IgG Kappa Multiple Myeloma Research Articles

Clinical and Diagnostic Challenges in Patients with Concomitant Plasma Cell Disorders and Myeloproliferative Neoplasms

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell precursor disease that regularly precedes the development of multiple myeloma (MM). It accounts for about 4.5% in the entire population, however patients with myeloproliferative neoplasms (MPN) seem at a higher risk for MGUS with a reported rate of concomitant disease at 3-14%. The reason for this co-occurrence of MGUS and MPN remains unclear, and a common cell of origin has not yet been defined. Inversely, constant MPN-driven inflammation in the bone marrow microenvironment (BM) may stimulate the expansion of a pre-existing plasma cell clone thereby promoting the transition from MGUS to active MM. Here, we investigated the clinical and molecular characteristics of a comprehensive series of cases treated for MGUS/MPN overlap at our center. Methods: Patients who were diagnosed with concomitant MGUS/MM and MPN between 2006 and 2023 were identified by retrospective chart review, yielding a total of 13 cases. Results: We identified 5/13 patients with a confirmed diagnosis of MGUS and 8/13 cases with active MM, all coinciding with a diagnosis of MPN (5 polycythemia vera (PV), 4 chronic myelomonocytic leukemia (CMMol), 3 primary myelofibrosis (PMF), 1 chronic myelogeneous leukemia (CML)). Median age at diagnosis was 66 (range 44-78) years for MGUS/MM and 64 (range 43-81) years for MPN. Overall survival in our cohort was rather short at a median of 8.2 (range 0-16) years. For clinical management, anti-MM therapy was prioritized over MPN treatment in the majority of patients, with the exception of CMMol. MPN-related organ restrictions significantly limited treatment options for MM, including bleeding disorders, infectious complications and impaired hematopoiesis (in PMF). High-dose concepts were performed in transplant-eligible cases, including autologous in 4 and allogenic stem cell transplantation in 2 patients. Two out of 6 patients died under transplant (1 autologous graft failure), indicating a comparably high transplant-related mortality. Another patient died from MM progression as PMF-induced anemia did not allow for more intense treatment. To examine the evolutionary path from MGUS to MM and the potential impact on this transformation by a concomitant MPN, we next examined the clinical course of disease in each patient. Six out of 13 patients had secondary MPN after prior MGUS/MM diagnosis, 5/13 patients were diagnosed with MPN first, and for 2/13 cases BM assessment revealed coincidental findings of MPN/ MM at the same time. For the cases of secondary MPN after initial diagnosis of MM/MGUS, latency between both diseases was shorter, than vice versa (40.2 vs. 73.6 months, P=0.19). No association was observed between secondary MPN and prior treatment for MM, as only 1/6 patients was diagnosed with PV following high-dose melphalan chemotherapy, potentially pointing towards a negligible role of treatment-induced secondary primary malignancies the context of MM/MPN overlap. In contrast, MGUS progression to active MM was observed in 1 patient with hyperdiploid IgG kappa MM (including trisomy 9) and long-term coexistent JAK2-mutated PV. Another patient was diagnosed with IgG kappa MM and 9p gain along with concomitant JAK2-mutated PMF. Whole-genome sequencing (WGS) is currently ongoing for these patients to decipher the temporal relationship of MM/MGUS and JAK2-mutated MPN. Conclusions: The prevalence of MGUS/MM in MPN patients seems modestly increased as compared to the entire population. From a clinical viewpoint, overlap of both diseases poses significant challenges to healthcare providers as treatment-related mortality tends to be higher than in patients with mutually exclusive MPN/ MM. Improved understanding of the molecular interplay of both diseases will inform risk-adjusted treatment decisions and will lead to improved outcomes in this highly challenging subgroup of patients.

MM-010 Spontaneous Prosthetic Fracture in a Patient With Relapsed Multiple Myeloma

Plasmacytomas are a form of plasma cell dyscrasia that present as a single mass of monoclonal plasma cells located either extramedullary or intraosseous. They can present as a solitary or multiple mass, either at diagnostic or in the context of a relapsed refractory patient. The latter scenario usually has a dismal prognosis. Bone fractures are frequent in patients with multiple myeloma (MM), sometimes requiring a surgical approach. Eventually, plasmacytomas can also develop surrounding a synthetic prothesis. Prosthetic fractures are a rare complication and usually present a challenging situation. To describe a case of prosthetic spontaneous fracture and exposure. Case report. A 52-year-old woman with a history of IgG kappa MM diagnosed in 2014 was admitted for severe back pain. Her MM was treated with CyBorD and consolidation with an autologous stem cell transplant. She also underwent surgery for a dorsal vertebral fracture at diagnosis. She had a first relapse in 2018 receiving a carfilzomib-based regimen as re-induction. In 2019 she had a 3° relapse with extensive bone disease and supraclavicular plasmacytoma in a lymph node. She received VTD-PACE for 3 cycles, achieving a partial response. At admission in 2020, dorsal x-ray showed prosthetic fracture. She also had a dorsal plasmacytoma. Her ECOG performance status was 4, and she received palliative care and a VAD regimen. The plasmacytoma continued to grow and ulcerated. Prothesis exposure was confirmed. Because of her bad performance status, she received palliative treatment. Extramedullary relapses of plasma cell dyscrasias are usually aggressive and have a dismal prognosis. Rare reports and recommendations are available in the literature regarding the treatment of prosthetic fractures, and there is currently no consensus about the standard management for these patients. We present this case because of the rare incidence of prosthetic fractures.

