Lambda Light Chain Multiple Myeloma Research Articles

Light Chain Multiple Myeloma: A Case of Distinctive Presentations

Multiple Myeloma (MM) is a malignancy of immunoglobulin-producing plasma cells. Lambda Light Chain Multiple Myeloma (LCMM) is a less common type of MM with a more aggressive course, which presents a diagnostic challenge due to the absence of typical M-spike on screening and unspecific manifestations. This case presented an initially misdiagnosed patient, who had an uncommon light chain pattern on electrophoresis, atypical plasmocytes in bone marrow smear, particular complications and risks associated with LCMM, and a worse prognosis.

The correlation between serum free light chain levels and plasma cell ratio in bone marrow biopsy in multiple myeloma

Aims: MM (Multiple myeloma) is the second most common hematological malignancy. In addition to the recent advances in treatment, new parameters are used in clinical practice in diagnosis and follow-up. sFLC (free chain kappa and lambda) shows the activation of the disease depending on the rate of MM malignant cell secretion in serum. However, the plasma cell (PC) ratio in bone marrow biopsy is still the gold standard in diagnosis. We examined the dynamic correlation between the PC ratio and the number of sFLC-related cells and the secretion rate. We aimed to examine whether a low PC ratio could be in a more aggressive form with a higher sFLC secretion with too much activity, thus examining the correlation between them.
 Methods: A total of 62 newly diagnosed MM patients admitted to Başkent University Faculty of Medicine İstanbul Hospital were included in the study. At the time of diagnosis, sFLC values were requested simultaneously with bone marrow biopsy. Radiological images were obtained with PET CT/MRI or CT.
 Results: In all MM groups, bone marrow PH percentages were not correlated with sFLC regardless of subtype. IgG kappa type MM had the highest sFLC values despite the lowest number of PHs, while Lambda light chain MM had the lowest sFLC despite the highest PH rates. 
 Conclusion: These results showed us that sFLC rates are independent of the percentage of PC in MM. We believe that the two are not correlated and should be followed up together in the follow-up of the disease.

Functional Characterization of GPRC5D alteration and Its Impact on Talquetamab Resistance in Relapsed/ Refractory Multiple Myeloma

Background T-cell engaging (TCE) antibodies show unprecedented efficacy in heavily pretreated penta-refractory multiple myeloma (MM). Responses however are often not durable as resistance mechanisms can arise despite the initial absence of resistance-conferring mutations. Biallelic loss of GPRC5D on chr.12p is a rare, yet well-established mechanism of acquired resistance to the first-in-class anti-GPRC5D directed TCE talquetamab (Lee et al., 2022). At the same time, monoallelic GPRC5D frameshift and missense mutations are much more common and occur in up to 15% of MM patients (Truger et al., 2021). In this study, we investigated the functional relevance of monoallelic GPRC5D alterations and their impact on talquetamab resistance. Methods GPRC5D alterations were modeled in vitro by using CRISPR-Cas9 editing in the OPM-2 MM cell line. The bioluminescence-based cytotoxic assay was performed using PBMCs as effector cells to measure the resistance to talquetamab. Quantitative PCR (qPCR), immunohistochemistry, bulk whole genome sequencing (WGS), and whole genome bisulfite sequencing (WGBS) were performed for molecular, genomic, and epigenetic characterization in a patient with acquired talquetamab resistance. Results Using CRISPR-Cas9, we generated cell line models with mono- vs. biallelic deletions in the GPRC5D gene. Clones with biallelic alterations (OPM-2 Del/Del) displayed a 96.4%, reduced expression of GPRC5D ( p < .0001), leading to in vitro resistance to talquetamab. GPRC5D expression levels in monoallelic models (OPM-2 Wt/Del) decreased by 57.4% ( p = .0004) compared to the wild type. Sensitivity to talquetamab in these clones was equally impaired, however, less pronounced than in the biallelic knock-outs. To assess the impact of monoallelic GPRC5D deletions in the clinic, we next investigated the case of a heavily pretreated 58-year-old patient with lambda light-chain MM treated at our institution with talquetamab in his 7th line of therapy. qPCR was used to measure GPRC5D expression in CD138+ MM cells from the bone marrow of this patient before and at the time of relapse to talquetamab after 15 months of treatment (best response: CR). At the time of relapse, we observed a 94.0% ( p < .0001) decrease in GPRC5D expression upon qPCR assessment as compared to the pre-treatment time point which was confirmed by immunohistochemistry. WGS revealed a novel monoallelic loss of chr.12p encompassing GPRC5D in talquetamab-resistant CD138+ MM cells. Since monoallelic alterations seem unlikely as the sole drivers of resistance, we hypothesized that epigenetic modifications may have contributed to talquetamab resistance in this patient. To this end, WGBS was performed and uncovered a significant shift towards hypermethylation of two regulatory regions of GPRC5D, most likely resulting in the silencing of the second GPRC5D allele. Time-course experiments are currently ongoing to explore the methylation landscape of our CRISPR-Cas9-generated clones with monoallelic GPRC5D deletions. Data for these validation experiments will be presented at the meeting. Conclusions Our study provides the first evidence of the functional impact of monoallelic GPRC5D alterations resulting in relative resistance to talquetamab in vitro. We further report on epigenetic regulation as a potential second-hit mechanism conferring clinical resistance to anti-GPRC5D-directed TCE therapy. This data suggests that patients with monoallelic GPRC5D deletions may be at particular risk for developing resistance to talquetamab.

