Setting Of Multiple Myeloma Research Articles

Top 10 Clinical Pearls in Paraproteinemic Neuropathies.

Paraproteinemic neuropathies represent an important subset of peripheral neuropathies. Once identified, further evaluation into the paraproteinemic subtype, clinical exam pattern, and electrodiagnostic phenotype helps clarify if the paraproteinemia is coincidental or causal of the neuropathy, as not all paraproteinemias cause neuropathy. Of all paraproteinemias, immunoglobulin M (IgM)-associated peripheral neuropathy, or IgM neuropathy, is of particular importance as half of IgM neuropathies also harbor anti-myelin-associated glycoprotein antibodies, which produce a characteristic demyelinating pattern on nerve conduction testing. Immunoglobulin G and immunoglobulin A paraproteinemias are less strongly associated with peripheral neuropathy, except in the setting of multiple myeloma or osteosclerotic myeloma (POEMS syndrome), which have characteristic systemic features. In multiple myeloma, chemotherapy is more likely to result in neuropathy than the myeloma itself. Finally, the presence of systemic features (e.g., cardiomyopathy, nephropathy, recurrent carpal tunnel syndrome, and autonomic insufficiency) should raise concern for hereditary or acquired light (AL) chain amyloidosis. AL amyloidosis can occur in the setting of any light or heavy chain paraproteinemia. Central to the proper evaluation of paraproteinemic neuropathy is electrodiagnostic testing, which helps delineate axonal versus demyelinating paraproteinemic neuropathy, the latter often misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy.

Atypical Central Retinal Vein Occlusion in an Older Man With Multiple Myeloma: A Case Report.

This report aims to describe the clinical presentation of a patient with an atypical central retinal vein occlusion (CRVO) in the setting of multiple myeloma. The patient was a 72-year-old man with an extensive hematologic-oncologic history and cardiovascular risk factors who presented with new-onset blurry vision and visual acuity (VA) of 20/40 in the left eye. The VA worsened to 20/60 two months after the initial presentation. By the 6-month follow-up visit, a series of three intravitreal bevacizumab injections for macular edema improved VA from 20/60 to 20/40. This case demonstrates the importance of fluorescein angiography in diagnosing a CRVO and exemplifies an atypical presentation on exam and imaging studies. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Hyperammonemic Encephalopathy in Multiple Myeloma: Systematic Review and Case Series

Objectives: To better understand the presentation and clinical outcomes of hyperammonemic encephalopathy in multiple myeloma, we report 3 cases from our institution and present 55 published cases from the literature. Background/Intro: Hyperammonemia is a rare but life-threatening complication of multiple myeloma with poor survival despite treatment. Little is known about the clinical presentation and outcomes of patients suffering from this entity. We hereby report a systematic review and a meta-analysis of cases with hyperammonemic encephalopathy. Methods: Case reports and case series were identified using the Medline database, as well as PubMed search engine. Clinical and pathological data were collected and stratified by demographics and treatment. The data was further analyzed using SPSS. Results: A total of 58 patients were included in the study. The mean age of the affected patients was 64.4 years, male to female ratio was 1.15:1. The median ammonia level measured was 123 μmol/L. Stage III disease was most prevalent in reported cases (89%). Most common MM subtype was IgG (38%) followed by IgA (36%). Thirty-seven patients (64%) had relapsed disease, while 17 (29%) were new diagnoses. Overall, 35 out of 58 (60%) patients died while being treated as inpatients. Chemotherapy was the only variable associated with an improved survival with p-0.02. Conclusion: Hyperammonemia in the setting of multiple myeloma is an uncommon complication. It is associated with poor prognosis. Treatment should begin as soon as the diagnosis is confirmed with myeloma directed therapy in order to improve survival.

