Diagnosed Myeloma Patients Research Articles

Multiple Myeloma in Hispanics: Incidence, Characteristics, Survival, Results of Discovery, and Validation Using Real-World and Connect MM Registry Data

BackgroundMultiple myeloma (MM) in Hispanics has never been studied. We therefore sought to determine the clinical characteristics and overall survival in MM of Hispanics compared to non-Hispanic whites (NHW) and non-Hispanic blacks (NHB). Patients and MethodsA single-center analysis of 939 patients diagnosed with MM from 2000 to 2017 with a large representation of NHB (n = 489), Hispanics (n = 281), and NHW (n = 169) was conducted to evaluate outcomes and disease characteristics. We used the Connect MM Registry, a large US multicenter prospective observational study with newly diagnosed MM patients, as a validation cohort. ResultsHispanics had a higher incidence of MM compared to NHW. The median age at presentation was 5 years younger (median, 65 years) in Hispanics compared to NHW (median, 70 years), and patients were more likely to present with renal dysfunction (estimated glomerular filtration rate < 30 mL/min). Hispanics had a higher proportion of Revised International Staging System (R-ISS) stage I disease compared to NHW and NHB (P = .03), while there was no difference in cytogenetics between Hispanics and NHB/NHW. In the multivariate analysis, only high-risk disease and response to first-line therapy significantly affected survival. ConclusionIn this first and largest analysis of MM in Hispanics, we found that Hispanics present at a younger age, have a higher incidence of renal dysfunction, and have low R-ISS stage disease at presentation. With equal access to therapy, Hispanics have survival similar to NHW/NHB.

Clinical Validation of a NGS Capture Panel to Identify Mutations, Copy Number Variations and Translocations in Patients with Multiple Myeloma

Clinical Validation of a NGS Capture Panel to Identify Mutations, Copy Number Variations and Translocations in Patients with Multiple Myeloma

The Addition of Carfilzomib to a Lenalidomide-Based Triplet Improves Outcomes in Newly Diagnosed Transplant Eligible Myeloma Patients with Renal Impairment: A Subgroup Analysis of the Myeloma XI Trial

The Addition of Carfilzomib to a Lenalidomide-Based Triplet Improves Outcomes in Newly Diagnosed Transplant Eligible Myeloma Patients with Renal Impairment: A Subgroup Analysis of the Myeloma XI Trial

Trial in Progress: A Prospective Phase I/II Trial to Jointly Optimize the Administration Schedule(s) and Dose(s) of Melphalan for Injection (Evomela) As a Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma

Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is considered to be the standard of care treatment for transplant-eligible patients with multiple myeloma (MM). The most commonly used conditioning regimen in this setting is high-dose melphalan by intravenous administration. Conventional melphalan formulations, when administered at high doses, can put patients at risk of potential propylene glycol-associated toxicities. Melphalan for injection (Evomela) is propylene glycol free (PGF), can be dissolved directly using saline, and as a PGF reformulation of Alkeran, incorporating Captisol brand of beta-cyclodextrin sulfobutyl ethers sodium salts, overcomes previous formulation limitations. In 2016 Evomela was the first product approved by the US FDA for high-dose conditioning treatment prior to HCT in MM patients and it is also indicated for the palliative treatment of patients with MM for whom oral therapy is not appropriate. Reconstituted Evomela solution can be stored in the vial for up to 1 hour at room temperature or up to 24 hours at 2-8 °C with no significant degradation. After storage in the vial, it remains stable for an additional 3 to 29 hours after, preparation of admixture solution in infusion bags at concentrations of 0.25 to 5.0 mg/mL, respectively. As well, Evomela solution in saline, at concentration of 5.0 mg/mL melphalan, was bacteriostatic through 72 hours when stored at 2-8 °C. This stability allows for less frequent handling by pharmacy and nursing staff, resulting in a concomitant decrease in exposure risks, increased convenience and administration flexibility, suggestive of an improved ease of handling and administration, when compared to Alkeran. Further, Evomela may actually be less toxic due to the absence of propylene glycol. Although increased melphalan doses have previously demonstrated signals of improved response, the most commonly used dose of melphalan is 200 mg/m2, primarily due to concerns of toxicity. Emerging data regarding higher stability and potentially less toxicity of PGF melphalan (Evomela) supports dose escalation evaluation in order to improve the outcomes. Previous trial data have shown that continuous infusion or frequent fractionated-dose delivery increases the antitumour activity of several drugs. Due to the instability of currently available Alkeran at the room temperature, infusional studies have not been feasible. This limitation is overcome by Evomela, being that the compound is stable for several hours at the room temperature, thus allowing evaluation of infusional schedules in addition to the traditional 30-60 minute bolus doses. Here, we describe a trial designed to assess whether the above noted characteristics of Evomela allow for the escalation of dose and prolongation of infusion time, in order to increase the efficacy of melphalan in patients undergoing auto-HCT. Study Design/Methods: This is a two-stage phase I-II trial to optimize the dose and schedule of Evomela given as a single agent preparative regimen for auto-HCT. Up to 60 participants may be included if they are 18-70 years of age, with non-relapsed MM, have a Karnofsky performance score ≥70%, who have received at least two cycles of initial systemic therapy, and are within 2 to 12 months of the first dose. Patients will be randomized 1:1 to two different infusion schedules (30-60 minute infusion or 8-9 hour infusion) using Evomela (2mg/ml) at two dose cohorts (200mg/ml2 or 225mg/m2). Because 2 mg/mL Evomela is stable for 10 hours, patients receiving the 8-9 hour infusion will receive the total dose in one single infusion bag. The primary objectives are to determine the optimal dose and schedule of Evomela before auto-HCT for MM and collect pharmacokinetic data and compare the exposure-response evaluations between the two infusion schedules. Secondary outcomes will include incidence of treatment-related mortality, rate of minimal residual disease negative complete response at 90 days post auto-HCT, progression-free survival and overall survival after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. The active study follow-up period will be up to one-year post auto-HCT. Figure Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Takeda: Other: Advisory Board, Research Funding; Celgene: Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board. Qazilbash:Amgen: Research Funding; Bioclinica: Consultancy; Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding.

Quality of Life Data from a Prospective Randomised Trial of Newly Diagnosed Myeloma Patients with Renal Failure: Optimal Trial

Quality of Life Data from a Prospective Randomised Trial of Newly Diagnosed Myeloma Patients with Renal Failure: Optimal Trial

Newly diagnosed multiple myeloma patients treated with tandem auto-allogeneic stem cell transplant have better overall survival with similar outcomes at time of relapse compared to patients who received autologous transplant only.

Long-term survival in patients progressing after tandem autologous-allogeneic stem cell transplant (SCT) has been reported, suggesting a persistent graft-vs-myeloma (GvM) effect even after post-transplant progression. In order to confirm this observation, we updated the results of our previously published cohort of 92 newly diagnosed myeloma patients who received tandem transplant and compared them with 81 contemporary patients who received autologous transplant only. With a median follow-up of 13.1 and 10.2 years, respectively, median overall survival (OS) in the tandem group has not been reached, compared with 6.1 years after auto-SCT (P≤.001). Disease progression occurred less frequently after tandem transplant, with an estimated 10-year cumulative incidence of 49% vs 76% (P≤.001). Cumulative incidence of extensive chronic graft-vs-host disease (cGVHD) was high at 83%, with modest benefits on OS (60% vs 49%, P=.550) but sharp improvement of progression-free survival (PFS; 55% vs 10%, P=.002) at 10 years associated with development of cGVHD. After first progression, median OS was 5.8 years in tandem and 5.2 years in the auto-group (P=.062); median PFS was also similar. Despite confirmation of better outcomes after upfront tandem transplant, our data do not support persistence of a strong, clinically significant graft-vs-myeloma effect after first progression, emphasizing the need to better characterize the GvM effect.

Post-transplant consolidation based on combination of lenalidomide and proteasome inhibitors in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy due to uncontrolled proliferation of neoplastic plasma cells in the bone marrow, associated to chromosomal instability and cytogenetic abnormalities, which could have an impact on prognosis. Response to treatment and survival of newly diagnosed myeloma patients is heterogeneous, with median overall survival ranging from two to more than ten years, due to clinical and biological factors. To warrant long-term control of disease, several strategies have been proposed in the last years, including short-term high-dose of treatment, named as consolidation, before maintenance. This review will discuss the role of consolidation in the current myeloma treatment landscape, and further improvements required to optimize tailored front-line therapy.