786 SYSTOLIC ANTERIOR MOVEMENT OF MITRAL VALVE: NOT ONLY HYPERTROPHIC CARDIOMYOPATHY, BUT ALSO CARDIAC AMYLOIDOSIS

Abstract A 71 years-old man was diagnosed with lambda light chain multiple myeloma evolving from monoclonal gammopathy of unknown significance during hematological follow-up. Serum creatinine and blood urea were normal, but proteinuria was significant. A subsequent renal biopsy showed amyloid deposits in renal glomeruli. He had no comorbidities or previous cardiologic history. To provide a complete diagnostic work-up, an echocardiogram was performed, showing marked and asymmetric left ventricular hypertrophy (interventricular septum diastolic thickness IVSd 15 mm) with dynamic left ventricular outflow tract obstruction (LVOTO) due to an incomplete systolic anterior motion (SAM) of mitral valve. ECG showed sinus rhythm with 1st degree atrio-ventricular block; notably, there was no electrocardiographic sign of left ventricular hypertrophy. Therefore, a Cardiac Magnetic Resonance (CMR) was performed, showing left ventricular hypertrophy (interventricular septum thickness 15 mm) with normal contractility. Mild left atrial enlargement and thickening of the interatrial septum were found, together with mild circumferential pericardial effusion. No perfusion defects were recorded, but late gadolinium enhancement (LGE) pattern was not assessable because of difficult myocardial signal nulling point. These findings were consistent with cardiac amyloidosis (CA). By the time, histological demonstration of amyloid was mandatory, so an endomyocardial biopsy was performed. Amyloid deposits were found to be in the myocardial interstitial space and into the myocardial vessel walls. Immunohistochemical staining revealed diffuse and high reactivity for lambda free light chains and moderate reactivity for kappa chains. No transthyretin was found in the specimens. Finally, a diagnosis of AL amyloidosis with cardiac and renal involvement associated with lambda light chain multiple myeloma was made and chemotherapy with bortezomib, thalidomide and dexamethasone (VTD) was started. During the cardiologic follow-up, three syncope with prodromal symptoms have occurred. In all these circumstances, no arrhythmias were found at prolonged ECG Holter monitoring. Echocardiogram showed a progression of the dynamic outflow obstruction to 80 mmHg and increasing mitral regurgitation associated with complete systolic anterior motion of the valve. Given the echocardiographic features and the clinical events, we performed a genetic blood test which excluded sarcomeric genes mutations. Also, familial screening with ECG and echocardiogram was negative. A better management of pharmacological therapy, together with avoidance of hypovolemia and supportive treatment of anemia finally relieved patient's symptoms. Conclusions we presented this case to underline that, although rare, cardiac amyloidosis can resemble other hypertrophic cardiomyopathies with left ventricular outflow tract obstruction due to SAM of the mitral valve and irregular septal hypertrophy, caused by amyloid deposits. Most of these cases are seen in the senile transthyretin type, but sometimes they are observed in AL patients. Nowadays, it is crucial to diagnose these patients correctly as early treatment is critical for survival in this population.