Prevalence, Characteristics, and Clinical Impact of Clonal Hematopoiesis of Indeterminate Potential in AL Amyloidosis

Backgrounds: AL Amyloidosis is a plasma cell dyscrasia whose hallmark is the circulation and deposition of immunoglobulin free light chains in target organs. The extent and severity of cardiac involvement are the primary determinants of mortality in AL amyloidosis. Patients harboring clonal hematopoiesis of indeterminate potential (CHIP) have an increased cardiovascular risk compared to the general population. In the setting of multiple myeloma receiving autologous stem cell transplants, CHIP presence has been associated with decreased overall survival. Still, large studies looking at the incidence and outcome of patients with concurrent CHIP and AL amyloidosis are missing. Herby, we present the results of a single-center, retrospective cohort study, where we assessed the prevalence of CHIP in AL amyloidosis and associated disease characteristics and outcomes. Methods: We collected the demographics and clinical characteristics of patients with AL amyloidosis at Dana Farber Cancer Institute (DFCI) from January 2018 to April 2023 who underwent a bone marrow aspirate/biopsy with a rapid heme panel. Variables of interest included age, ethnicity, Mayo 2004 stage, Palladini renal stage, involved organs, FISH abnormalities, left ventricular ejection fraction (LVEF), documented coronary artery disease (CAD), orthostatic hypotension (OH), chemotherapy (CT) treatment received and related response. The primary outcome was major organ dysfunction progression-free survival (MOD-PFS), defined by Kastritis et al. The variant allele fraction (VAF) to define CHIP was set at 2%. Two samples t-test, Wilcoxon rank sum test, and Fisher's exact test were used to compare groups. Univariate and stratified multivariate Cox proportional hazard regression models were used to estimate the association between CHIP status and MOD-PFS. Analyses were carried out with the Stata statistical package. This study was approved by the DFCI Institutional Review Board and performed in accordance with the Declaration of Helsinki. Results: We identified 76 patients as meeting the inclusion criteria. The median age was 67 years. FISH was available for 54 patients. All patients received cytoreductive CT (CyborD 47%, DaraCyborD 37%). CHIP was identified in 16 patients (21%), a significantly higher figure as compared to historical age-matched healthy controls. DNMT3A was the most frequently involved gene (7/16, 44%), followed by GNB1, TET2, ATM (each 2/16, 12.5%), and SF3B1, ZRSR2, EZH2, BRCC3, PPM1D, ASXL1 (6%) (Figure 1). The presence of CHIP strongly associated with t(11;14) (11/13, 85% in patients with CHIP, versus 15/41, 37%, in patients without CHIP, p=0.004) and with a lower Palladini renal stage in patients with renal involvement (p=0.001). The median follow-up time for the entire cohort was 25 months (range 1 - 175 months). In a univariate analysis, CHIP presence was not associated with lower MOD-PFS (hazard ratio [HR] 0.998, 95% CI 0.38 - 2.64). In a univariate analysis, a Mayo stage >2 (HR 4.82, 95% CI 1.95 - 11.91, p = 0.001), the presence of CAD (HR 4.97, 95% CI 1.79 - 13.79, p=0.02), LVEF ≤40% (HR 3.18, 95% CI 1.17 - 8.66, p = 0.023), and OH requiring treatment (HR 2.65, 95% CI 1.74 - 5.97, p = 0.019) were associated with a decreased MOD-PFS. In a multivariate model stratified for age, only the presence of CAD and OH requiring treatment remained associated with worse MOD-PFS (HR 5.65, 95% CI, 1.33 - 23.99, p = 0.019; HR 4.57, 95% CI, 1.30 - 16.05, p = 0.018, respectively). In the multivariate Cox regression model (Figure 2), CHIP presence was not associated with a decreased MOD-PFS (HR 1.32, 95% CI, 0.44 - 3.98, p = 0.624). When focusing on the impact of only DNMT3A, a tendency towards a statistically significant association with worse MOD-PFS was noted in the multivariate model (HR 3.72, 95% CI 0.92 - 15.01, p = 0.065). Conclusion: We present the largest dataset exploring the prevalence of CHIP in AL amyloidosis patients and its clinical correlates. We noted an association between the presence of CHIP and t(11;14), the most frequent cytogenetic abnormality in AL amyloidosis, and adverse prognostic factors. Patients with CHIP were also found to have a lower Palladini renal risk score. Harboring CHIP was not associated with worse MOD-PFS; however, DNMT3A mutation tended to correlate with worse MOD-PFS. Larger prospective studies are warranted to validate these findings and better elucidate the impact of CHIP in patients with AL amyloidosis.

