Faculty Bibliography

BACKGROUND:Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS:subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS/RESULTS:Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION/CONCLUSIONS:Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING/BACKGROUND:Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.

MRD is a powerful predictor of survival outcomes in multiple myeloma but treatment regimens show increasing duration and complexity for both TE and TNE populations. For this reason, sequential assessments are preferable to single timepoints. This has been evaluated in the Myeloma XI trial, which was a phase 3 trial with three potential randomisations to determine induction therapy, consolidation therapy and maintenance in both TE and TNE patients. Bone marrow aspirates were obtained after induction, post consolidation (if given), post ASCT for TE patients and 6 months post maintenance randomisation. MRD was assessed using flow cytometry (minimum sensitivity 0.004%). This analysis represents a subset of 1630 samples that represent all patient groups and therapeutic timepoints. Overall MRD-negativity post-induction was 164/722 (22.7%). 70.1% of patients randomised to CCRD were MRD-negative compared to 19.6% after CTD or RCD in TE patients and 12.7% after CTDa and 19.2% after RCDa (p <0.001) in TNE patients. Levels of residual disease in MRD-positive patients were lower following CCRD induction; median 0.08% of leucocytes (range 0.001-9.5%), compared to medians of 0.31%, 0.23%, 0.38% and 0.42% following CTD, RCD, CTDa and RCDa respectively. MRD-negativity was demonstrated in 16/54 (29.7%) of patients who received bortezimib-based consolidation following a suboptimal response to induction. Post ASCT, 257/413 (62%) of samples were MRD-negative, with a significant increase in MRD-negativity rate relative to post induction seen with CTD (59.2% vs 19.6% post induction) and RCD (53.6% vs to 19.6% post induction). The level of conversion from MRD-positive post induction to MRD-negative post-ASCT was lower in the CCRD cohort (83.3% MRD-negative post ASCT compared to 70.1% following induction). Amongst the patients who underwent maintenance randomisation, MRD-negativity was demonstrated in 238/413 (57.6%). Conversion to MRD-negativity was seen in 32% of MRD-positive patients on lenalidomide maintenance, whilst those patients who became MRD-positive during maintenance had poor outcome. For those patients that remained MRD-positive, lower levels of residual disease were noted in those receiving maintenance (median 0.15% on maintenance vs 0.39%, p=0.04). Sequential MRD monitoring allows for the assessment of individual components of complex myeloma therapeutic strategies. It enables comparison of induction regimens, possibly identifying patients that may not require ASCT. Consolidation or maintenance strategies can also be assessed. This data suggests a potential future role for flow cytometric MRD assessment in individual patient management. A full dataset of >4000 samples and mature outcome data will be presented at the meeting. Keywords: Flow Cytometry Minimal residual disease Tracks: Myeloma Response Assessment including MRD
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Background: Multiple myeloma (MM) is a heterogeneous disease with variable outcomes. In the past several years, serum proteins, cytogenetics and gene expression profiling (GEP) have been used to predict outcomes of MM patients. Patients identified by the prognostic GEP70 gene signature as high risk (HR) have more aggressive disease and shorter survival compared to patients identified as low risk (LR). We have analyzed cfDNA levels in LR and HR patients and determined its correlation to GEP70 risk score. In a subset of patients, we performed low-pass whole genome sequencing (LP-WGS) and targeted sequencing to determine genomic alterations in cfDNA.
Method(s): GEP was performed on CD138+ plasma cells from bone marrow using Affymetrix U133 Plus 2.0 arrays. Low-risk (n=38) and high-risk MM patients (n=44) as determined by GEP70 score were selected. Plasma cells in bone marrow aspirate were ascertained for tumor burden by flow cytometry. cfDNA was extracted from plasma using QIAamp circulating nucleic acid kit (Qiagen) and was measured using Qubit fluorometer. In a subset of patients, plasma cfDNA, matched tumor DNA and matched white blood cell genomic DNA were sequenced using a targeted panel covering key driver genes and immunoglobulin regions involved in translocations in myeloma. Targeted sequencing was performed on NextSeq500 (Illumina) to a depth of 400-600x. LP-WGS was performed at 0.1X coverage. Sequencing data were analyzed using Strelka and ichor.
Result(s): Total cfDNA (ng/ml plasma) was significantly higher in the HR group compared to the LR group, median cfDNA LR=18.76 ng/ml range 0.2-140 ng/ml plasma vs. HR=33 ng/ml plasma range 7.3-726.66 ng/ml; p=0.02. cfDNA levels among different GEP subgroups did not reach significance, however patients in the PR subgroup had higher cfDNA in plasma compared to other subgroups. Ranked cfDNA levels correlated with GEP risk score r=0.32, p=0.0029 (Spearman's test). cfDNA levels also correlated with tumor burden r=0.41, p<0.0001 (Pearson's test). Additionally, LP-WGS analysis performed in a subset of patients showed that circulating tumor DNA (ctDNA) fraction correlated strongly with GEP70 risk score (Spearman r=0.83, p=0.0012). Monitoring of cfDNA levels in patients before and after chemotherapy showed an increase in cfDNA levels between 3-5 days after chemotherapy and fell to baseline levels a week later. Variant allele frequencies of NRAS and KRAS mutations were higher immediately post-chemotherapy compared to baseline in 3/4 patients.