Myelomatous pleural effusion developing after autologous stem cell transplantation in a patient with multiple myeloma: A rare case

ABSTRACT Myelomatous pleural effusion (MPE) is a very rare condition with a poor prognosis. In our case of multiple myeloma (MM) with early recurrence presenting with a MPE, management of the treatment is discussed together with the case presentation. A 35 year old female patient with a diagnosis of lambda light chain MM presented with complaints of dyspnea and pain in the left shoulder 2 months after autologous transplantation. On physical examination, respiratory sounds were decreased in the lower lobe of the left lung and there was dullness. Pleural effusion and plasmacytoma, more prominent on the left, were detected on chest X ray and thorax computed tomography (CT). The pleural fluid collected during therapeutic thoracentesis was examined by flow cytometry, cytology, and peripheral smear examination and as a result, the patient was considered to have early recurrence after autologous transplantation, DRd chemotherapy was immediately started, and clinical and radiological improvement was observed. Pleural effusion developing in patients with MM should be evaluated in terms of MPE. In the presence of MPE, the duration of response to treatment is short, thus effective and dynamic treatment methods for bridging should be used before referral of the patients to clinical trials and hematopoietic stem cell transplantation.

S2556 Not Your Everyday Duodenal Ulcer: Massive GI Bleed Secondary to Extramedullary Plasma Cell Myeloma

Introduction: Plasma cell neoplasms are defined by a monoclonal proliferation of a single clone of immunoglobulin producing plasma cells. Extramedullary plasmacytomas are rare plasma cell dyscrasias that arise outside of the bone marrow, most commonly in the head or neck. Extramedullary multiple myeloma (MM) involves the gastrointestinal (GI) tract in < 5% of cases, and often presents with non-specific symptoms. Here we discuss one such case of uncommon GI involvement of a plasma cell tumor. Case Description/Methods: A 62-year-old male with active lambda light chain MM presented with global fatigue, melena, and hematemesis. Initial vitals included blood pressure 90/62 mmHg and heart rate 95 bpm, with labs revealing normocytic, normochromic anemia with hemoglobin (Hgb) 3.9 g/dL. He was transfused 4 units of packed red blood cells with an appropriate Hgb response to 8.6 g/dL. Immediate esophagogastroduodenoscopy (EGD) found a nonbleeding cratered duodenal ulcer with adherent clot, not amenable to endoscopic intervention (Figure a). He remained hemodynamically stable, and given the lack of continued evidence for GI bleed over the following days, vascular interventional radiology (VIR) embolization was deferred. Prior to discharge, patient was having light brown stools with no active signs of bleeding. He was discharged on pantoprazole, with plan for repeat Hgb within 1 week and repeat EGD in 1 month. Unfortunately, patient was readmitted in cardiac arrest within 24 hours of discharge, with oropharyngeal blood and melena. Resuscitation attempts were unsuccessful. Autopsy determined cause of death to be extramedullary GI disease, with plasma cell infiltration and resultant transmural duodenal ulceration involving the gastroduodenal artery having caused acute hemorrhage (Figureb-c). Discussion: While incredibly rare, due to high mortality and swift progression it is crucial for providers to consider GI extramedullary disease in patients with a history of plasma cell neoplasm who present with upper GI bleed. This holds especially true in cases where the identified lesion is not amenable to endoscopic therapy. Though our patient underwent appropriate resuscitation and evaluation with apparent resolution of symptoms, he died within a day of discharge. Further workup including advanced imaging studies, such as positron emission tomography/computed tomography (PET-CT), or consideration of VIR embolization (deferred here given clinical cessation of bleeding) could be lifesaving.Figure 1.: (a) Ulcer at the duodenal bulb, completely obstructing duodenum. (b) Gastroduodenal ulcer (brackets) with eroded gastroduodenal artery (arrow). (c) H&E, 2X: artery with overlying fibrin cap (1), and surrounding pancreatic parenchyma (2) with plasma cell infiltrate (3).