THU464 An Uncommon Case Of Adult-Onset Hypophosphatemic Osteomalacia

Abstract Disclosure: P.M. Lockhart Pastor: None. N.M. Maalouf: None. Introduction: Hypophosphatemic conditions that interfere with bone mineralization and cause osteomalacia comprise many hereditary and acquired diseases. We describe a case of acquired hypophosphatemic osteomalacia associated with Multiple Myeloma (MM). Case Report: A 45-year-old man with MM and systemic AL amyloidosis was referred to our clinic for evaluation of low bone mass on DXA scan. He presented with progressive back pain, proximal muscle weakness, weight loss, and worsening proteinuria, eventually leading to the diagnosis of AL amyloidosis on fat pad biopsy and MM on bone marrow biopsy. Biochemical work up was remarkable for elevated serum alkaline phosphatase at 463 U/L (reference range 46-116) determined to be of skeletal origin. Additional studies included serum phosphorus 1.9 mg/dl (2.4-4.5), creatinine 1.0 mg/dl (0.7-1.2), calcium 9.0 mg/dl (8.4-10.2), albumin 4.1 g/dl (3.5-5.2), PTH 17.1 pg/ml (15-77), and 25-OH-D 52 ng/ml (30-80). Skeletal survey and PET/CT identified diffuse osteopenia but no fracture or lytic lesion. DXA scan showed Z-score of -5.0 at the L-spine and -4.2 at the femoral neck. Further work-up of hypophosphatemia was notable for fractional excretion (FE) phosphate of 37% (<20), serum 1,25-OH2-D 74 pg/ml (18-64), FGF-23 <14 pg/ml (<59), hypouricemia with high FE uric acid, and normoglycemia with glucosuria. Given his marked bone pain, hypophosphatemia, hypouricemia, glucosuria, and elevated alkaline phosphatase, he was diagnosed with hypophosphatemic osteomalacia presumably secondary to light chain accumulation in kidneys leading to proximal tubule dysfunction (acquired Fanconi syndrome). In addition to MM treatment (5 cycles of Dara-CyBorD then stem cell transplantation), he was started on phosphate supplementation, with marked improvement in bone pain, muscle strength, and serum alkaline phosphatase over 6 months. No anti-resorptive agents were used in treating his MM. Conclusion: This case highlights an unusual presentation of hypophosphatemic osteomalacia. It is important to recognize that bone pain in patients with MM is not only caused by osteolytic lesion but can also result from osteomalacia due to Fanconi syndrome due to light chain kappa deposition. In this patient, treatment with phosphate supplementation resulted in clinical improvement of bone pain and biochemical markers. To date, there are only few reported cases of hypophosphatemic osteomalacia due to Fanconi syndrome in the setting of MM. Presentation: Thursday, June 15, 2023

A real-life study of daratumumab-bortezomib-dexamethasone (D-VD) in lenalidomide exposed/refractory multiple myeloma patients: a report from the Triveneto Myeloma Working Group.

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3-4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting.