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects.

Simple SummaryMultiple myeloma (MM) is a still uncurable tumor of mainly elderly patients originating from the terminally differentiated B cells. Introduction to the treatment of MM patients of a new class of drugs called proteasome inhibitors (bortezomib followed by carfilzomib and ixazomib) significantly improved disease control. Proteasome inhibitors interfere with the major mechanism of protein degradation in a cell leading to the severe imbalance in the protein turnover that is deadly to MM cells. Currently, these drugs are the mainstream of MM therapy but are also associated with an increased rate of the injuries to multiple organs and tissues. In this review, we summarize the current knowledge on the molecular mechanisms of the first-in-class proteasome inhibitor bortezomib-induced disturbances in the function of peripheral nerves and cardiac and skeletal muscle.The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.

MM-252: Aberrant Plasma Cells in the Apheresis Product as a Prognostic Factor for Minimal Residual Disease Negativity After Transplant in Newly Diagnosed Myeloma Patients

Context: Autologous stem cell transplantation (ASCT) is the standard frontline therapy for newly diagnosed multiple myeloma (MM) eligible patients. “Contamination” of leukapheresis products with aberrant plasma cells (PCs) has been considered as a possible predictive factor for response and outcome. Objective: To evaluate the frequency and clinical value of clonal PCs remaining in leukapheresis products using next generation flow cytometry (NGFC), which is able to detect aberrant clonal PCs at levels reaching 10−6. Design: Prospective study. Setting: A referral center in Athens, Greece. Patients: MM patients after four cycles of induction therapy (VCD or VRD) followed by ASCT in the Department of Clinical Therapeutics, University of Athens, Greece. Interventions: Ninety-eight patients with newly diagnosed multiple myeloma were assessed for the presence of clonal PCs with the 8-color NGFC protocol suggested by EuroFlow. Eight to ten million cells were examined; the median sensitivity of the test was 2–4 × 10−6 per sample. All patients received high-dose melphalan and ASCT. Using the same NGFC protocol, 53 patients who achieved complete response (CR) post-ASCT, based on the IMWG criteria, were also examined for the presence of minimal residual disease (MRD). Main outcome measures: Aberrant PCs in leukapheresis products. Results: This analysis revealed 58 (59%) “uncontaminated” (con-) and 40 (41%) “contaminated” (con+) leukapheresis products. The majority of con+ cases had very low numbers of aberrant plasma cells detected; 18 (45%) at the level of 10−615 (38%) at the level of 10−4 and 7 (18%) at levels ≥10−3. On day 100 post-ASCT, MRD evaluation was performed on 33 con- and 20 con+ patients, who had achieved CR. MRD positivity was found in 11 out of 53 cases (20.8%). Only 3 out of 33 (9.1%) con- patients were found MRD+, all of which at very low levels ( Conclusions: Using NGFC, we were able to detect aberrant plasma cells in 40% of apheresis products at the level of 10−6. The presence of aberrant plasma cells in the apheresis products correlates with higher probability for MRD+ after ASCT, whereas their absence predicts MRD negativity.

Autologous stem-cell collection following VTD or VRD induction therapy in multiple myeloma: a single-center experience.

Triplet-drug regimen bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-lenalidomide-dexamethasone (VRD) are considered as standard of care induction prior autologous stem-cell transplantation (ASCT) in myeloma. In addition to improve response rate, induction therapy should preserve an adequate stem-cell collection. In the present retrospective study, we analyzed stem-cell collection in 325 newly diagnosed myeloma patients who received either VTD or VRD induction before ASCT. Stem-cell mobilization consisted of intravenous cyclophosphamide plus G-CSF. Plerixafor was administered preemptively to rescue mobilization. In comparison with VTD, VRD induction was associated with a more frequent use of plerixafor (19.3% versus 5.4%, p = 0.004) and with an increased number of apheresis to reach adequate collection (>2 apheresis required in 42.3% versus 30.2%, p = 0.05). Moreover, more patients experienced collection failure in the VRD group (6% versus 1.8%, p = 0.004). The median number of CD34-positive cells (×106/kg) was lower in the VRD group: 8.5 versus 9.3 (p = 0.05) in the VTD group. The vast majority of patients underwent ASCT (93% versus 98%, in VRD and VTD group, respectively). These data highlight the need of optimal stem-cell collection strategy, especially in the context of tandem transplantation and incorporation of anti-CD38 monoclonal antibody into induction.

