Non-Secretory Multiple Myeloma Associated With High-Risk Phenotype and Complex Cytogenetics Including t(8;22).

Multiple myeloma (MM) is a plasma cell dyscrasia which is typically characterized by identifiable paraprotein in the blood or urine. However, the minority of patients in whom paraprotein cannot be identified are designated non-secretory MM (NSM). Evaluation of treatment response is more difficult in these patients as paraprotein levels cannot be followed. A dearth of clinical trials including these patients exists because of an inability to measure response by classical serum and urine measurement mechanisms as well as seemingly decreased overall survival compared to secretory MM. NSM is subdivided into four subgroups: "non-producers", "true non-secretors", "oligosecretors" and "false non-secretors". The "non-producers" phenotype is associated with more aggressive disease course. Translocations such as those involving the proto-oncogene c-MYC (chromosome 8) and the lambda light chain gene IGL (chromosome 22) - more commonly associated with Burkitt lymphoma - are rare in MM. We describe a 60-year-old male with NSM who was identified as having multiple high-risk features including complex cytogenetics and a non-producer phenotype, which are features not considered in conventional MM staging and risk stratification. This case highlights the need for awareness of phenotypes and cytogenetics associated with higher clinical risk that are not included in the revised International Staging System.

The Impact of Renal Impairment in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation With Melphalan Conditioning.

Background: There are no standard renal dose adjustments for melphalan conditioning for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients. The objective of this study was to evaluate the effect of melphalan dosing and chronic kidney disease (CKD) on transplant-related outcomes, progression-free survival (PFS), and overall survival (OS). Methods: A retrospective chart review was performed, and MM patients who underwent ASCT between February 2016 and September 2021 were included. Melphalan 200 mg/m2 (Mel200) or 140 mg/m2 (Mel140) was administered. The cohort was divided based on renal function: creatinine clearance (CrCl) ≥ 60 mL/min (no-CKD) and CrCl < 60 mL/min (CKD). Outcomes measured include PFS, OS, treatment-related mortality (TRM), incidence of adverse events, hospitalization duration, and hospital readmission within 30 days. Statistical analysis included Chi-square test, t-test, and Kaplan-Meier method. Logistic regression model was used to account for melphalan dose adjustment. Results: A total of 124 patients were included (n = 108 no-CKD, and n = 16 CKD). Median age was 62 years, majority (62%) were male, and 97% had at least a partial response at time of ASCT. Of the 124 patients, nine (7%) received Mel140. Five of these patients had CKD (CrCl range: 26 - 58 mL/min), with one on hemodialysis. Median time to neutrophil engraftment was 13.6 vs. 14.9 days and median time to platelet engraftment was 18.3 vs. 18.5 days in the CKD group vs. no-CKD group, respectively (P = 0.03 and P = 0.8). When adjusting for melphalan dose reduction, the median time to neutrophil engraftment was not statistically significant (P = 0.11). At a median follow-up of 28.7 months, the median PFS for the CKD vs. no-CKD group was 60 vs. 46 months (P = 0.3). One-year OS was 93.8% in the CKD group vs. 97% in the no-CKD group. There was a higher incidence of grade 3 or 4 mucositis in the CKD group vs. no-CKD group (P = 0.013). Conclusions: There is no significant difference in engraftment, PFS, or OS for MM patients with CKD vs. no-CKD receiving melphalan conditioning for ASCT. Severe mucositis was significantly more common in the CKD group, including when accounting for melphalan dose reduction.

Macroglossia as the initial presentation of AL amyloidosis: review and updates in treatment.

We encountered a man in his 60s presenting with worsening macroglossia. The patient underwent extensive otolaryngology evaluation and was diagnosed with primary (AL) amyloidosis on tongue biopsy with Congo red stain. The patient then underwent a bone marrow biopsy and was also found to have concurrent multiple myeloma. He started induction therapy with daratumumab and CyBorD (cyclophosphamide, bortezomib, dexamethasone). Cardiac MRI revealed extensive cardiac amyloidosis and the patient was deemed high risk for autologous stem cell transplant (auto-HCT). Unfortunately, the patient underwent hospitalisation for heart failure exacerbation requiring extensive medical management and passed away as a result of this pathology. AL amyloidosis is a rare disease to begin with and macroglossia as the only presenting sign is notable. This case emphasises the importance of considering AL amyloidosis in patients presenting with similar complaints as macroglossia can be attributed to other less serious aetiologies.