A case of Lambda light chain multiple myeloma revealed by an atypical electrophoretic profile

A case of Lambda light chain multiple myeloma revealed by an atypical electrophoretic profile

Rapid Removal of Myeloma Light Chains By Continuous Veno-Venous Hemofiltration in a Patient with Acute Cast Nephropathy As a Result of Lambda Light Chain Myeloma

Myeloma cast nephropathy or myeloma kidney (MK) is a complication observed in up to one third of patients with multiple myeloma (MM). MM patients who recover kidney function have longer remissions and increased overall survival. Previous attempts at light chain reduction with the use of plasma exchange in addition to chemotherapy have not consistently improved patient outcomes and remains an area of research. The inefficiency of plasma exchange is due to the high volume of distribution of light chains in the extravascular space which will repopulate the vascular space once the exchange procedure is complete.Continuous Veno-Venous Hemofiltration (CVVH) is a form of continuous hemodialysis (HD). The use of CVVH in addition to chemotherapy in MK is rational, as continuous filtration allows for ongoing equilibrium between the extravascular and intravascular compartments, thus reducing the total body MM protein load. The Purema 500 (NxStage Medical, Lawrence, MA) filter used for CVVH has an average pore size of 65 kDa, and albumin Sieving co-efficient of 0.05. The myeloma kappa light chain is approximately 25 kDa whereas the lambda light chain (LLC), circulating as a dimer, is approximately 45 kDa and the average IgG complex is approximately 150 kDa. These data suggest that CVVH filtration could reduce the light chain MM protein in patients with MK, but would likely be ineffective for IgG, IgA or IgM MM.This hypothesis was tested in a 60 year-old-man with known normal baseline kidney function and LLC MM, who developed MK in the perioperative period, of a hip stabilization procedure, at the time of MM recurrence. Biopsy showed the kidney failure was due to MK. The LLC concentration at the time of kidney failure was 3,750 mg/L. We employed CVVH, run 24 hours a day for 72 hours, with concurrent high dose intravenous dexamethasone 40mg days 1-4 and IV bortezomib 1.3mg/m2 days 1,4,8, 11.Serum protein electrophoresis (SPEP) obtained prior to CVVH showed a monoclonal spike of 6.7 g/L or 11.5% of the total protein (figure 1A). Protein electrophoresis (PEP) of the first bag of spent dialysate showed a restricted peak 1.1g/L or 2.1% of the total protein with a similar appearance to the monoclonal spike on the SPEP, demonstrating removal of the LLC by CVVH (figure 1B). 72 hours after the initiation of CVVH and chemotherapy, the LLC concentration decreased 77% from 3,750 to 850 mg/L (figure 1D), SPEP showed the monoclonal spike had decreased to 0.5 g/L or 1% of the total protein (figure 1C). The patient became dialysis independent three months following CVVH.Previous series have reported on 11 patients with acute MK, who have been treated with as specialized high cut-off hemodialysis (HCO-HD) filter, which has a pore size of 45 kDa, and concurrent chemotherapy. Seven of these patients (63%) became dialysis independent. These studies showed an overall reduction of serum light chain protein in their patients, but did not report if the light chains were present in the dialysate. The EUropean trial of free LIght chain removal by exTEnded haemodialysis in cast nephropathy (EuLITE) reported an improved rate of renal recovery 33% vs 43% with the use of HCO-HD versus standard HD.By way of comparison, CVVH, which is widely available in the United States, rapidly decreased the LLC myeloma protein. Our data supports the depletion of the LLC stores in the extravascular compartment as we did not see a rebound of LLC after stopping CVVH (figure 1D). As kappa light chains have a lower molecular weight than LLC, we would expect the same result with kappa light chain MM. Patients with IgG MK may also benefit from CVVH, as we saw proteins with a molecular weight higher than 65 kDa in the spent dialysate PEP, including proteins in the IgG range (figure 1C). CVVH filters lead to less protein wasting as compared to the HCO-HD filters which would negate the need for albumin replacement. The observed rapid rate of decline of the light chain concentration in this case supports the addition of CVVH to chemotherapy, as the clearance of the myeloma protein was more rapid than has been described in previous trials using bortezomib and dexamethasone alone. Randomized clinical trials would need to be conducted to know if this approach is superior to chemotherapy alone. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PRIMARY MALIGNANT MYELOMATOUS EFFUSION IN MULTIPLE MYELOMA PATIENT