The Leucine-Rich α2-Glycoprotein-1 Levels in Patients with Multiple Myeloma

Introduction: Angiogenesis is considered important in the pathogenesis of multiple myeloma (MM), as well as in the targeted treatment of the disease. Leucine-rich α2-glycoprotein 1 (LRG1) is a protein that participates in angiogenesis and its effect on solid organ tumors has been investigated recently. This study aimed to investigate the relationship between MM and LRG1. Methods: The MM patients who admitted to Hatay Mustafa Kemal University Hematology Clinic between September 2021 and October 2022 were included in the study. The study consists of a total of 4 groups: newly diagnosed MM (NDMM), relapsed refractory MM (RRMM), MM in remission (Rem-MM), and control group. Demographic data were retrieved from hospital records. Blood samples of our study groups were centrifuged at 1,500 × g for 10 min and serum was collected. LRG1, IL-6, IL-8, TGF-β1, HIF-1α, FGF-2, and VEGF levels were analyzed in all groups by ELISA method, and statistical analysis was performed. Results: A total of 112 individuals, including NDMM (n: 27), RRMM (n: 18), Rem-MM (n: 42), and control group (n: 25), were enrolled in the study. Based on the analyses, the NDMM group exhibited significantly elevated levels of LRG1 (p < 0.001), TGF-1 (p < 0.001), and HIF-1α (p = 0.046, p < 0.001, and p = 0.003 compared to the RRMM, Rem-MM, and control groups, respectively) compared to the other groups. LRG1 levels were positively correlated with creatinine (r: 0.363, p = 0.001), calcium (r: 0.344, p = 0.001), total protein (r: 0.473, p < 0.001), erythrocyte sedimentation rate (r: 0.547, p < 0.001), lactate dehydrogenase (r: 0.321, p = 0.003), beta-2-microglobulin (r: 0.312, p = 0.017), IL-6 (r: 0.478, p < 0.001), IL-8 (r: 0.240, p = 0.03), TGF-β1 (r: 0.521, p < 0.001), and HIF-1α (r: 0.321, p = 0.003) levels and were negatively correlated with hemoglobin (r: −0.512, p < 0.001) and albumin (r: −0.549, p < 0.001) levels. Receiver operating characteristics (ROC) analysis revealed the association of LRG1 with the highest AUC value of 0.959 (95% CI: 0.904–1, p < 0.001) and the optimal cut-off value of 534.95 ng/mL (sensitivity: 93% and specificity: 99%) in the NDMM group compared to the control group. Conclusion: In this study, providing data for the first time on LRG1 levels in the setting of MM. LRG1 levels were found to be significantly higher in NDMM patients and in our study discriminate this patient population from RRMM, Rem-MM, and normal controls. Therefore, LRG1 seems to a potential biomarker that should be evaluated in future studies addressing the diagnosis, staging, follow-up, prognosis, and treatment target of MM.

107 Linear IgA/IgG bullous dermatosis with autoantibodies to multiple hemidesmosome antigens in the setting of multiple myeloma

107 Linear IgA/IgG bullous dermatosis with autoantibodies to multiple hemidesmosome antigens in the setting of multiple myeloma

Survey of patients and physicians on shared decision-making in treatment selection in relapsed/refractory multiple myeloma.

Shared decision-making (SDM) is a key component of patient-centered healthcare. SDM is particularly pertinent in the relapsed and/or refractory multiple myeloma (RRMM) setting, in which numerous treatment options can present challenges for identifying optimal care. However, few studies have assessed the extent and relevance of SDM and patient-centered communication (PCC) in RRMM. To describe treatment decision-making patterns between physicians and patients in the RRMM setting, we conducted online surveys of patients and physicians in the USA to compare their perspectives on the process of treatment decision-making. We analyzed the surveys descriptively. Two hundred hematologists/oncologists and 200 patients with RRMM receiving second-line (n = 89), third-line (n = 65), and fourth-line (n = 46) therapy participated. Top treatment goals for physicians and patients included extending overall survival (among 76% and 83% of physicians and patients, respectively) and progression-free survival (among 54% and 77% of physicians and patients, respectively), regardless of the number of prior relapses. Thirty percent of physicians believed patients preferred a shared approach to treatment decision-making, while 40% of patients reported most often preferring a shared role in treatment decision-making. One-fourth of patients most often preferred physicians to make the final treatment decision after seriously considering their opinion. Thirty-two percent of physicians and 16% of patients recalled ≥3 treatment options presented at first relapse. Efficacy was a primary treatment goal for patients and physicians. Discrepancies in their perceptions during RRMM treatment decision-making exist, indicating that communication tools are needed to facilitate SDM and PCC.

Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis

Lenalidomide has been standard therapy for multiple myeloma and other haematological malignancies for more than a decade. Previous meta-analyses identified an association between lenalidomide and second primary malignancies (SPM) in patients with multiple myeloma. However, newer randomised controlled trials using lenalidomide for other indications have not reported an increased incidence of SPM. The aim of this study was to investigate the risk of developing SPM with lenalidomide use in all disease settings. We did a systematic review of randomised controlled trials that reported SPM in patients treated with lenalidomide. PubMed, Embase, CENTRAL, Europe PubMed Central, and ClinicalTrials.gov were searched from Jan 1, 2004, to March 18, 2022. Randomised controlled trials with at least one lenalidomide group and one non-lenalidomide group were selected, regardless of the disease setting. Studies with a median follow-up of less than 12 months were excluded. Summary data were extracted by two reviewers (KS and KL) independently and verified by a third reviewer (JF). We then conducted a meta-analysis to assess the risk ratio (RR) of SPM with lenalidomide use across various disease subtypes using a random-effects model. We chose random effects for the primary analysis because of anticipated heterogeneity between different diseases, but we used fixed effects for stratified meta-analysis of multiple myeloma studies. Risk of bias was assessed with the PROTECT tool. The study was registered with PROSPERO, CRD42021257508. Our search yielded 9078 studies, and 38 trials that included 14 058 patients were eligible for meta-analysis after screening, 18 of which were in multiple myeloma. The RR across all malignancies was 1·16 (95% CI 0·96-1·39). However, there was heterogeneity across indications (p=0·020). The RR when lenalidomide was used for multiple myeloma was 1·42 (1·09-1·84). There was no increase in SPM in lymphoma or chronic lymphocytic leukaemia (0·90 [0·76-1·08]) and myelodysplastic syndrome (0·96 [0·23-3·97]) trials. In the setting of multiple myeloma, lenalidomide increased both solid and haematological SPM, both in the no-transplantation and post-transplantation settings. From the 38 trials, 21 (55%) had low risk of bias, 12 (32%) had unclear risk of bias, and five (13%) had high risk of bias. Based on the current data, lenalidomide-induced SPM seem to occur exclusively in patients with multiple myeloma. Thus, lenalidomide can be used for other indications without the major concern of a therapy-related neoplasm. In the multiple myeloma setting, lenalidomide is an effective drug, but patients should be monitored both for haematological and solid tumour SPM. This monitoring includes patients that have not received autologous haematopoietic stem-cell transplantation. Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma. None.

S1897 A Rare Case of Hypercalcemia in the Setting of Relapsing Multiple Myeloma Presenting as Acute Pancreatitis

Introduction: Hypercalcemia induced pancreatitis has a reported prevalence of 1.5-8%. Most reported cases have been secondary to hyperparathyroidism and few are secondary to malignancies or granulomatous diseases. Despite multiple myeloma (MM) commonly presenting with hypercalcemia, there are very few cases reported in literature of hypercalcemia induced pancreatitis in patients with MM. Case Description/Methods: A 70-year-old male with past medical history significant for MM and chronic kidney disease presented to the hospital with recurrent, constant dull epigastric abdominal pain, non-radiating, 6/10 in intensity, worsened by movement and deep inspiration with no relieving factors. He denied any associated factors. He has undergone a bone marrow transplant in 2017 for his MM but relapsed in 2019. On initial presentation workup was significant for pancytopenia, an elevated lipase level of 1170 and an elevated corrected calcium level of 15. Computed tomography (CT) of the abdomen and pelvis revealed no abnormality of the pancreas. MRCP ruled out choledocholithiasis and gallbladder US was negative for cholelithiasis. He denied alcohol use and triglyceride levels were not significantly elevated. Medication overview did not show any relevant medications that may induce pancreatitis. It was determined that the etiology of his pancreatitis was hypercalcemia in the setting of MM. Discussion: Hypercalcemia is present in 30% of patients with malignancy. MM commonly presents with hypercalcemia (19% of cases) but there are a handful of cases reported of calcium induced pancreatitis MM patients. Extensive workup is required to determine the etiology of acute pancreatitis starting from common to uncommon predisposing factors. In some cases it may remain cryptogenic. Multiple Myeloma patients may present with hypercalcemia in the setting of increased bone resorption caused by osteoclast activation. It is suggested that high serum calcium levels could be responsible for calcium deposit in the pancreatic ducts and activation of pancreatic enzymes, ultimately leading to pancreatitis. It is important as clinicians to keep in mind this rare presentation of hypercalcemia in MM patients in order to treat and manage the disease effectively and in a timely manner, improving patient outcomes. As calcium levels were normalized by hypercalcemia treatment, our patient's presenting symptoms significantly improved and later resolved.

