not meet the criteria for non-inferiority compared with autologous HSCT, but the marginal difference in progression-free survival suggests that further studies are warranted to explore deferred autologous HSCT in some subgroups, such as individuals who are MRD negative after induction. FUNDING: Cancer Research UK and Amgen.

Diagnostics in Waldenström's macroglobulinemia: a consensus statement of the European Consortium for Waldenström's Macroglobulinemia.

The diagnosis of Waldenström's macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, can be challenging due to the different forms of disease presentation. Furthermore, in recent years, WM has witnessed remarkable progress on the diagnostic front, as well as a deeper understanding of the disease biology, which has affected clinical practice. This, together with the increasing variety of tools and techniques available, makes it necessary to have a practical guidance for clinicians to perform the initial evaluation of patients with WM. In this paper, we present the consensus recommendations and laboratory requirements for the diagnosis of WM developed by the European Consortium of Waldenström's Macroglobulinemia (ECWM), for both clinical practice as well as the research/academical setting. We provide the procedures for multiparametric flow cytometry, fluorescence in situ hybridization and molecular tests, and with this offer guidance for a standardized diagnostic work-up and methodological workflow of patients with IgM monoclonal gammopathy of uncertain significance, asymptomatic and symptomatic WM.

The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial.

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.

Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial.

Prediction of individual patient benefit from lenalidomide (Len) maintenance after autologous stem cell transplant (ASCT) remains challenging. Here, we investigated extended molecular profiling for outcome prediction in patients in the National Cancer Research Institute Myeloma XI (MyXI) trial. Patients in the MyXI trial randomized to Len maintenance or observation after ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q), and del(17p) and co-occurrence of risk markers was computed. Progression-free survival (PFS), subsequent progression (PFS2), and overall survival (OS) were calculated from maintenance randomization, and groups were compared using Cox proportional hazards regression. Of 556 patients, 17% with double-hit multiple myeloma (MM) (≥2 risk markers), 32% with single-hit (1 risk marker), and 51% without risk markers were analyzed. Single-hit MM derived the highest PFS benefit from Len maintenance, specifically, isolated del(1p), del(17p), and t(4;14), with ∼40-fold, 10-fold, and sevenfold reduced risk of progression or death (PFS), respectively, compared with observation. This benefit translated into improved PFS2 and OS for this group of patients compared with observation; median PFS was 10.9 vs 57.3 months for observation vs Len maintenance. Patients with isolated gain(1q) derived no benefit, and double-hit MM limited benefit (regardless or risk lesions involved) from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway. This trial was registered at www.isrctn.com/ISRCTN49407852 as # ISRCTN49407852.

Risk and response adapted therapy following autologous stem cell transplant in patients with newly diagnosed multiple myeloma (RADAR (UK-MRA Myeloma XV Trial): study protocol for a phase II/III randomised controlled trial.

INTRODUCTION: Multiple myeloma is a plasma cell malignancy that accounts for 1%-2% of newly diagnosed cancers.At diagnosis, approximately 20% of patients can be identified, using cytogenetics, to have inferior survival (high-risk). Additionally, standard-risk patients, with detectable disease (minimal residual disease (MRD)-positive) postautologus stem cell transplant (ASCT), fare worse compared with those who do not (MRD-negative). Research is required to determine whether a risk-adapted approach post-ASCT could further improve patient outcomes. METHODS: RADAR is a UK, multicentre, risk-adapted, response-guided, open-label, randomised controlled trial for transplant-eligible newly diagnosed multiple myeloma patients, using combinations of lenalidomide (R), cyclophosphamide (Cy), bortezomib (Bor), dexamethasone (D) and isatuximab (Isa).Participants receive RCyBorD(x4) induction therapy, followed by high-dose melphalan and ASCT. Post-ASCT, there are three pathways as follows:A phase III discontinuation design to assess de-escalating therapy in standard-risk MRD-negative patients. Participants receive 12 cycles of Isa maintenance. Those who remain MRD-negative are randomised to either continue or stop treatment.A phase II/III multiarm multistage design to test treatment strategies for treatment escalation in standard-risk MRD-positive patients. Participants are randomised to either; R, RBorD(x4) +R, RIsa, or RBorIsaD(x4) + RIsa.A phase II design to assess the activity of intensive treatment strategies in high-risk patients. Participants are randomised to RBorD(x4) +R or RBorIsaD(x4) + RIsa.1400 participants will be registered to allow for 500, 450 and 172 participants in each pathway. Randomisations are equal and treatment is given until disease progression or intolerance. ETHICS AND DISSEMINATION: Ethical approval was granted by the London-Central Research Ethics Committee (20/LO/0238) and capacity and capability confirmed by the appropriate local research and development department for each participating centre prior to opening recruitment. Participant informed consent is required before trial registration and reconfirmed post-ASCT. Results will be disseminated by conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISCRTN46841867.

Clinical characteristics and outcomes of IgD myeloma: experience across UK national trials.

Immunoglobulin D (IgD) myeloma is a subtype often considered to have adverse features and inferior survival, but there is a paucity of data from large clinical studies. We compare the clinical characteristics and outcomes of patients with IgD myeloma from UK phase 3 myeloma trials analyzed in 2 groups: old (1980-2002) and recent (2002-2016) clinical trials, based on the time of adoption of novel myeloma therapies. Patients with IgD myeloma comprised 44 of 2789 (1.6%) and 70 of 5773 (1.2%) of the old and recent trials, respectively. Overall, IgD myeloma was associated with male predominance, low-level paraproteinemia (<10g/L), and λ light chain preference. The frequency of ultra-high-risk cytogenetics was similar in IgD myeloma compared with other subtypes (4.3% vs 5.3%, P > .99). Despite the old trial series being a younger group (median age: 59 vs 63 years, P = .015), there was a higher frequency of bone lesions, advanced stage at diagnosis, worse performance status, and severe renal impairment compared with the recent trials. Furthermore, the early mortality rate was significantly higher for the old trial series (20% vs 4%, P = .01). The overall response rate following induction therapy was significantly higher in the recent trials (89% vs 43%, P < .0001), and this was consistent with improved median overall survival (48 months; 95% confidence interval [CI] 35-67 months vs 22 months; 95% CI, 16-29 months). Survival outcomes for IgD myeloma have significantly improved and are now comparable to other myeloma types because of earlier diagnosis, novel therapies, and improved supportive care. This trial was registered at clinicaltrials.gov as # NCT01554852.

Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial.

INTRODUCTION: Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life. METHODS AND ANALYSIS: Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively.All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North East-Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN17973108, NCT03720041.

Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk.

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.