SESSION TITLE: Medical Student/Resident Disorders of the Pleura Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Malignant pleural effusion secondary to Multiple Myeloma (MM) is most commonly a consequence of end organ damage secondary to pleural infiltration with monoclonal gammopathy. It occurs in about 6% of cases of multiple myeloma; approximately 1% of those patients have Primary Malignant Myelomatous Effusion (PMMPE), which occurs due to myelomatous involvement of the pleura or surrounding structures. The diagnosis of PMMPE can be difficult to make with flow cytometry; definitive diagnosis is made with pleural biopsy. CASE PRESENTATION: 53-year-old female with a past medical history of hypertension presented with two months of worsening dyspnea, weight loss, and early satiety. Initial evaluation on admission included a chest x-ray, which showed a large left-sided pleural effusion requiring thoracentesis. Admission laboratory testing showed hypercalcemia and an acute kidney injury, which prompted further diagnostic testing to evaluate for underlying malignancy; which included protein electrophoresis demonstrating markedly elevated free lambda, bone marrow biopsy, which showed 66% plasma cell differentiation, confirming the diagnosis of lambda light chain MM. Her hospital course was complicated by recurrent, rapid re-accumulation of her left-sided pleural effusion requiring two additional thoracenteses. She ultimately had a Pleur-X chronic indwelling chest catheter placed for symptomatic relief. Pleural fluid cytopathology was inconclusive and immunophenotype showed no significant abnormalities. No pleural biopsy was done; however, the initial presentation of a large left-sided pleural effusion would indicate that this was more than likely PMMPE. She was started on outpatient chemotherapy, however her condition continued to deteriorate requiring multiple readmissions, and she unfortunately passed away within four months of initial diagnosis. DISCUSSION: MM is one of the most common forms of cancer in the United States. It represents 10% of all malignant hematological diseases, which mainly affect the bone marrow, although extramedullary tissues may be infiltrated as well. Pleural effusions may be a sign of thoracic involvement in approximately 6%, however 1% of these can be primary pleural effusions. PMMPE is seen very late in the disease process associated with light chain kappa MM, with left-sided effusions being more common. Median survival time after diagnosis is approximately 4 months. Cytological identification of malignant plasma cells within the pleural effusion has been the best test for diagnosis, however due to the limited number of malignant plasma cells and in vitro degeneration, cytological studies can be unreliable. Pleural biopsy may be the most accurate diagnostic test however this can also be inconclusive due to patchy infiltration of pleura. CONCLUSIONS: PMMPE is seen very late in the disease process, can be very difficult to diagnose. Prognosis is poor after diagnosis. Reference #1: Mangla, A., Agarwal, N., Kim, G., Catchatourian, R. Primary Malignant Myelomatous Pleural Effusion. Clinical Case Reports. 2016; 4(8): 803-806. Reference #2: Zhang LL, Li YY, Hu CP, Yang HP. Myelomatous pleural effusion as an initial sign of multiple myeloma—a case report and review of literature. J Thorac Dis 2014;6(7):E152-E159. https://doi.org/10.3978/j.issn.2072-1439.2014.06.48 Reference #3: Xu et al.: A case of bilateral pleural effusion as the first sign of multiple myeloma. European Journal of Medical Research 2013 18:7. https://doi.org/10.1186/2047-783X-18-7. DISCLOSURES: No relevant relationships by Jasmine Sekhon, source=Web Response No relevant relationships by Ximena Solis, source=Web Response No relevant relationships by Divya Vangipuram, source=Web Response