Primary Hepatic Amyloidosis Associated with Multiple Myeloma Causing Acute Liver Failure: A Case Report

Primary amyloidosis is the most prevalent type of amyloidosis and is usually due to plasma cell dyscrasia. It more commonly presents with renal and cardiac involvement and, although the liver is frequently involved in primary amyloidosis, it rarely causes clinically apparent disease. The most common form of hepatic involvement is hepatomegaly and mild elevation of alkaline phosphatase. Diagnosis requires tissue biopsy that demonstrates positive staining for Congo red and treatment is ideally a combination of chemotherapy and hematopoietic cell transplantation. The prognosis of hepatic amyloidosis associated with liver failure is poor. Here, we report a fatal case of primary amyloidosis in the setting of multiple myeloma in a 54-year-old man who presented with acute liver failure.

Pomalidomide- and dexamethasone-based regimens in the treatment of refractory/relapsed multiple myeloma.

Pomalidomide is a potent immunomodulatory agent that is currently a standard of care backbone for the treatment of multiple myeloma (MM) patients in the relapsed/refractory setting after exposure to lenalidomide and a proteasome inhibitor. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients. Pomalidomide has direct myeloma cell tumoricidal effects by activating proteasomal degradation of Ikaros and Aiolos transcription factors and also indirect effects by modulation of immune responses, interaction with bone marrow stromal cells, and inhibition of angiogenesis. It is approved by regulatory authorities as doublet combination with dexamethasone but four more triplets are also approved for this setting. Many ongoing trials are evaluating the pomalidomide–dexamethasone backbone with newer anti-myeloma class agents or in quadruplet combinations. Pomalidomide–dexamethasone is currently one of the powerful tools available for use in the relapsed/refractory MM setting. Insights into the synergistic immunomodulatory effects of pomalidomide and other anti-myeloma agents and the mechanisms that overcome clonal resistance will potentially allow targeted use of triplet combinations at each relapse.

An overview of treatment options for patients with relapsed/refractory multiple myeloma and renal impairment

Renal impairment (RI) is a relatively common complication of multiple myeloma, which increases in frequency as disease becomes more advanced and recovery of renal function becomes less likely as patients progress through lines of therapy. Clinical trials in the relapsed/refractory multiple myeloma (RRMM) setting have not uniformly included patients with RI or robustly reported their outcomes. Here, we review existing data among patients with RI and RRMM across drug classes (including immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and exportin-1 inhibitor) to provide an improved understanding of available treatment options for this important population. We highlight data from pivotal clinical trials, including data relating to renal response (as defined by the International Myeloma Working Group) and discuss real-world experiences in patients with RI, where applicable. Despite substantial advances in RRMM treatment, the presence of RI remains associated with reduced overall survival. Consistent inclusion of patients with RI, and uniform reporting of their outcomes, should be encouraged in future prospective trials of treatments for RRMM.

Non-Invasive Liquid Biopsy to Quantify and Molecularly Characterize Circulating Multiple Myeloma Cells in the Assessment of Precursor Disease Pathology