The Role of 18F-FDG-PET/CT Scan in the Management of Multiple Myeloma

Bone lesion is a myeloma-defining event which is reported in 80% of multiple myeloma patients. Imaging of bone is essential in the evaluation of pattern and extent of bone involvement. Recently, whole body X ray (WBXR) has been replaced by more accurate imaging such as whole bode MRI and FDG-PET/CT scan. This review article provides the advantages and role of PET/CT scan in the diagnosis and management of multiple myeloma patients. Generally, PET/CT in diagnosis of bone involvement of newly diagnosed myeloma patients is more sensitive than WBXR. The prognostic value of PET/CT in newly diagnosed patients has been described as well. Different studies have demonstrated that several PET parameters such as the number of focal lesions (FL), SUVmax and extramedullary disease(EMD) may affect the outcome of multiple myeloma patients. Interstingely, the main role of PET/CT in myeloma patients is treatment response monitoring and to some extent assessment of MRD. PET/CT appears to be superior than MRI in evaluation of response due to its ability in differentiating active lesion from negative one.

Preclinical evaluation of CD8+ anti-BCMA mRNA CAR T cells for treatment of multiple myeloma.

Chimeric antigen receptor (CAR) T-cell therapy remains limited to select centers that can carefully monitor adverse events. To broaden use of CAR T-cells in community clinics and in a frontline setting, we developed a novel CD8+ CAR T-cell product, Descartes-08, with predictable pharmacokinetics for treatment of multiple myeloma. Descartes-08 is engineered by mRNA transfection to express anti-BCMA CAR for a defined length of time. Descartes-08 express anti-BCMA CAR for 1 week, limiting risk of uncontrolled proliferation; produce inflammatory cytokines in response to myeloma target cells; and are highly cytolytic against myeloma cells regardless of presence of myeloma-protecting bone marrow stromal cells, exogenous a proliferation-inducing ligand, or drug resistance including IMiDs. The magnitude of cytolysis correlates with anti-BCMA CAR expression duration, indicating a temporal limit in activity. In the mouse model of aggressive disseminated human myeloma, Descartes-08 induces BCMA CAR-specific myeloma growth inhibition and significantly prolongs host survival (P<.0001). These preclinical data, coupled with an ongoing clinical trial of Descartes-08 in relapsed/refractory myeloma (NCT03448978) showing preliminary durable responses and a favorable therapeutic index, have provided the framework for a recently initiated trial of an optimized/humanized version of Descartes-08 (i.e., Descartes-11) in newly diagnosed myeloma patients with residual disease after induction therapy.

Bortezomib Maintenance Therapy as a Standard of Care Provides Favorable Outcomes in Newly Diagnosed Myeloma Patients: A Multisite Real-Life Study

BackgroundLenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM. Patients and MethodsA retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m2) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy. ResultsA total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P < .001) and OS (P < .001) among transplant-ineligible but not transplant-eligible patients. ConclusionAnalysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease.

Efficacy of daratumumab + SOC versus SOC in myeloma induction regimens, by risk-stratification: Meta-analysis of phase III randomized control trials.