A CASE OF TYPE 1 CRYOGLOBULINEMIA PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

A CASE OF TYPE 1 CRYOGLOBULINEMIA PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

IgG kappa multiple myeloma with isolated central nervous system relapse.

A 76-year-old male presented with acute renal failure and cast nephropathy was diagnosed with IgG kappa multiple myeloma (MM). His paraprotein was 40 g/L, kappa-free light chain level was 17,058 mg/L, kappa: lambda light chain ratio was 1445. An automated full blood count showed hemoglobin 90 g/L, white blood cells 2.96 × 109/L, neutrophil 1.7 × 109/L, and platelet 179 × 109/L. Bone marrow trephine sample was hypercellular with nearly 100% plasma cells, which were positive for CD138, CD56, and cyclin D1, and showed kappa light chain restriction. Fluorescence in situ hybridization analysis with dual color/dual probes for immunoglobulin heavy chain (IGH) and MYC genes (Cytocell) and whole genome screening using 8 × 60K oligonucleotide arrays (Agilent) performed on the CD138 enriched cells (CD138 microbeads Miltenyi Biotech) from the liquid bone marrow sample showed no evidence of IGH rearrangement, MYC rearrangement, 1q gain, 1p loss, 17p loss, or any clinically significant imbalance. He was treated with eight cycles of bortezomib, cyclophosphamide, and dexamethasone (VCD) to very good partial response. He relapsed 30 months after diagnosis with paraprotein of 36 g/L, kappa light chains of 10,000 mg/L, and creatinine of 498 μmol/L. He was treated with eight cycles of bortezomib, thalidomide, and dexamethasone (VTD) to paraprotein undetectable and kappa light chain 29 mg/L. Seven months post completion of VTD (4 years after myeloma diagnosis), he presented with abnormal gait, falls, and a left-sided facial droop. His paraprotein was 2 g/L and serum-free kappa light chain was 81 mg/L. Magnetic resonance imaging (MRI) head and whole spine showed multifocal diseases in spinal canal and intracranially, involving the cranial nerves most prominent the fifth, seventh, eighth, and hypoglossal nerve on the left, anterior surface of the inferior pons medulla (Figure 1A). There were multiple lesions in the cervical spine as well as in the thoracic spine (Figure 1B). Computerized tomography (CT) chest abdomen pelvis did not show the evidence of other new diseases. Plasma cells were detected in cerebral spinal fluid (CSF) (Figure 1C, May–Grünwald–Giemsa stain x100 objective). He was treated with pomalidomide and dexamethasone. Weekly cytarabine intrathecal (IT) treatment was given until the clearance of plasma cells from CSF samples for three times. Four months later, he achieved the complete remission on MRI head and whole spine with undetectable paraprotein and normal light chain ratio. Serial MRI scans confirmed ongoing remission. A year later, he relapsed again with worsening mobility and reappearance of myeloma cells in CSF. By flow cytometry, these cells were positive for CD138, CD38, CD56, CD117, and negative for CD19. MRI head showed leptomeningeal disease with a new 2.2 cm frontal lobe lesion. His paraprotein remained undetectable and kappa light chain remained at below 100 mg/L. He continued systemic pomalidomide and dexamethasone chemotherapy and received palliative whole brain radiotherapy 20 Gy in 5 fractions for symptom control. His disease continued progressing and he passed away 3 months later (5.5 years after myeloma diagnosis). Here, we reported a myeloma patient with isolated CNS relapse, who achieved 1 year of remission with combination of intrathecal chemotherapy and systemic pomalidomide and dexamethasone treatment, but sadly passed away 4 months after second CNS relapse. CNS MM is a rare form of extramedullary disease, but carries a very poor prognosis. The optimal approach to treatment of CNS MM is not currently known. The current approach includes systemic therapy with agents known to cross the blood brain barrier, intrathecal therapy, and CNS irradiation. Innovative approach to treatment is urgently needed. The authors received no specific funding for this work. Ke Xu and Lucy Kamuriwo wrote the manuscript. Ke Xu, Lucy Kamuriwo, Claire Anderson and Parag Jasani critically revised the final version of the manuscript. The authors declare they have no conflicts of interest. No written or verbal consent obtained from patient. Patient has passed away.