Conclusion(s): cfDNA levels correlate with GEP70 risk score. In the small subset of sequenced patients, ctDNA fraction also correlated with GEP70 risk score. Molecular monitoring of myeloma using cfDNA can capture the mutational landscape in myeloma and can be a potential prognostic biomarker for MM disease. Keywords: cell-free DNA Gene expression profiling Whole genome sequencing Tracks: Multiple Myeloma Genomics
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Background: Multiple myeloma (MM) has significant spatial and temporal clonal heterogeneity suggesting therapeutic agents with different mechanisms of action, delivered in combination or sequentially, are required to maximize the depth of response and improve outcomes. The UK NCRI Myeloma XI phase III randomized trial compared induction with the second generation proteasome inhibitor carfilzomib and lenalidomide containing quadruplet, KCRD, vs a response-adapted approach of sequential triplet therapies in newly diagnosed transplant eligible patients.
Method(s): 1056 patients were randomized between KCRD (28 day cycles of carfilzomib (K) 36mg/m2 IV d1-2,8-9,15-16, cyclophosphamide (C) 500mg PO d1,8, lenalidomide (R) 25mg PO d1-21, dexamethasone (D) 40mg PO d1-4,8-9,15-16) and immunomodulatory drug (IMiD) triplet CTD/CRD prior to ASCT. Patients with a suboptimal response to CTD/CRD underwent response-adapted intensification randomization to a proteasome inhibitor (bortezomib, CVD) containing triplet or no CVD. A maintenance randomization at 3 months post ASCT compared lenalidomide to observation. Molecular high-risk (HiR) was classified by t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) with ultra-high risk (UHiR) the presence of >1 lesions.
Result(s): KCRD was associated with a significantly longer PFS than IMiD triplet therapy (HR 0.63, 95%CI 0.51, 0.76, 3yr PFS KCRD 64.5% vs CTD/CRD 50.3%, p<0.0001). PFS2 was also significantly improved with KCRD (HR 0.75, 95% CI 0.56, 0.99, 3yr PFS2 KCRD 81.8% vs CTD/CRD 75.1%). Deeper response rates were seen in patients treated with KCRD vs CTD/CRD pre and post-transplant (p<0.0001). All regimens were well tolerated with no significant additional toxicity due to the quadruplet regimen. A higher proportion of patients receiving KCRD induction were able to undergo ASCT than those who received response-adapted induction and in an analysis restricted to those who had completed ASCT, KCRD induction was still associated with a significantly longer PFS. There was no significant heterogeneity in PFS outcome between molecular risk groups with a benefit for KCRD over triplets in all. In patients receiving KCRD there was no difference in response rate at the end of initial induction by risk group but UHiR disease was associated with significantly shorter PFS than both SR and HiR, whilst there was no difference in outcome between patients with HiR (one adverse lesion only) and SR. An exploratory analysis compared the patients receiving KCRD to patients in the CTD/CRD arm who had received the optimum response-adapted approach (i.e. excluding those with a suboptimal response randomized to no CVD). KCRD was associated with significantly longer PFS than using a response adapted sequential triplet approach (HR 0.64, 95% CI 0.52, 0.78, p<0.0001).
Conclusion(s): KCRD was well tolerated with deep responses pre- and post-transplant and a significant PFS benefit compared to triplet therapy across all risk groups. Keywords: carfilzomib carfilzomib-lenalidomide-dexamethasone Lenalidomide Tracks: Treatment of Newly Diagnosed Myeloma Transplant Eligible
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FRAX is a commonly used tool to evaluate patient fracture risk based on individual patient models that integrate the risks associated with clinical risk factors with or without bone mineral density (BMD) at the femoral neck. Retrospectively, factors identified by the FRAX scoring algorithm were used to predict the risk for vertebral compression fractures at baseline in newly diagnosed multiple myeloma patients. The data were derived from myeloma patients enrolled in Total Therapy Protocols (TT4 & TT5) between 8/2008 and 9/2017. FRAX scores were calculated and baseline PET and MRI imaging obtained. Univariate and multivariate logistic regression analyses determined the association between FRAX components and the existence of vertebral compression fractures, both pathologic and osteoporotic. The patient population had a median age of 61 years (43-76), 37% female, and 87% white. The median major osteoporotic score (MOS) and Hip fracture scores (HFS) for TT4 patients (low-risk myeloma) were 5.6 and 0.5, respectively, while median MOS and HFS for TT5 (high risk myeloma) patients were 6.2 and 0.7, respectively. The odds ratio for fracture at diagnosis in patients with elevated MOS (>2), and HFS (>4.5) was significant OR (1.48, 95% confidence interval (1.35,1.62)) and OR (1.61, 95% confidence interval (1.42, 1.81)), respectively. In sum, an elevated baseline FRAX score was highly predictive of baseline vertebral fractures in MM patients at presentation. In addition, patients with higher FRAX scores had significantly shorter survival in the low-risk (TT4) group but this survival effect was not seen in the high-risk (TT5) group. These findings suggest that FRAX assessment of baseline fracture risk is beneficial in MM patients to identify an individual patients' risk of vertebral fracture.