MON-199 KIDNEY TRANSPLANTATION IN MULTIPLE MYELOMA: CASE REPORTS

Renal transplantation is traditionally contraindicated in Multiple Myeloma (MM) due to increased risk of post-transplant disease recurrence and associated complications. However, with recent advances in MM treatment modalities and overall survival, renal transplant centers are reporting increasing success in carefully selected groups of patients with treated plasma cell dyscrasias. We hereby present our experience through 3 case reports. A 72-year-old Caucasian male with IgG smoldering MM, and end stage diabetic nephropathy, received prophylactic Bortezomib chemotherapy for high lambda light chain burden, 6 months prior to an ABO incompatible living related kidney transplant in 2015. A stable renal function and ongoing hematological remission without further maintenance therapy was achieved for the next 24 months. MM progression in the form of gastrointestinal amyloidosis and plasma cell infiltration of his renal allograft was diagnosed 2 years post transplant. This was successfully mitigated with further cycles of Bortezomib containing chemotherapy, stabilizing his serum creatinine around 180umol/L. A 68-year-old Caucasian male, with stage 3 lambda light chain MM and end stage cast nephropathy was evaluated for renal transplantation. Hematological remission was achieved through Bortezomib based induction and subsequent autologous stem cell transplant, with thalidomide maintenance therapy. Unfortunately, no suitable living related donor was available, and he received a cadaveric renal transplant 2.5 years later in 2017. 10 months post transplant, he was diagnosed with CMV pneumonitis, and required CMV immunoglobulin therapy as a consequence of residue hypogammaglobulinemia secondary to his MM. His renal function has remained stable post transplant with a baseline serum creatinine of 120umol/L. A 49-year-old Greek female, with end stage cast nephropathy secondary to stage 3 kappa light chain MM. Remission of her myeloma was achieved through Bortezomib containing induction therapy followed by an autologous stem cell transplant. She subsequently underwent a successful ABO incompatible living related kidney transplant 10 months later in 2018. Her allograft function has remained stable with a serum creatinine of 90umol/L. Sustained renal allograft function can be achieved in MM patients with hematological remission, improving quality of life off dialysis whilst broadening myeloma treatment options previously limited by end stage renal failure. Logistically, living related donors provide a favorable option, significantly reducing the duration of wait time and risk of further deterioration. Unique complications associated with underlying MM, in the form of disease recurrence or increased predisposition to opportunistic infections can occur post renal transplant. However, early recognition and mitigation will ensure perseverance of allograft function.

Myelosuppression-sparing treatment of central nervous system nocardiosis in a multiple myeloma patient utilizing a tedizolid-based regimen: a case report

Central nervous system (CNS) nocardiosis is a recognised opportunistic infection in immunocompromised patients. Treatment involves prolonged institution of antibiotics, making oral agents a convenient and desired option. Unfortunately, devising an effective, well-tolerated antimicrobial for the duration required to treat CNS nocardiosis is challenging owing to treatment intolerance and toxicities. This report highlights myelosuppression-sparing treatment with an oral tedizolid-based regimen following a complicated course with standard agents. A 68-year-old female from Florida (USA) with low-risk lambda light chain multiple myeloma complicated by persistently low CD4 counts, absolute neutrophil counts and IgG levels presented 18 months after diagnosis with fever, pneumonia, new-onset atrial fibrillation, right-sided hemiparesis, encephalopathy and slurred speech. Magnetic resonance imaging (MRI) showed numerous ring-enhancing lesions, and blood cultures were positive for Nocardia farcinica. The patient failed initial therapy with trimethoprim/sulfamethoxazole (SXT), linezolid and imipenem plus surgical debridement of the frontal lobe abscess. Intraoperative cultures were positive for N. farcinica. The treatment course was also complicated by steadily declining white blood cell and platelet counts despite receiving filgrastim. She was therefore placed on SXT and tedizolid for 6 months. Subsequent brain MRI showed complete resolution of the lesions and thus chemotherapy for multiple myeloma was re-initiated. In conclusion, tedizolid-based regimens may be an option for patients with myelosuppression requiring prolonged antibiotic therapy for CNS nocardiosis.

Multiple myeloma presenting as bilateral breast lumps in pregnant woman

Multiple myeloma (MM) is a systemic disease in the elderly. Its incidence in patients younger than 40 years old and especially in pregnant women is extremely rare. MM may involve extraosseous sites, and only in rare cases it is observed in the breast. We describe the case of a 39-year-old woman diagnosed with an IgG lambda light-chain MM (Durie-Salmon stage IIIA, International Staging System II) in the 26th week of pregnancy, presenting with bilateral breast lumps. Dexamethasone (20 mg/m(2)/day on days 1-4, 9-12, and 17-20) was given as an induction agent to decrease tumor mass during pregnancy. Adverse response to dexamethasone was minor with excellent tolerance. A healthy baby was delivered at week 34 of gestation. Breast nodules revealing MM are extremely rare. Clinical and radiological features are atypical. Presentation during pregnancy is extremely rare, making anti-MM treatment potentially challenging.