Bilateral corneal opacities and surface irregularity: role of contact lenses in a case of paraproteinemic keratopathy and multiple myeloma

Introduction: This report features an interdisciplinary approach to diagnose and manage a case of paraproteinemic keratopathy and multiple myeloma. In addition, it suggests that rigid gas-permeable contact lenses (RGP CLs) may be a viable alternative to corneal surgery to reduce visual symptoms. Patient and clinical findings: A 57-year-old man symptomatic for progressive blur and glare over 2 years presented with an outside diagnosis of corneal dystrophy. An examination revealed bilateral diffuse subepithelial corneal crystals in conjunction with peripheral annular deposits with demarcated ridges. Corneal topography revealed central irregular astigmatism induced by these peripheral corneal opacities. Diagnosis, intervention, and outcomes: A hematological workup confirmed IgG Kappa monoclonal gammopathy and multiple myeloma. Visual rehabilitation for paraproteinemic keratopathy was achieved with RGP CLs, which are expected to maintain stable visual acuity while the patient undergoes systemic chemotherapy. Conclusions: This report emphasizes the value of thoroughly investigating dystrophy-like corneal deposits of unknown etiology as monoclonal gammopathy can have adverse or even fatal systemic implications. To the authors’ knowledge, this is the first study to directly suggest RGP CL as an adaptable and economical means to improve acuity in certain cases of paraproteinemic keratopathy without resorting to surgical intervention.

Progressive Multifocal Leukoencephalopathy in Multiple Myeloma: A Single Institution Case Series

IntroductionProgressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, is an infection that requires immunosuppression for its manifestations and is fatal disease in many cases. (1) After asymptomatic primary infection, which occurs in childhood, the virus remains quiescent. (1,4) The classical clinical presentation is that of a subacute symptomatology that develops over weeks or months and consists of diverse sensorimotor abnormalities depending on the site of brain involvement. Approximately 22 cases of PML amongst patients with multiple myeloma (MM) have been reported in the literature between 1965 and April 2020. (5)MethodsWe performed a retrospective chart review of all myeloma patients who were treated at the Princess Margaret Cancer Center from 2010-2020 to identify cases of PML. Patient and disease characteristics, responses, and survival outcomes were collected from Myeloma and Stem Cell Transplant databases and electronic patient records under REB approval.ResultsWe identified 3 cases of PML in MM patients at our center over the past 10 years, all of which occurred in patients receiving therapy containing an immunomodulatory derivative (IMID), i.e., thalidomide, lenalidomide or pomalidomide.Patient 1A 52-year-old male with kappa light chain MM presented in 2009 on hemodialysis and received upfront bortezomib and dexamethasone followed by melphalan 200mg/m 2 and autologous stem cell transplantation (ASCT) in March 2010; maintenance with thalidomide was given until July 2011 when he presented to the ER with left-sided weakness, facial droop, and decreased strength. CT scan showed right-sided hypodensity in keeping with demyelination. PML was confirmed by MRI, lumbar puncture with positive PCR for JC virus, and a brain biopsy (Fig 1 A-C). He was treated with mirtazapine, and also developed status epilepticus controlled with phenytoin and phenobarbital. His myeloma treatment was never resumed after the diagnosis of PML due to concerns about viral reactivation. Approximately 3 years after PML diagnosis, his serum free kappa protein levels started to increase; he remained on hemodialysis but experienced no new myeloma-related organ damage and no myeloma treatment was offered. His last follow-up in clinic was in March 2019. However, he succumbed to S. pneumonia septicemia in July 2019.Case 2A 68-year-old female with IgG kappa MM diagnosed in 2004 was treated with high-dose dexamethasone induction followed by melphalan 200mg/m 2 and ASCT and relapsed 2 years later. She commenced cyclophosphamide and prednisone until July 2011 when treatment was changed to lenalidomide and prednisone; subsequent progression in February 2014 was treated with pomalidomide/bortezomib/prednisone. In November 2014, we noticed worsening vision. Brain MRI showed hyperintensity in T2 in the occipital lobe. Her myeloma treatment was stopped and she received corticosteroids with no improvement. LP in January 2015 was positive for JC virus and the diagnosis of PML was made. She was managed with supportive measures. Her last clinic follow-up was in 2015 and the patient died from progression in September 2015.Case 3A 52-year-old male with IgA lambda MM diagnosed in 2015 was treated with CYBOR-D induction followed by melphalan 200mg/m 2 and ASCT. He initially received lenalidomide maintenance which was changed to bortezomib due to toxicity. On progression in January of 2019 he was placed on a clinical trial of the anti-BCMA antibody drug conjugate belantamab mafodotin in combination with pomalidomide and dexamethasone on which he achieved a VGPR. In October 2020, he developed confusion and memory problems, as well as involuntary twitching. A brain MRI showed possible demyelination Two LPs were negative for JC virus, but a targeted brain biopsy confirmed the diagnosis of PML (Fig 1 D-F). His myeloma treatment was discontinued, and he was started on mirtazapine. At his most recent clinic visit in May 2021 his speech, memory and functional status had improved considerably and there were no signs of myeloma progression.ConclusionOur current series of PML in MM showcases the potential contribution of IMIDs and other novel agents–such as the newer monoclonal antibodies like belantamab mafotidin– to the reactivation of JC virus and subsequent PML. Our series also demonstrates that neurologic improvement and longer survival can be observed with earlier management. [Display omitted] DisclosuresReece: BMS: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

S2749 A Rare Cause of Liver Cirrhosis and Gastritis: Primary Gastrointestinal Amyloidosis in a Patient With Multiple Myeloma