e20512 Background: Addition of daratumumab, a CD38 monoclonal antibody, to standard of care (SOC) myeloma induction regimens resulted in deeper responses. Phase 3 trials comparing daratumumab + SOC vs SOC consistently favored the daratumumab combinations. The objective of this analysis is to test the hypothesis that high-risk patients benefit from the addition of daratumumab to SOC induction regimens. Methods: We identified four phase 3 clinical trials (RCT) that randomized newly diagnosed myeloma patients to receive daratumumab +SOC vs. SOC. The GRIFFIN trial did not have PFS events and was excluded. A meta-analysis of 3 RCTs with updated data from ASH 2019 (ALCYONE, MAIA, CASSIOPEIA) was performed using the fixed (Mantel-Haenszel) model to calculate the impact of daratumumab + SOC versus SOC. The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was &lt; 0.1 and I2 statistic was &gt; 50%. Results: The pooled hazard ratios (HR) for standard risk patients for PFS was HR 0.589 (95% CI 0.502-0.691; P &lt; 0.001) in favor of daratumumab. Q-statistic for PFS ( P= 3.462; df= 2; I2 = 42.23) suggests homogeneity across studies. The pooled hazard ratios (HR) for high risk patients for PFS was HR 0.799 (95% CI 0.609-1.047; P= 0.104) in favor of daratumumab. Q-statistic for PFS ( P= 1.306; df= 2; I2 = 0.00) suggests homogeneity across studies. Conclusions: Our meta-analysis demonstrates that addition of daratumumab to SOC myeloma induction regimens prevented progression in both standard and high-risk patients, though the impact was more pronounced in the standard-risk patients. This benefit seems to improve with longer follow up, as seen both in ALCYONE (Mateos et al ASH 2019) and MAIA trial (Bahlis et al ASH 2019). Focused accrual of high-risk patients in larger daratumumab induction trials and longer follow up of the existing trials are further needed.

Multiple Myeloma DREAM Challenge reveals epigenetic regulator PHF19 as marker of aggressive disease

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients does not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involves assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post-challenge analysis identified a novel expression-based risk marker, PHF19, which has recently been found to have an important biological role in multiple myeloma. Lastly, we show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.

Bortezomib-Based Transplantation and Consolidation Therapy Followed by Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma

Bortezomib-Based Transplantation and Consolidation Therapy Followed by Lenalidomide Maintenance for Newly Diagnosed Multiple Myeloma

Efficiency and Tolerability of Induction and Consolidation Therapy with Arsenic Trioxide/Bortezomib/Ascorbic Acid/Dexamethasone (ABCD) Regimen Compared to Bortezomib/Dexamethasone (BD) Regimen in Newly Diagnosed Myeloma Patients.

PurposeThis study was aimed at comparing the efficacy and tolerability of an arsenic trioxide/bortezomib/ascorbic acid/dexamethasone (ABCD) regimen with efficacy and tolerability of a bortezomib/dexamethasone (BD) regimen in patients with newly diagnosed myeloma.Patients and MethodsFifty-seven and sixty-four patients were treated with the ABCD and BD regimens, respectively. Eligible and agreeable patients received autologous hematopoietic stem cell transplantation followed by consolidation.ResultsThe response rates (above VGPR) were 74.1% and 32.8% in the ABCD- and BD-treated groups, respectively (P = 0.000). Compared to BD regimen, ABCD regimen significantly improved PFS (P = 0.026) and OS (P = 0.000) in newly diagnosed patients. Patients with a high tumor burden, low or standard risk, and without auto-HSCT seemed to especially benefit compared to the same group with BD regimen. ABCD also showed better tolerability with lower bone marrow suppression (P = 0.026). Furthermore, complete response or near CR after induction therapy was a good prognostic factor for ABCD-associated OS and PFS.ConclusionABCD is an effective and tolerable regimen compared with BD regimen in newly diagnosed myeloma patients. ABCD regimen could be an economical, effective, and tolerable choice in low- and standard-risk patients.

Potential Relationship between Clinical Significance and Serum Exosomal miRNAs in Patients with Multiple Myeloma.

This study evaluated the potential relationship between exosomal miRNAs and clinical symptoms in patients with multiple myeloma (MM). Forty-eight newly diagnosed myeloma patients and sixteen normal donors were enrolled in the study. The results showed that the relative expression levels of let-7c-5p, let-7d-5p, miR-140-3p, miR-185-5p, and miR-425-5p in the exosomes of MM patients were significantly lower than those of healthy controls. Furthermore, there were significant differences in the clinical characteristics of myeloma, such as kidney damage, while the expression levels of the same miRNA in exosomes and serum are not correlated. The expression of exosomal miRNA is related to the expression levels of clinical feature-related factors, such as creatinine, β2-microglobulin, β-CTX, and IL-6 in serum. Establishing this relationship could contribute to understanding the pathogenesis of MM.