Marked efficacy of rituximab in two patients with Waldenstrom macroglobulinemia-like multiple myeloma.

e18548 Background: Rituximab (R) has been deemed to be ineffective in multiple myeloma (MM), despite CD20 expression in 10-15% of MM. Here we report two cases, selected by a genomic approach, with an excellent response to single agent R. Methods: as below Results: Patient 1: A 49 yr old male with IgG lambda MM with 80% bone marrow (BM) plasma cells (PC) and IgG level of 23 g/L had been treated elsewhere with one cycle of CRD. Here, we noted CD-2 subclass by gene expression profilin (GEP), however without spiked expression of CCND1 and CCND3 genes as manifestation of a t[11:14] or a t[6:14]. GEP further revealed a del 6q and overexpression of EBI2, both commonly seen in Waldenstrom Macroglobulinemia (WM). All findings were confirmed by FISH. Unsupervised clustering in the context of MGUS, untreated MM and WM-PC, confirmed WM-like MM in this patient. Sole therapy with R (750 mg/m2/d x 5d, weekly x 4, bi-weekly x 4 and then monthly) resulted in a reduction of IgG from 1850 mg/dL to 950 mg/dl and BM PC from 60% to 10% at 9 months and a decrease in sLFLC from 68 mg/dL to 10 mg/dL at 12 months follow up. Patient 2: Based on the above observation, we identified a second patient. This 37-yr old male had been diagnosed with lambda light chain MM 42 months earlier with a BM PC of 15%, lambda light-chain proteinuria of 1.9 g/d and sLFLC in the 200mg/dL range. Because of absence of CRAB criteria, he was followed expectantly. Rising BM PC to 50% and concern for end-organ damage motivated a detailed examination of GEP data. GEP showed high expression of CD20 and EBI2 and absence of CCND1 and CCND3 spikes. This was confirmed by FISH, which also revealed a del 6q. As in the first case, this patient co-segregated with WM. R treatment on the same schedule resulted in a reduction of sLFLC levels from 249 mg/dL to 29.9 mg/dl and of Bence Jones proteinuria from 1766 mg/d to 242 mg/d. Conclusions: The presumed lack of activity of R in MM needs to be revisited in light of the marked response noted in these 2 patients. Studies are in progress (a) to extend R therapy to similar cases, and (b) to more fully characterize the prevalence of genetic/phenotypic characteristics, as seen in these 2 cases, among several thousand MM patients. This updated information will be presented at the meeting.

Assessment of Free Light Chains in the Ascites and Pleural Effusion in Patients with Multiple Myeloma: A Report of 2 Cases

Abstract 5078A recently developed free light chain (FLC) immunoassay has made possible the quantitative measurement of kappa and lambda FLCs by automated nephelometry. Significant clinical evidence indicates the benefit of serum FLCs in the diagnosis of monoclonal gammopathies, AL amyloidosis and nonsecretory MM patients missed by conventional electrophoretic methods. Reference and diagnostic intervals for FLCs have been developed for serum and urine analyses. FLCs in other bodily fluids may provide a valuable tool in other conditions. For example, kappa FLCs are frequently elevated in the cerebrospinal fluid of patients with clinically suggested multiple sclerosis, and therefore can assist in confirming the diagnosis. Analysis of other bodily fluids for FLCs posts theoretical concerns which relate to a lack of standard reference, as well as, the plausible interference of both cellular and protein content in the fluid with data interpretation.We report the use of FLC levels in discerning the etiology of recurrent ascite and pleural effusion in 2 patients with a known diagnosis of multiple myeloma. Samples were centrifuged prior to analysis. Other steps of sample processing were based on a standard serum protocol. FLC was analyzed using the FreeLite™ assay (Binding Site) on Beckman Coulter Image analyser.Patient #1: A 64 year old man was diagnosed with IgG kappa multiple myeloma which was in complete remission according to the International Myeloma Working Group criteria after an induction therapy with lenalisomide and dexamethasone followed by high dose chemotherapy and stem cell transplantation. He presented with abdominal distention and progressive weight loss. A CAT scan of the abdomen showed moderate amount of ascites with no other detectable pathology. Ascite fluid analysis showed 200 nucleated cells/mm3. Differential counts included 8% neutrophils, 30% monocytes, 61% lymphocytes and 1% eosinophils. Serum-ascitic albumin gradient was 0.9 gm/dl. No atypical cells were seen by histological or flow cytometric analyses. Cultures for bacteria and fungi were negative. Serum CA19-9, CEA, AFP and PSA were normal. Serum and protein electrophoresis did not show M spike. Serum kappa FLC and lambda FLC were 10.5 and 6.97 ug/ml, serum K/L FLC was 1.51. Kappa FLC and lambda FLC in ascetic fluid was 12.1 and 8.4ug/ml, respectively. Peritoneoscopy with a peritoneal biopsy showed nodular deposits on the peritoneal lining and pathology confirmed a poorly differentiated adenocarcinoma.Patient #2: A 62-year old lady was diagnosed with lambda light chain multiple myeloma when she presented with transfusion dependent anemia and renal failure. She was treated with la enalidomide and dexamethasone combination and had stable disease. Her treatment regimen was changed to a bortezomib, liposomal doxorubicin and dexamethasone combination, which she progressed on. The patient was treated with salvage combination of D-PACE as a bridge to high dose chemotherapy and stem cell transplantation. One week after treatment, she developed progressive shortness of breath and confusion. She was noted to be hypoxic at room air and had decreased breath sound on the right side of her chest. Laboratory tests were significant for WBC of 0.3x 103/mm3. Chest X-ray and CAT scan of the chest showed large amount of pleural fluid with lower lobe atelectasis, and cardiomegaly. An echocardiogram showed a left ventricular ejection fraction of 40% with no wall motion abnormality. The patient was treated empirically with broad spectrum antibiotics and dieresis. The amount of pleural fluid did not improve in 48 hours after treatment. Thoracentesis was performed and pleural fluid kappa and lambda FLCs were <3.00 mg/L and 3221 mg/L respectively. Subsequent cytology and flow cytometric analysis confirmed a monoclonal plasma cell population that expresses CD138, CD38, CD56 and lambda light chain. Conclusion:We report that FLC analysis of other bodily fluids, aside from serum and urine, is feasible and may provide complimentary value to other histologic and biochemical analyses especially in discerning whether the etiology for the fluid accumulation related to the underlying multiple myeloma. Disclosures:Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees.