Introduction: The most common form, systemic amyloidosis, is characterized by production of amyloidogenic precursor proteins at a site, remote from the organs of amyloid deposition. Case Description/Methods: A 65-year old male with a 25 year history of chronic alcoholism, presented to the emergency department for a 2 week history of non-radiating right upper quadrant abdominal pain associated with pruritus, nausea, coffee ground emesis, and clay colored stools. The exam was notable for icteric sclera, right upper quadrant abdominal tenderness, ascites, and hepatomegaly. Initial work up revealed new onset unexplained elevated liver enzyme. Abdominal Ultrasound was significant for hepatomegaly with perihepatic ascites. The CT scan revealed diffuse liver cirrhosis, periportal lymphadenopathy, and stigmata of portal hypertension including hepatosplenomegaly, intra-abdominal ascites, and varices. Esophagogastroduodenoscopy with endoscopic ultrasound was performed, which showed gastritis, and enlarged porta hepatis, which was ultimately biopsied and sent for cytology and pathology. Given the unexplained elevation of the liver enzymes, and liver biopsy revealed extracellular amyloid deposition in peri-sinusoidal spaces consistent with amyloidosis. Transesophageal echocardiogram which raised suspicion for cardiac involvement with amyloid deposit. Immunoglobulin levels were subsequently investigated and showed elevated IgG antibodies. A K/L free ratio was elevated to 94.7. A myeloma flow cytometry exhibited an IgG kappa monoclonal-gammopathy. Finally, a CT-guided bone marrow biopsy from the iliac crest was obtained, confirming an IgG kappa multiple myeloma with 80% proportion of plasma cells (DS 2A, ISS 3). The patient was started on steroids, and chemotherapy with daratumumab, however his condition was complicated by septic shock, which led to an admission in the ICU followed by endotracheal intubation and multi-organ failure and eventual palliative care. Discussion: Localized GI and hepatic amyloidosis have rarely been described in the literature. This condition poses great diagnostic challenges and warrants extensive work up before definitive diagnosis. Our case highlights the importance of clinical suspicion of GI amyloidosis in patients with constitutional symptoms including fatigue, weight loss, and unexplained liver disease. Once amyloidosis is considered, the diagnosis can be obtained by tissue biopsy from either the GI tract or subcutaneous adipose tissue.Figure 1.: CT scan (A-B) showing hepatosplenomegaly, and peri-splenic varices (arrowheads). Pathologic findings (C-G) of AL type amyloidosis of the luminal gastrointestinal tract. C. Histologic examination (Hematoxylin-Eosin staining) of a gastric antral type mucosa with chronic inactive gastritis and interstitial deposition of pink amorphous material (white asterisk). Histologic examination of liver with amorphous material deposition: Hematoxylin-Eosin staining (black asterisk in D-E), and crystal violet staining (G). F. Vascular wall are almost always involved first in the systemic amyloidosis (Hematoxylin-Eosin staining).

IgA nephropathy in IgG kappa multiple myeloma.

Multiple myeloma (MM) frequently affects kidney function through multiple mechanisms. Nonetheless, some patients develop kidney injury due to other causes. A 54-year-old woman was diagnosed with IgG kappa MM developed IgA nephropathy without cast nephropathy. Further studies did not show criteria for MM progression or other causes. This case highlights the need for further investigation of kidney injury in MM patients (such as toxicity of previous drugs, infectious events, or immune-mediated disorders).

Factitious Total Triiodothyronine(T3) Elevation in a Euthyroid Patient With Paraproteinemia