Glanzmann's Thrombasthenia: How Listening to the Patient Is Sometimes the Simple Key to Good Medicine!

Introduction. Glanzmann's thrombasthenia is a rare clotting disorder caused by impaired platelet function. Lack of awareness of the appropriate management of rare medical conditions may lead to patient dissatisfaction and potentially poor treatment outcome. Case Report. A 78-year-old male with a history of Glanzmann's thrombasthenia was admitted to the trauma service following a fall in which he sustained a facial laceration as well as maxillary sinus and nasal fractures. He received DDAVP 20 mcg and tranexamic acid upon presentation to the emergency department (ED). In the ED, the patient requested administration of platelet transfusion but was refused due to a normal platelet count. During the course of his hospital stay, he complained of epistaxis and was noted to have a downtrending hemoglobin from 11.0 g/dl to 9.0 g/dl. The patient and his family were not comfortable when the discharge plan was finalized and demanded platelet transfusion (due to history of needing platelets in association with injuries or procedures in the past) was refused by the primary team as they continued to state that his platelet count is normal. On hospital day 3, hematology was consulted as the patient and his family were extremely angry and hematology recommended platelet transfusion. Further clinical information was not available as the patient was transferred to another facility per family request as they wanted to be at a center which had the patient's primary hematologist. Discussion. A delay in specialist consultation resulted in patient dissatisfaction and extended the length of stay. Patients with rare medical conditions and potential for major complications should be managed aggressively with appropriate specialist consultation to promote patient satisfaction and improve the overall quality of care. This case shows that as physicians it our duty to listen to our patient's concerns and involve them in the medical decision-making to provide optimal patient-centered care.

Senile Systemic Amyloidosis Presenting as Hematuria: A Rare Presentation and Review of Literature.

INTRODUCTION: Senile systemic amyloidosis is a multisystem disease where wild-type insoluble transthyretin (ATTRwt) protein gets deposited in the tissues leading to organ dysfunction. METHODOLOGY: We present the case of a patient who presented with hematuria and bladder involvement by ATTRwt amyloidosis who ultimately died of multiorgan failure. RESULTS: The patient was an 82-year-old white male with a history of ischemic cardiomyopathy (ejection fraction (EF): 20-25%), chronic atrial fibrillation, chronic kidney disease (CKD), and carpal tunnel syndrome who presented with acute hematuria, urinary retention, and progressive fatigue. He underwent cystoscopy and bladder biopsy which was positive on congo-red stain diagnostic for amyloidosis. Echocardiogram demonstrated worsening of EF to 10-15% and concentric left ventricle hypertrophy. MRI was not performed due to underlying CKD. His condition deteriorated during the hospital stay, and he developed cardiogenic shock and progressive liver dysfunction. Infectious workup was negative. Meanwhile, the biochemical investigations (serum protein electrophoresis, immunofixation, and urine kappa/lambda chains) ruled out plasma cell dyscrasias. Mass spectrometry analysis of the bladder biopsy specimen confirmed wild-type transthyretin (ATTRwt) amyloidosis consistent with senile systemic amyloidosis. Due to patients' extremely poor prognosis, his family wished to focus on patient's comfort-oriented measures only, and patient passed away shortly thereafter. CONCLUSION: Senile systemic amyloidosis can rarely present in an atypical fashion such as hematuria. The treatment options are limited in this disease process. Novel therapies are in the early phases of development. Concern also exists that in patients with multiple comorbidities, this entity is under recognized until the more advanced stages.

Vitamin C deficiency: rare cause of severe anemia with hemolysis.

Historically known to be a disease of sailors and soldiers in the seventeenth and eighteenth century, scurvy is a rare nutritional deficiency in the developed world, but it can still be seen among the alcoholics and the malnourished. We present a case of a 39-year-old alcoholic male who presented with progressive fatigue and diffuse purpuric rash with scattered ecchymosis for 2 months. Blood work was remarkable for hemoglobin of 9.1 g/dl, which further dropped to 7 g/dl over the next few days. He was then found to have hemolysis on lab work. After an extensive workup, the common causes of hemolytic anemia were ruled out, vitamin C level was checked, which interestingly resulted as 0 mg/dl. Supplementation with oral vitamin C resulted in the gradual resolution of hemolytic anemia and rash. Hemoglobin improved to 15 g/dl in 4 weeks, with normalization of vitamin C level. The clinical features of scurvy can easily be confused with conditions such as vasculitis, deep venous thrombosis, and systemic bleeding disorders. Therefore, comprehensive workup up is required prior to the diagnosis. Although rare, being a reversible condition, early diagnosis and treatment of scurvy in high-risk populations cannot be stressed enough.