▪Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective new therapies, most MM patients inevitably relapse and require further treatment, highlighting the need for better early detection methods for precursor patients and targeted interventions to prevent early disease from progressing.The initial diagnosis of MGUS/SMM remains an incidental process following the identification of increased clonal immunoglobulin in the blood. BM biopsy is the gold standard for diagnosis and monitoring of MM progression, but is intrusive, painful, and comes with possible secondary complications for patients. Consequently, repeated assessment is not a feasible option for MGUS and SMM patients who are asymptomatic. Here we tested the utility of circulating multiple myeloma cells (CMMCs) from non-invasive blood biopsy to accompany BM as a method to monitor disease development, by enumerating CMMCs from MGUS/SMM patients.Methods: Peripheral blood from 185 precursor patients (75 MGUS and 110 SMM) from the Dana-Farber Cancer Institute observational PCROWD study (IRB #14-174) was collected in CellRescue TM Preservative Tubes and processed on the CellSearch CellTracks Autoprep system using the CMMC assay kit using 4mL of blood. This assay employs the enrichment of CMMCs through the immunophenotype of CD138 +CD45 -19 -, and leukocyte exclusion based on CD45 +CD19 +. Nucleated cells were identified using DAPI staining. The CellTracks Analyzer II fluorescence microscope system was subsequently used to scan captured CMMC cartridges, with software allowing the automated scoring and enumeration of CMMCs. Additional molecular analyses were carried out on SMM patients. Briefly, minipools of CMMCs were sorted by DEPArray and underwent whole genome amplification using Ampli1 kit, PCR-free library construction, quantification and low pass whole genome sequencing (~0.5x) on the Illumina HiSeq2500. To assess whether molecular analyses can be performed to detect hyperdiploidy as a genomic biomarker of MM disease, ichorCNA analyses was performed to determine copy number variant (CNV) events and infer tumour fraction.Results: CMMCs were detected in 27% of MGUS patients collected, with a median count of 2 CMMCs (range 0 to 1328). Comparably, CMMCs were detected in 57% of SMM patients, with a median enumeration of 13 CMMCs (range 0 to 43836). Enumeration of CMMCs illustrated a correlation with clinical measure of disease including the International Myeloma Working Group 2/20/20 risk stratification model. A higher CMMC count was associated with increasing risk group based on the 3-risk factor model, with a median of 5, 29 and 59 CMMCs detected at low, intermediate, and high-risk SMM groups, respectively. CMMC counts were significantly increased at intermediate (P = 5.0 x 10 -4) and high-risk stages (P = 3.7 x 10 -3) compared to low-risk.While enumeration provides a correlative measure of CMMCs that may be of tumor origin, downstream molecular characterization can confirm MM-associated genetic alterations. At the precursor stages, a low tumour burden is evident clinically, thus both normal and malignant plasma cells are present. Therefore, to determine the concordance between bone marrow and peripheral blood CMMCs, we performed genomic analyses to identify arm level gain or loss events. Molecular analyses of CMMCs was carried out in patients who had matched BM and clinical fluorescent in situ hybridization (FISH) results. We showed that CMMCs can capture 100% of clinically annotated BM FISH CNV events. Furthermore, CMMC samples identified additional yield, with further CNVs identified that were not observed by FISH. In cases that did not have BM biopsy results, sequencing of CMMCs revealed the existence of genetic aberrations.Conclusion:Our results demonstrate clinical correlation and molecular characterization of CMMCs from MGUS/SMM patients. This study provides a foundation for non-invasive detection, enumeration and genomic interrogation of rare CMMCs from the peripheral blood of MGUS/SMM, illustrating the clinical potential of using liquid biopsies for monitoring and managing disease in the precursor setting of MM. DisclosuresGetz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy.

Simple SummaryTargeted radionuclide therapy (TRT) and immunotherapy, an example being chimeric antigen receptor T cells (CAR-Ts), represent two potent means of eradicating systemic cancers. Although each one as a monotherapy might have a limited effect, the potency can be increased with a combination of the two therapies. The complications involved in the dosing and scheduling of these therapies make the mathematical modeling of these therapies a suitable solution for designing combination treatment approaches. Here, we investigate a mathematical model for TRT and CAR-T cell combination therapies. Through an analysis of the mathematical model, we find that the tumor proliferation rate is the most important factor affecting the scheduling of TRT and CAR-T cell treatments with faster proliferating tumors requiring a shorter interval between the two therapies.Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.

P-008: First report of a patient with systemic light chain amyloidosis in the course of Multiple Myeloma treated with CAR T cells directed against B-cell maturation antigen

<h3>Background</h3> Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop a light-chain (AL) amyloidosis due to the deposition of amyloidogenic light chains causing organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become the most promising approach in treating cancer patients, especially hematologic malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA) CART which is currently being tested in a clinical trial for relapsed/refractory MM. <h3>Methods</h3> A 61-year-old woman diagnosed with an IgA-lambda symptomatic MM in 2014, with several prior lines of treatment presented with edema and significant non-selective albuminuria (24-hour proteinuria of 2626 mg with urinary M-protein of 307 mg, serum albumin 28 g/L) with preserved renal function (creatinine 0.6 mg/dL) and an increase in serum M protein, with a bone marrow (BM) infiltration by 23% plasma cells. There was no evidence of extramedullary disease by PET-CT and no CRAB signs were found. A subcutaneous fat aspiration and a renal biopsy established the diagnosis of systemic AL amyloidosis without cardiac involvement. At this point AL amyloidosis was the main reason to treat the patient, who received a fractioned dose of 3×10⁶/kg BCMA-CAR T cells after lymphodepletion, developing a grade I cytokine release syndrome and treatment-related cytopenias (grade 4 neutropenia and grade 2 thrombocytopenia), with no neurotoxicity. <h3>Results</h3> On day +28, the patient had already obtained a deep hematologic response with negative measurable residual disease by flow cytometry in the BM. After 3 months, the patient maintained the hematologic complete response and achieved renal response. After 1 year follow-up, the patient remains in hematologic complete remission and renal response with a decrease in proteinuria of 70%. <h3>Conclusions</h3> Here, we present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of a MM, successfully treated with CART therapy targeting BCMA. This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.