Background: We report a rare case of a patient treated with levothyroxine for hypothyroidism who also had paraproteinemia and was found to have a clinically inconsistent elevation of T3 by RIA. Clinical Case: A 72 Year old African American female with a history of hypothyroidism and IgG kappa Multiple Myeloma (MM) was admitted to the hospital for altered mental status. Her hypothyroidism had been well controlled for years on a stable dose of levothyroxine 0.075mg daily. Review of systems were negative pertinent to thyroid dysfunction. Family history: negative for thyroid disease. On physical exam, an elderly female clinically euthyroid without palpable thyromegaly but was confused and disoriented. Initial Vital signs: BP 117/67, HR 62, RR 14, T 98, SpO2 99% on room air. BMI 19. EKG: normal sinus rhythm, CXR: normal, TSH: 6.27 (0.55-4.78 uIU/mL), total T3: >600 (60-181ng/dL), total T4: 4.5 (3.2-12.6 ug/dL), FT4: 1.22 (0.89-1.76 ng/dL), hemoglobin: 6.6 (12-16 g/dL), hematocrit: 20.9 (38-47 %), Na: 132 (136-145 mmol/L), K: 4.0 (3.5-5.1 mmol/L), Cl: 104 (98-10/ mmol/L), BUN: 45 (20-31 mmol/L), creatinine: 2.8 (0.6-1.0 mg/dL), total protein: 10.1 (5.7-8.2 g/dL), albumin: 1.8 (3.4- 5.0 g/dL), A:G ratio: 0.22 (0.60-1.50 mmol/L). Serum protein electrophoresis revealed Gamma Globulin 5.8 (0.8-1.7 g/dL), Kappa 9270 mg/L (3.3 -19.4 mg/L) Lambda 9.3 (5.7-26.3mg/L), K/L 996.7 (0.26 -1.65), B2 - macroglobulin: 17.9 (ref: <or= 2.51mg/L) which is consistent with an M- spike migrating in the gamma globulin region. Serum TPO, TG, TSI antibodies were negative. Further testing again reported Total T3 >600 with normal reverse T3 21(8-25 ng/dL). Conclusion: Rare cases of factitious elevations of thyroid hormone have been reported in patients with elevated abnormal IgG or IgA proteins having high binding affinity for thyroid hormone.[1] This hypothyroid patient was clinically and biochemically euthyroid except for a dramatic but clinically inconsistent elevated total T3. She also had multiple myeloma with paraproteinemia (IgG Kappa M spike). The few cases reported to date have shown factitious elevation of either or both total T4 and total T3. In our case the factitious elevation was limited to total T3. We alert clinicians to be aware of factitious elevation of thyroid hormones due to high affinity binding to immunoglobulins. In our case this caused spurious elevation of total T3, but not total T4, in a patient with multiple myeloma and an IgG kappa M spike paraprotein. Reference: 1: Marianna Antonopoulou, Arnold Silverberg, “Spurious T3 Thyrotoxicosis Unmasking Multiple Myeloma”, Case Reports in Endocrinology, vol. 2013, Article ID 739302, 3 pages, 2013. https://doi.org/10.1155/2013/739302

Successful Non-surgical Treatment of an Acute Calculous Cholecystitis in a Myeloma Patient with Covid-19: Case Report.

COVID-19 has a wide spectrum of clinical phenotypes. While fever and cough are the most common symptoms, abdominal pain is rarely reported. We report the first case of COVID-19 pneumonia in an elderly patient with multiple myeloma (MM), complicated by acute calculous cholecystitis (ACC). A 73-year-old gentleman with underlying IgG kappa MM, presented with fever, cough and dyspnoea. His nasopharyngeal swab was positive for SARS-CoV-2. Piperacillin/tazobactam and oral hydroxychloroquine were started in addition to granulocyte colony-stimulating factor (GCSF) support due to neutropenia. Patient deteriorated on day 5, requiring high flow oxygen support. Dexamethasone, low molecular weight heparin prophylaxis and one dose of intravenous immunoglobulin were given. Despite negative swab on day 10, he developed ACC on day 17. With antibiotics and supportive care, patient showed full recovery without any surgical intervention. It remains elusive whether the gallbladder might be vulnerable to COVID-19, necessitating further validation via prospective studies.

Successful Treatment of Concurrently Diagnosed Multiple Myeloma and Myelodysplastic Syndrome with Isolated Del(5q) with Lenalidomide, Bortezomib, and Dexamethasone

Lenalidomide is known to be an effective therapy for multiple myeloma (MM) and for myelodysplastic syndrome with isolated del(5q). However, there have been very few reports of treatment of both conditions using lenalidomide when they are diagnosed concurrently. A review of the literature revealed two reports of MM and del(5q) MDS treated with lenalidomide. We report the case of a patient simultaneously diagnosed with multiple myeloma and myelodysplastic syndrome with isolated del(5q) who was treated successfully with lenalidomide. The patient is a 74 year old female who was referred to hematology for worsening chronic macrocytic anemia with a hemoglobin of 9.4 g/dL. A serum protein electrophoresis (SPEP) was obtained during her workup and demonstrated an IgG kappa monoclonal spike of 4.7 g/dL. Free light chain analysis demonstrated a kappa/lambda ratio of 36.7. The patient was mildly hypercalcemic at 10.6 g/dL but had no renal insufficiency. Platelet and white blood cell counts were normal. There were no osteolytic lesions on skeletal survey and a whole body PET scan identified no bony disease or plasmacytomas. A β-2 microglobulin level was 3.7 mg/L and albumin was 3.3 g/dL. Bone marrow biopsy revealed 60% plasma cells in a 70% cellular marrow. Granulocytic and megakaryocytic dysplasia was identified. Fluorescence in situ hybridization returned showing a 4:14 translocation in 72% of analyzed nuclei and monosomy 13 in 61% of nuclei analyzed consistent with an unfavorable risk profile. Chromosome analysis also revealed a 5q deletion in 15 of 20 analyzed cells. Bone marrow blasts were measured at 1%. Therefore, the patient concurrently met diagnostic criteria for stage II IgG kappa multiple myeloma per the International Staging System and low risk myelodysplastic syndrome with isolated del(5q) per the 2016 WHO classification of MDS with a Revised International Prognostic Scoring System Score (IPSS-R) of 2. She was started on lenalidomide 25 mg daily, bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 and dexamethasone 20 mg on days 1, 8, and 15 of a 21 day cycle. After 3 cycles of therapy, serum immunofixation electrophoresis showed an unquantifiably low IgG kappa monoclonal spike and the patient's kappa/gamma light chain ratio had normalized to 1.1. Hemoglobin and calcium returned to normal. On repeat bone marrow biopsy, there was normocellular marrow with 4% polytypic plasma cells by kappa/lambda immunohistochemistry. No dysplasia was identified and bone marrow blasts were 1.5%. Therefore, the patient achieved a very good partial response (VGPR) to therapy for multiple myeloma according to International Myeloma Working Group criteria within 3 months. She met National Comprehensive Cancer Network criteria for response of her MDS to lenalidomide by normalization of hemoglobin. The patient's case demonstrates successful treatment of concurrently diagnosed multiple myeloma and MDS with isolated del(5q) using lenalidomide. Among the two other similar cases we discovered in the literature, one patient was treated with low-dose lenalidomide and dexamethasone [Nolte, et al. Eur J Haematol. 2017 Mar;98(3):302-310.], and the other patient was treated with high-dose lenalidomide and dexamethasone, achieving a partial response [Ortega, et al. Leuk Res. 2013 Oct;37(10):1248-50.]. Neither patient received a proteasome inhibitor. In our case, the patient was treated with higher intensity induction therapy for multiple myeloma and achieved a VGPR. She did not have worsening cytopenias during therapy, and in fact experienced normalization of her blood counts. Therefore, it is reasonable to treat patients simultaneously diagnosed with MM and MDS with isolated del(5q) with standard three-drug induction therapy for multiple myeloma. While our approach makes sense in the abstract, hematology/oncologists should be aware that it works in practice. Disclosures No relevant conflicts of interest to declare.