Lambda light chain multiple myeloma presenting as pleural mass

Light chain multiple myeloma occurs in 20% of multiple myeloma cases. Extramedullary dissemination of multiple myeloma is rare and involvement of pleura by it is even more rare. A 40 years old female patient presented with complains of recurrent vomiting for last 2 months and cough with expectoration for last 1 week. Chest X-Ray (PA view) showed a rounded homogenous opacity in mid zone of left lung field. CECT (thorax) showed pleura based soft tissue density mass lesions overlying apicoposterior segment of left upper lobe and lingular lobe with lytic destruction of underlying 2nd rib. Ultrasound scan of abdomen was normal. CT guided FNAC from soft tissue mass lesion of left side revealed atypical plasma cells, some of them were binucleate and few appear pleomorphic. Bone marrow aspiration showed 20% atypical plasma cells. Serum protein electrophoresis revealed a thin discrete band in gamma globulin region, while serum immunofixation electrophoresis showed presence of lambda light chain band only, with absence of kappa band, IgG band, IgM band and IgA band. Patient was diagnosed as a case of lambda light chain multiple myeloma with extramedullary dissemination to pleura presenting as pleural mass.

Lambda light chain myeloma with pleural involvement

A case is reported of lambda light chain multiple myeloma complicated by a myelomatous pleural effusion. Pleural effusions are uncommon in multiple myeloma, and most are secondary to nonmalignant causes. The clinical characteristics, natural history and pathophysiology of myelomatous pleural effusions are reviewed.

Multiple myeloma presenting as space-occupying lesions of the Liver

Initial myeloma presentation as discrete liver nodules is unusual. A 59-year-old man who presented with hepatomegaly and multiple space-occupying lesions in the liver and who was found to have a lambda light chain multiple myeloma with hepatic plasmacytomas is described and a review of liver involvement in multiple myeloma is presented.

“Myeloma lung”—A previously unreported complication of multiple myeloma

A 52-year-old man with known lambda light-chain multiple myeloma developed chronic renal failure, which was proven by renal biopsy to be the result of "myeloma kidney." Terminally, disseminated pulmonary infiltrates developed. Postmortem examination showed the infiltrates to consist of neoplastic plasma cells with crystalline casts, strikingly similar to those found in the kidneys. The term "myeloma lung" is proposed to describe this unusual and heretofore unreported complication of multiple myeloma.