The Transmembrane Receptor Roundabout 1 (ROBO1) Is Necessary for Multiple Myeloma Proliferation and Homing to the Bone Marrow Niche

Introduction Multiple myeloma (MM) is characterized by dissemination and accumulation of plasma cells in the bone marrow (BM), which promotes tumor cell growth and therapy resistance. ROBO1 is a conserved transmembrane receptor of the Ig superfamily with no intrinsic catalytic activity, and its role in MM pathogenesis is unknown. Material and Methods We first analyzed ROBO1 expression via western blot and/or immunohistochemistry (IHC). Gene expression profiling in a cohort of 170 newly diagnosed MM patients (IFM170) was used to compare ROBO1 expression across primary MM and BM stroma cells (BMSC), and normal BM plasma cells (PC). We used short hairpin RNA (shRNA) for stable ROBO1 knock down (KD) and CRISPR-Cas9 for ROBO1 knock out (KO). For protein structure-function and rescue studies, ROBO1 KO MM cells were transduced with a lentiviral vector expressing either full-length (FL) or truncated ROBO1 mutants devoid of extracellular (Cyt) or intracellular domain (DeltaCyt), including patient-derived truncating mutations, with a C-terminus triple FLAG tag. FLAG immunoprecipitation (IP) followed by mass spectrometry or western blotting and immunofluorescence (IF) were used to identify ROBO1 interacting partners and ROBO1 cellular localization. We used a hydrogel encapsulation system to study proliferation in a 3D system. To study extramedullary and intramedullary MM growth in vivo, WT and ROBO1 KO OPM2 were injected either subcutaneously (plasmacytoma model) or intra-medullary in femoral bones of donor mice which were then implanted subcutaneously in recipient SCID mice (µ-SCID model). PET-CT was used to assess tumor volume. Mouse tumors were retrieved for IHC and RNA extraction followed by RNA sequencing. To study dissemination and homing, KO and FL addback OPM2 cells were injected intravenously in SCID mice. Femurs and plasmacytoma were retrieved at endpoint for IHC. Results ROBO1 is highly expressed in human MM cell lines and primary MM cells with highest expression in cells carrying the high risk t(4;14) cytogenetic and low/absent expression in normal PC. Of human cancer cell lines, ROBO1 expression was limited to late B cell lineage; and ROBO1 KD was selectively cytotoxic against MM, but not other hematologic cancers. ROBO1 KO significantly decreases proliferation in a 3D culture system and tumor growth in extramedullary (mean tumor volume KO versus WT plasmacytoma: 457 versus 1323 mm3, p value= 0.02) and intramedullary (mean tumor volume KO versus WT: 823 versus 2684 mm3, p value= 0.001) murine models of human MM. ROBO1 KO MM cells show decreased adhesion to BM endothelial and BMSC, which is fully rescued by FL ROBO1 addback. To address whether ROBO1 loss alters dissemination/homing of MM cells in vivo, we injected mice intravenously with ROBO KO or FL addback OPM2 cells. While ROBO1 KO resulted in a modest, non-statistically significant prolongation in mouse OS (90 versus 75 days, respectively, p value 0.2), the pattern of disease was strikingly different. As expected, ROBO1 FL mice developed hindlimb paralysis with extensive BM infiltration with MM. Importantly, ROBO1 KO mice demonstrated reduced BM infiltration and developed solitary plasmacytoma. We next showed that ROBO1 C-terminus domain is necessary and sufficient to rescue ROBO1 KO proliferative defect while expression of ROBO1 truncations, including patient-derived frameshift mutations, acted as dominant negative. IP showed avid interaction of ROBO1 with ABL1. Interestingly, we showed that the cytosolic domain of ROBO1 undergoes cleavage and translocates to the nucleus, where its function is now being studied. Conclusions We show that ROBO1 is necessary for MM homing to the BM niche and for MM growth within and outside the BM space. ROBO1 cytosolic domain undergoes proteolytic cleavage and translocates to the nucleus and is necessary and sufficient to rescue ROBO1 KO defective proliferation. Based on our data, we propose a dual model for ROBO1 in MM: the full transmembrane receptor is involved in regulating adhesion, dissemination and homing of MM cells within the BM niche; the cleaved intracellular C-terminus domain participates in transcriptional regulation, promoting MM proliferation. These data suggest that ROBO1 C-terminus may be a novel molecular target in MM. Disclosures Roccaro: Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; Associazione Italiana per al Ricerca sul Cancro (AIRC): Research Funding; European Hematology Association: Research Funding; Transcan2-ERANET: Research Funding; European Hematology Association: Research Funding; AstraZeneca: Research Funding; Transcan2-ERANET: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding. Ghobrial:Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Real Life Use of Imaging in the Management of Newly Diagnosed Patients with Myeloma- Practical Perspectives from a UK Hospital