A Case of Pancoast Syndrome Caused By an Extramedullary Plasmacytoma in Relapsed Multiple Myeloma

Extramedullary plasmacytomas are present in 7-18% of multiple myeloma at diagnosis, and up to 13-20% at the time of disease relapse. (Blade J et al., 2011; Varettoni M et al., 2010) A case series in 2010 with 1003 patients found involvement of soft tissues surrounding the axial skeleton in 85% of cases at diagnosis, and 72% of cases at time of relapse. Other sites of involvement included lymph nodes, liver, kidney, airways, skin, breast, and the gastrointestinal tract. (Varettoni M et al., 2010) An extramedullary plasmacytoma leading to Pancoast syndrome has been reported only 3 times in previous literature, in 1979, 1983, and 1984. (Brenner B et al., 1984; Chen KT et al., 1983; Wilson KS et al., 1979) A case of this uncommon presentation is reported here. The patient is a 70-year-old male with a diagnosis of ISS-3 IgG Kappa multiple myeloma (serum monoclonal protein 10 g/L, Kappa light chain 2356.29 mg/L, free light chain ratio 386.28, bone marrow biopsy 61.8% plasma cells) the year prior to the current presentation. He was not a candidate for autologous stem cell transplant due to poor pulmonary function, and hence had a treatment plan for 9 cycles of cyclophosphamide/bortezomib/dexamethasone (CyBorD), of which 6 were completed. Treatment was then stopped due to a macrocytic hypoproliferative anemia thought to be related to early hypoplasia from prior CyBorD. At this time, he was in complete remission with bone marrow biopsy showing 2.8% plasma cells. His medical history was otherwise significant for coronary artery disease with prior myocardial infarction, previous transient ischemic attack with carotid stenosis and carotid endarterectomy, hypertension, dyslipidemia, spinal stenosis with multilevel degenerative changes most pronounced at L3-4, and osteoarthritis. He had a 30 pack-year smoking history, and continued to smoke cigars. The patient presented to hospital 5 months after completion of the above therapy with 2 weeks of right shoulder pain radiating down the arm, and right hand weakness, numbness, and tingling. He had also noted right lower extremity weakness and numbness with some incontinence. The physical exam was significant for right ptosis and myosis (Figure 1), decreased strength and sensation in the right C8-T1 distribution, inability to lift the right lower extremity off the bed, reduced anal sphincter tone, and a post-void residual volume of 700 mL. CT brain and cervical spine showed new abnormal mass-like tissue within the right hemithorax apical region with apparent extension into the cervicothoracic junction. Given his history of multiple myeloma as well as his smoking history, the mass was thought to either be a primary lung malignancy, or an extramedullary plasmacytoma. The patient was therefore admitted for ongoing management and diagnostic work-up. He was seen by the inpatient Hematology service, and noted to have progression of his multiple myeloma with Kappa light chain 885.99 mg/L (free light chain ratio 48.67). He was started on pulse steroids with a plan for daratumumab/lenalidomide/dexamethasone (DRd) with dose reduction of the lenalidomide given his prior history of myelosuppression. Further imaging with MR entire spine showed the right lung apical soft tissue mass extending into the epidural space from C7-T2 with severe spinal cord compression and spinal cord edema (Figure 2), as well as epidural extension of disease at L5 resulting in moderate spinal canal stenosis. The patient was then seen by Radiation Oncology and received 8 Gy as a single fraction to the apical lung mass. Subsequent biopsy of the mass showed a plasma cell neoplasm, Kappa restricted by in-situ hybridization, and compatible with a plasmacytoma. The patient then received two cycles of DRd and thought to be in very good partial response with Kappa light chain 32 mg/L, free light chain ratio 3.8, and resolution of previous apical lung mass and L5 epidural extension on subsequent MR spine. We document here a rare case of plasmacytoma leading to Pancoast syndrome. Given the difference in therapeutic options and prognosis between an extramedullary plasmacytoma and a primary lung malignancy, it is important to recognize this presentation as a diagnostic possibility, and to pursue relevant investigation and targeted management for the same. Disclosures Sharma: Enstasis therapeutics: Current equity holder in private company; Pfizer: Current equity holder in private company; Gilead: Other: shareholder; Contrafect corporation: Current equity holder in private company; Moderna: Other: shareholder.