P-020: Altered mRNA splicing identifies novel biomarkers and therapeutic targets in AL (Amyloid light-chain) Amyloidosis

<h3>Background</h3> Amyloid light-chain Amyloidosis (ALA) is a plasma cell (PC) dyscrasia characterized by the accumulation of amyloid fibrils formed by clonal PCs in the bone marrow (BM). While multiple myeloma (MM) is present at the time of diagnosis in 10% of patients with ALA, nearly 30% of MM patients have subclinical amyloid deposits in the BM and/or in vital organs. Differential diagnoses of ALA, monoclonal gammopathy of undetermined significance (MGUS), and MM are challenging because these malignancies share genetic similarities. Unrecognized ALA in an MM setting can be life-threatening due to the side effects of some MM treatment regimens. Thus, a molecular signature selectively associated with ALA is needed to improve patient outcomes. <h3>Methods</h3> To identify a selective gene-signature linked to ALA, we evaluated altered mRNA splicing (AltS) events in 8 ALA, 24 MGUS, 33 smoldering MM, 40 MM patient samples and 10 normal donor plasma cells (NPC). We used the custom pipeline to identify AltS events present only in ALA cells and absent in other PC dyscrasias. Gene and transcript level analyses showed that 1609 genes are aberrantly spliced (894 genes are upregulated and 615 downregulated) in ALA patients compared to NPC (P< 001). <h3>Results</h3> Focusing on upregulated gene-splicing events occurring in the mRNA coding region, we observed significant upregulation of CD200, CDKN2B, and B7H3 splice variants in ALA PCs. Since splicing of these genes was also detected in other PC dyscrasias, custom transcript level analyses were used to identify ALA-specific AltS events. These analyses indicated that ~19% of the mRNAs were aberrantly spliced in each subgroup of patient samples, and ~17% retained introns, a marker of malignant transformation. In ALA patients we identified 1607 unique AltS events on 624 genes, 132 of which retained introns, 429 showed exon skipping alterations, and 250 were subjected to nonsense-mediated decay and degraded. These analyses showed significant upregulation of certain splice variants of CD200 and B7H3 in ALA PCs. These variants are attractive targets for therapy; CD200 and B7H3 are immune checkpoint proteins and targeting them may overcome checkpoint-induced drug resistance. In patient's samples harboring upregulated spliced genes, we evaluated the expression of cis-/trans-splicing molecules. Samples with upregulated AltS variants overexpressed SNRPN70 and RBM8A genes, both of which are part of the U1 spliceosome. Alteration of this complex assembly leads to AltS at the 5'sites of exons, causing intron retention and/or uncontrolled exon skipping. Therefore, targeting these splicing factors has the potential to control AltS in ALA. <h3>Conclusion</h3> Our study (i) identifies splice variants that are selectively expressed in ALA PCs, (ii) provides potential ALA molecular biomarkers to aid the differential diagnoses of ALA and other PC dyscrasias, and (iii) identifies potential therapeutic strategies targeting altered splicing in ALA.

Soft Tissue Coverage with Submental Flap in Massive Medication-Related Osteonecrosis of the Mandible

Intravenous Bisphosphonates (BPs) are used to treat cancer-related conditions, including hyperkalemia of malignancy, Skeletal-Related Events (SREs) associated with bone, and for management of lytic lesions in the setting of multiple myeloma. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) is a severe complication of BPs, which affects the patient's quality of life. In the treatment of BRONJ, soft tissue coverage for coverage of the debrided bone is essential. In severe soft tissue deficiency, the use of local or distant soft tissue flap is necessary this case report; a massive BRONJ was described in which a submental flap was used to cover the mandibular bone.