BACKGROUND:Autologous stem cell transplantation (ASCT) is a commonly used treatment for multiple myeloma (MM). This retrospective cohort study characterizes the risk factors and outcomes associated with bacteremia following ASCT at a single center. METHODS:We conducted a retrospective analysis in subjects who underwent ASCT for multiple myeloma and other malignancies from May 2014 to March 2015 at a single center. The control cohort included all subjects undergoing ASCT in the same time period who did not develop bacteremia. RESULTS:During the study period, 363 ASCTs were completed in 282 discrete patients. Bacteremia was documented in 13% of all transplants. Enterococcus faecium was the most frequent species overall (14/62, 23%). Vancomycin resistance was present in 93% of E faecium isolates. Bacteremia was associated with a significantly decreased survival in patients who received their transplant after the first year of myeloma treatment. Overall survival (OS) was not significantly different in the two cohorts among patients undergoing ASCT within the first year of myeloma treatment. Survival analysis showed a significantly decreased OS in patients who developed Enterococcus bacteremia as compared to the non-bacteremia cohort. Enterococcal bacteremia was associated with significantly longer duration of neutropenia (mean 14 vs 9.7 days, P = 0.01), hospitalization (mean 61.7 vs 20.4 days, P = 0.0006), and higher mortality (69% vs 25%, P = 0.01) as compared to other bacteremias. CONCLUSION/CONCLUSIONS:We found a high incidence of E faecium and a low incidence of MRSA and Pseudomonas bacteremias following ASCT in our patient population. Survival analysis in our cohort suggests that the effect of underlying disease status and cumulative chemotherapy is critically important in determining outcomes related to bacteremia. Enterococcal bacteremias following ASCT were associated with significantly higher morbidity and mortality than non-enterococcal bacteremias.

Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R²â€‰= 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R² of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.

The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.

Hyperhaploid multiple myeloma is a rare numerical aberration group defined by a range of 24-34 chromosomes, which is associated with a poor prognosis with a 5-year survival rate of 23%. Hyperhaploid patient samples (n=8) were sequenced and copy number and mutations identified. Samples had a median of 13 monosomies (range 12-14), which in general were those not associated with trisomies in hyperdiploid samples. The chromosomes traditionally trisomic in hyperdiploid myeloma were disomic in hyperhaploid myeloma with retention of heterodisomy. We examined the hyperhaploid samples for frequently mutated genes and found that 8/8 (100%) hyperhaploid samples had a mutation in TP53, exceeding the overall rate of mutation in newly diagnosed patients (5.5%), indicating an oncogenic dependency in this group. All samples with TP53 mutation also had monosomy of chromosome 17, indicating bi-allelic inactivation of TP53. As such, this high risk group is part of double-hit myeloma.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.