Management of Frail Older Adults with Newly Diagnosed Multiple Myeloma — Moving Toward a Personalized Approach

Case vignetteA 75-year-old male undergoes an evaluation for progressively worsening fatigue with associated shortness of breath. He also reports back pain worse at night, which does not resolve with acetaminophen. He is retired, but over the past 2 months he is unable to garden or perform household chores. Due to his pain and fatigue, he has limited his activity. He currently takes 9 prescription medications for chronic medical conditions, which include diabetes mellitus with neuropathy, hypertension, hyperlipidemia, and COPD. Initial evaluation reveals anemia (Hgb 9.0 g/dl last known normal was 2 years ago, Hgb 13.5 g/dl), renal impairment (serum creatinine 2.5 mg/dL), hypercalcemia (11.5 g/dl). Plain X-rays reveal compression fractures involving T3 and T4. Multiple myeloma is suspected, further labs confirm the diagnosis of IgG kappa multiple myeloma. LDH is elevated, beta-2-microglobulin is elevated at 6.1 mg/L and albumin < 3.5 mg/dl. Bone marrow aspiration and biopsy reveal plasmacytosis of 55% and on fluorescence in situ hybridization testing, del 17p/TP53 mutation in 85% of cells is detected. PET/CT confirms diffuse bone disease involving the axial and appendicular skeleton. His Karnofsky performance status (KPS) is 70%. He is widowed and lives alone but has 2 adult children who currently live out of state.This abstract will discuss how assessments of fitness/frailty may be used to develop personalized care tailored to the unique needs of older frail adults with multiple myeloma.

A case of severe asymptomatic hypercalcaemia in IgG kappa multiple myeloma, focal bone disease and inappropriately normal PTH as a differential diagnostic dilemma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A colonic mass revealing a disseminated crystal storing histiocytosis secondary to indolent multiple myeloma: a case report with literature review

BackgroundCrystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract.Case presentationWe present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response.ConclusionThis case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.

Verapamil as treatment for refractory status epilepticus secondary to PRES syndrome on a SARS-Cov-2 infected patient

We present the case of a 74-year-old male with an 18-year history of IgG kappa multiple myeloma who received multiple lines of treatment, including carfilzomib-dexamethasone every three weeks for the last 8 months.

First-in-Human Assessment of Feasibility and Safety of Multiplexed Genetic Engineering of Autologous T Cells Expressing NY-ESO -1 TCR and CRISPR/Cas9 Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T cells) in Advanced Multiple Myeloma (MM) and Sarcoma

Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Melenhorst:Incyte: Research Funding; Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau; Stand Up to Cancer: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding. Fraietta:Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Mangan:amgen: Speakers Bureau; takeda: Speakers Bureau; celgene: Speakers Bureau; janssen: Speakers Bureau. Lancaster:novartis: Research Funding. Suhoski:novartis: Research Funding. Fesnak:Novartis: Research Funding. Young:novartis: Research Funding. Chew:tmunity: Other: Scientific Founder, Research Funding; novartis: Research Funding. Zhao:Tmunity: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding. Hwang:Novartis: Research Funding; Tmunity: Research Funding. Hexner:novartis: Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties.

Evaluation of Re-Intensification of Daratumumab to Weekly or Biweekly Dosing Schedule

