Faculty Bibliography

BACKGROUND/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED:Primary financial support was from Cancer Research UK [C1298/A10410].

Prediction of individual patient benefit from lenalidomide (Len) maintenance post autologous transplant (ASCT) remains challenging. We investigated here extended molecular profiling for outcome prediction in NCRI Myeloma XI (MyXI) trial patients. MyXI patients randomized to Len maintenance or observation post-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 computed. PFS, PFS2 and OS were calculated from maintenance randomization, and groups compared using Cox proportional hazards regression. 556 MyXI patients, 17% with double hit MM (≥2 risk markers), 32% with single hit (1 risk marker) and 51% without risk marker, were analyzed. Single hit MM derived the highest PFS benefit from Len maintenance, specifically isolated del(1p), del(17p) and t(4;14), with approximately 40-fold (HR 0.02; 95% CI: 0.002-0.24; P=0.0012), 10-fold (HR 0.1; 95% CI: 0.02-0.58; P=0.0095) and 7-fold (HR 0.14; 95% CI: 0.04-0.45; P=0.0009) reduced risk of progression or death (PFS) compared to observation, respectively. This benefit translated into improved PFS2 HR 0.27 (95% CI: 0.13-0.54; P=0.0002) and OS HR 0.41 (95% CI: 0.18-0.93; P=0.03) for this group of patients over 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.

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.

In most patients with myeloma, the tumour cell produces a unique monoclonal immunoglobulin (Mig), which serves as a quantitative surrogate biomarker for tumour burden. Patients with non-secretory myeloma (NSM) represent 1%-3% of patients and do not produce a Mig suitable for standard monitoring. Therefore, clinicians rely on bone marrow biopsies and CT-PET/ WB MRI scans, which are challenging for patients/clinicians, especially when required regularly for monitoring. Consequently, there is an unmet need for a blood-based biomarker in this patient group to determine remission induction and disease relapse. We have developed a new method to detect monoclonal light chains in this series of patients with NSM, (negative on immunofixation and no measurable disease marker (sFLC <100 mg/L)). Isoelectric focusing (IEF) is well-established for detecting IgG oligoclonal banding in cerebrospinal fluid to diagnose multiple sclerosis. Using IEF, any monoclonal immunoglobulin displays a highly reproducible unique spectrotype of bands. We have developed serum IEF to identify monoclonal sFLCs using highly specific and sensitive monoclonal antibodies. Study patients were identified from the MRC Myeloma IX, CRUK Myeloma XI or NIHR TEAMM trials. Overall, serum IEF detected monoclonal FLC in 28/32 patients (88%): 14 patients with kappa FLC and 10 lambda FLC. One patient had both kappa and lambda FLC bands detected, likely reflecting bi-clonality with both active myeloma clone and secondary MGUS clone picked up by the sensitive IEF assay. Follow-up samples were available in 27/32 patients. Serum IEF identified response to therapy (disappearance of band) and relapse (reappearance of band). The method also allows serial sample dilution to determine percentage reduction in monoclonal protein and provide semi-quantitative results in response to therapy. The IEF method identified monoclonal FLC in 86% of NSM patients studied, indicating that most are low-level secretors rather than true non-producers. Although their Mig cannot be monitored using standard techniques, our highly sensitive IEF assay allows NSM patients to be diagnosed and monitored using blood samples. This approach could reduce reliance on bone marrow biopsy and imaging in this patient cohort. Mass spectrometry (MS) is emerging as another exciting blood-based option for Mig detection. However, the limit of detection for MS is <10 mg/L compared to IEF sensitivity <1 mg/L. Further, the IEF assay utilises a low-cost electrophoresis platform available in many laboratories that conduct myeloma testing, enabling easier integration into clinical practice. Future clinical studies are required to validate IEF and should include comparison to other technologies, including MS

BACKGROUND:Infections are a common reason for hospitalization and death in multiple myeloma (MM). Although pneumococcal vaccination (PV) and influenza vaccination (FV) are recommended for MM patients, data on vaccination status and outcomes are limited in MM. MATERIALS AND METHODS/METHODS:We utilized data from the global, prospective, observational INSIGHT MM study to analyze FV and PV rates and associated outcomes of patients with MM enrolled 2016-2019. RESULTS:Of the 4307 patients enrolled, 2543 and 2500 had study-entry data on FV and PV status. Overall vaccination rates were low (FV 39.6%, PV 30.2%) and varied by region. On separate multivariable analyses of overall survival (OS) by Cox model, FV in the prior 2 years and PV in the prior 5 years impacted OS (vs. no vaccination; FV: HR, 0.73; 95% CI, 0.60-0.90; P = .003; PV: HR, 0.51; 95% CI, 0.42-0.63; P < .0001) when adjusted for age, region, performance status, disease stage, cytogenetics at diagnosis, MM symptoms, disease status, time since diagnosis, and prior transplant. Proportions of deaths due to infections were lower among vaccinated versus non-vaccinated patients (FV: 9.8% vs. 15.3%, P = .142; PV: 9.9% vs. 18.0%, P = .032). Patients with FV had generally lower health resource utilization (HRU) versus patients without FV; patients with PV had higher or similar HRU versus patients without PV. CONCLUSION/CONCLUSIONS:Vaccination is important in MM and should be encouraged. Vaccination status should be recorded in prospective clinical trials as it may affect survival. This trial was registered at www. CLINICALTRIALS/RESULTS:gov as #NCT02761187.

PURPOSE/OBJECTIVE:Molibresib is a selective, small molecule inhibitor of the BET protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). EXPERIMENTAL DESIGN/METHODS:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg QD (for MDS) and 60 mg QD (for CTCL) were selected. Most common Grade 3+ AEs included thrombocytopenia (37%), anemia (15%) and febrile neutropenia (15%). Six patients achieved complete responses (three in Part 1 [two AML, one NHL], three in Part 2 [MDS]), and seven patients achieved partial responses (six in Part 1 [four AML, two NHL], one in Part 2 [MDS]). The ORRs for Part 1, Part 2, and the total study population were 10% (95% CI: 4.8-18.7), 25% (95% CI: 7.3-52.4), and 13% (95% CI: 6.9-20.6), respectively. CONCLUSIONS:While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could hold the key to identifying novel therapeutic approaches, yet the intrinsic variability in cellular populations between patients together with differences in sample processing and analysis methods have made it difficult to identify consistent changes between datasets. Here, we used single-cell RNA sequencing of BM cells from precursor stages, monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM) and newly diagnosed MM and analyzed our data in combination with a previously published dataset that used a similar patient population and sample processing. Despite vast interpatient heterogeneity, some alterations were seen consistently in both datasets. We identified changes in immune cell populations as disease progressed that were characterized by a substantial decrease in memory and naïve CD4 T cells and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of non-clonal memory B cells and an increase of CD14 and CD16 monocytes in MM compared to its precursor stages. These results provide crucial information of the immune changes associated with the progression to clinical MM and can help to develop immune based strategies for patient stratification and early therapeutic intervention.