Background: The role of imaging in myeloma has gained increasing importance over the past few years. Cross‐sectional imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and 18fluoro‐deoxyglucose (18F‐FDG) positron emission tomography (PET/CT) have increased sensitivity of detection of myeloma bone lesions compared to skeletal plain radiographs. However, there is huge variation in practice both within the United Kingdom and internationally, as to the choice of modality due to differences in access to the techniques and the subtleties of the information gained from each type of imaging. At present whole body (WB) diffusion weighted (DW) MRI is not yet available in our hospital. Aim: To review compliance of our current practice with the 2017 British Society for Haematology (BSH) guideline "Use of imaging in the management of patients with myeloma". To review the number of imaging modalities performed in newly diagnosed myeloma patients. Audit Standard Criteria range: 100%, or if not achieved, there is documentation in the case notes that explains the variance. • Patient with suspected myeloma underwent whole body MRI (WB-MRI) or CT (unless excluded due to unsuitability of procedure for the patient). • Patient without established myeloma defining event (MDE) but with bone marrow plasma cells 10-60% and/or M-protein &gt;30g/l underwent WB-MRI, WB-CT or PET/CT. • WB/DW-MRI or PET/CT performed in the assessment of oligosecretory myeloma. • Whole spine MRI performed and reported within 24 hours of suspected cord compression in myeloma. • PET/CT or WB/DW-MRI performed in the diagnostic assessment of possible solitary plasmacytoma. Method: Data collection period was between 1st July 2017 to 30th June 2018. We included all adult patients (age at least18 years) who were newly diagnosed with myeloma or plasmacytoma in our Trust during the data collection period, and had their diagnostic imaging in our Trust.Data were retrospectively collected from multidisciplinary meeting lists, chemotherapy list, radiology department data and electronic patient record (EPR). Results: Forty patients were included in the audit, which included 31 myeloma patients, 8 smouldering myeloma patients, one plasmacytoma patient. There were no non-secretory or oligosecretory myeloma cases and there were no newly diagnosed myeloma patients presenting with suspected cord compression in our Trust during the data collection period. All patients (100%) with suspected myeloma underwent cross-sectional imaging at diagnosis. Twenty nine (73%) patients had low dose (LD) WB-CT, four (10%) had PET/CT and one (2%) had WB-MRI. Eleven (27%) had CT chest abdomen pelvis (CT-CAP) ; this latter group of patients came through the suspected cancer referral pathway. No skeletal surveys were performed for patients with newly diagnosed myeloma or plasmacytoma during the data collection period. All smouldering myeloma patients underwent LDWB-CT. All solitary plasmacytoma patients had PET/CT or WB/DW-MRI. Twenty out of 40 (50%) patients had more than one imaging modality. For the majority of these patients this comprised a CT and MRI whole spine/pelvis (40%) and 10% had a CT and PET-CT. Two patients had three modes of imaging. The main reasons for requesting MRI spine/pelvis were back pain, CT showed lytic lesion or mass in spine, CT showed equivocal lytic lesion or abnormal marrow signal in spine, CT showed no lytic lesion but clinically strongly suspected lytic lesion in spine. The main reasons for requesting PET/CT were CT showed equivocal lytic lesion, and suspected cancer. Conclusion: Our Trust has excellent compliance with the BSH guideline as all new myeloma patients underwent cross-sectional imaging with a CT. However, for half of these patients CT alone was inadequate to fully assess their bone disease, requiring an additional modality. Discussion: Patients with suspected myeloma are referred to the haematology department through different pathways, most commonly suspected myeloma and back pain (73%), and suspected cancer (27%). The route of referral often determines first imaging modality. For many patients more than one modality is required to accurately assess their bone disease, eg presence of focal lesions, active lesions, spinal cord compromise. This causes delay of making diagnosis and increased cost. Access to WB-DWI/MRI may address some if not all these issues. Disclosures No relevant conflicts of interest to declare.