Introduction:Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/refractory MM. Daratumumab is typically dosed: 16mg/kg weekly (Weeks 1-8), then 16mg/kg biweekly (Weeks 9-24), then 16mg/kg monthly (Weeks 25 and beyond until disease progression).At Dana-Farber Cancer Institute (DFCI), some patients receiving a daratumumab-containing regimen were “re-intensified” upon progression of disease. “Re-intensification” could include (1) re-escalation to weekly dosing from biweekly or monthly dosing or (2) re-escalation to biweekly dosing from monthly dosing or (3) continuation of biweekly or monthly dosing. However, there is a lack of evidence to support the safety and efficacy of daratumumab dose “re-intensification” (Dara-RI) during treatment. We aimed to assess the efficacy and safety of Dara-RI, with or without the addition of other myeloma-agents, in 13 patients with disease progression while on a daratumumab-containing regimen.Method/Results:This is an institutional review board approved, descriptive, retrospective medical chart review of 13 adult patients with MM who received Dara-RI at DFCI from November 2015 to October 2017. The median age was 68 years (range, 53-88). Most patients (8) had IgG Kappa MM (62%) followed by 2 patients (15%) with Lambda Light Chain, 2 patients (15%) with IgA Kappa, and 1 patient (8%) with IgG Lambda.Of the 13 patients, 1 patient continued weekly dosing, 4 patients continued biweekly dosing; 5 patients re-intensified from monthly to biweekly dosing; 1 patient re-intensified from biweekly to weekly; and 2 patients re-intensified from monthly to weekly. Patients were re-intensified at a median of 14 months after starting a daratumumab-containing regimen (range, 4-26). Of the 13 patients, there were 5 patients who had another drug adjustment at the time of Dara-RI. Of note, there were 3 patients who were on a non-FDA approved daratumumab-containing regimen at the time of Dara-RI.At the time of our final analysis, there were 7 patients (54%) who remained on a daratumumab-based regimen. Of these 7 patients, 6 patients continued Dara-RI and 1 patient transitioned from biweekly to monthly daratumumab due to stable disease. Notably, 3 patients had another drug adjustment at the time of Dara-RI. The median length of Dara-RI is 8 months and ongoing (range, 4-12). There were 5 patients (38%) who discontinued their daratumumab-based regimen after Dara-RI. Of these 5 patients, 2 patients had another drug adjustment at the time of Dara-RI. All 5 patients had at least stable disease or partial response to Dara-RI, with exception of one individual who had progressive disease. In addition, all 5 patients who discontinued Dara-RI was within 4 months of starting Dara-RI. Uniquely, one patient had panobinostat added to their Dara-RI regimen after 1 month of re-intensification, but continued with Dara-RI.No patients experienced a dose delay due to adverse effects or were hospitalized after initiation of Dara-RI. Only one patient was prescribed antibiotics for treatment of a cold sore. There were no new hypersensitivity, cardiovascular, hematologic, gastrointestinal, or central nervous system toxicities noted after initiation of Dara-RI.Conclusion:Limitations of this study include other myeloma drug-related adjustments at the time of Dara-RI and the heterogeneous population as well as the retrospective nature of the study. In our experience with 13 patients, Dara-RI appears to be a safe and tolerable alternative regimen for patients who have disease progression on a daratumumab-containing regimen. DisclosuresRichardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy.

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

BackgroundBone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication.MethodsPatient chart review and PubMed literature search using the term, “transplant-associated thrombotic microangiopathy”.Case presentationA 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient’s condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa.ConclusionsTA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

Primary Amyloidosis Presenting as Hepatomegaly in a Patient With Undiagnosed Multiple Myeloma: A Challenging Case of Pneumococcal Meningitis and Hepatomegaly With Obstructive Jaundice

Inflammation secondary to sepsis can involve multiple organs, including liver. Hepatocellular injury in sepsis results from hypoperfusion and inflammatory cytokines, manifesting as elevated alkaline phosphatase, AST, ALT and bilirubin. However right upper quadrant scans should be performed when in doubt to rule out other life threatening pathologies. We report a case of undiagnosed multiple myeloma and primary amyloidosis with liver and pancreatic involvement, admitted for sepsis secondary to meningitis. A 65-year-old male was brought to hospital after wife found him confused, diaphoretic and nonverbal. He was febrile and somnolent. Lumbar puncture confirmed bacterial meningitis for which he was treated, but later developed jaundice. His liver function tests were consistent with cholestasis. Right upper quadrant (RUQ) ultrasonography (images 1,2) and CT abdomen (image 3) did not show any tumors, stones or strictures but demonstrated massive hepatomegaly. Malignancy work-up was initiated for hypercalcemia, as PTH, PTHrP and vitamin D levels were normal. Serum protein electrophoresis (SPEP) showed abnormal band suggestive of a paraprotein in gamma region (1.00 g/dL), along with elevation of free Kappa and lambda light chains. Bone marrow biopsy revealed 10% plasma cells. Alkaline phosphatase, AST, ALT, and bilirubin, continue to trend up, peaking at 1521 U/L, 138 U/L, 129 U/L and 4.1 mg/dL (2.9 mg/dL- direct bilirubin) respectively. GGT was elevated at 1364 U/L and CA 19-9 at 3386 U/L. MCRP was negative for biliary or pancreatic duct dilatation. Liver biopsy confirmed primary amyloidosis. Hence patient was started on chemotherapy for IgG kappa multiple myeloma and primary amyloidosis, and had significant improvement in liver function tests and CA 19-9 after first cycle. Amyloidosis is a process of extracellular insoluble protein deposition that commonly involves gastrointestinal tract, with up to 90 percent liver involvement. Jaundice along with elevated alkaline phosphatase and transaminases is seen frequently with liver involvement but jaundice is associated with poor prognosis. Liver alone is almost never the sole organ affected, and in the above-reported case, later on biopsy of the pancreas was also consistent with widespread amyloid deposits. Even though amyloidosis represents a rare cause of cholestatic jaundice, it is important to consider it in differentials due to high mortality with median one-year survival of fifty percent in untreated cases.Figure: Right upper quadrant ultrasound - hepatomegaly.Figure: RUQ ultrasound showing normal CBD.Figure: CT abdomen - hepatomegaly.