Aplastic anemia secondary to propylthiouracil: A rare and life-threatening adverse effect.

BACKGROUND: Propylthiouracil has been in use for more than half a century for the treatment of hyperthyroidism. While it is largely known to cause agranulocytosis, its association with aplastic anemia is rarely heard of. Our case will be the third in literature to suggest aplastic anemia as a manifestation of propylthiouracil, which unfortunately culminated in the death of the patient. CASE: A 67-year-old female, with recently diagnosed metastatic adenocarcinoma of the lung, developed hyperthyroidism after being started on Nivolumab and Iplimumab. After she developed atrial fibrillation, she was started on propylthiouracil to control the thyroid activity. Soon after that, she was admitted with severe neutropenia, which progressed to pancytopenia confirmed as aplastic anemia on a bone marrow biopsy. Despite discontinuation of propylthiouracil and aggressive treatment, she developed septic shock and multi-organ failure, leading to her death. CONCLUSION: Aplastic anemia has been sparingly reported as an extremely rare complication of propylthiouracil. Further adding to the ambiguity is the unknown etiology and lack of specific therapy for the complication when attributed to propylthiouracil. The disease can carry an extremely poor prognosis if untreated, as proven by our case. Due to the same reasons, we recommend that further investigations be done to elucidate the pathogenesis and assist with treatment of the disease when caused by propylthiouracil.

Hemophilia C: A Case Report With Updates on Diagnosis and Management of a Rare Bleeding Disorder.

Hemophilia C or factor XI deficiency is a rare clotting disorder with prevalence of only 1 per 1 million. A 24-year-old male with multiple abdominal surgeries complicated by wound infections and poor healing was admitted to plastic surgery service for an elective abdominoplasty. Hematology was consulted for increased intraoperative and postoperative bleeding. Laboratory workup showed high-normal activated plasma thromboplastin time of 31 s (reference: 23 - 34 s), prothrombin time (PT) of 15 s (reference: 11.8 - 14.3 s) and internationalized normal ratio (INR) of 1.2. Patient had normal factors VIII, IX, XIII levels and normal von Willebrand's factor level. The factor XI level came back at 0.28 (0.44 - 1.43 U/mL) diagnostic for intermediate factor XI deficiency. Factor XI is responsible for thrombin generation after clotting is initiated as well as clot stabilization. The confirmatory test is factor XI assay. The management of factor-XI deficiency is based on history of bleeding and nature of the procedure.

A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, described as a clinical triad of microthrombocytopenia, eczema and recurrent infections. Different mutations in WAS gene have been identified, resulting in various phenotypes and a broad range of disease severity, ranging from classic WAS to X-linked thrombocytopenia and X-linked neutropenia. WAS in some cases can be fatal without haematopoietic stem cell transplantation early in life. In this particular case, we present a novel mutation with a unique presentation. An 18-year-old man incidentally found to have macrothrombocytopenia and neutropenia at 16 years of age later found to be hemizygous for c. 869T>C (p.Ile290Thr) mutation in WAS gene. The late presentation, absence of other manifestations of WAS and presence of macrothrombocytopenia, rather than microthrombocytopenia, which is usually a characteristic finding in WAS, misled the initial diagnosis. On review of literature, this mutation has not been reported as causing WAS.

Cholestatic jaundice: a unique presentation leading to the diagnosis of HLH with Hodgkin lymphoma, HIV and EBV.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of dysregulated immune activity with macrophage activation that can manifest as pancytopenia, coagulopathy and other laboratory abnormalities, usually progressing to multiorgan failure and death. This report documents the rarely reported association between HLH and Hodgkin's lymphoma (HL) with simultaneous HIV and Epstein-Barr virus (EBV) and complete resolution with chemotherapy. The patient initially presented with cholestatic jaundice. He was then found to have HL associated with HLH with coexistent HIV and EBV viraemia. A-Brentuximab-VD regimen for the lymphoma was initiated, resulting in rapid resolution of HLH and ultimately remission of HL. HLH is a syndrome known to have high mortality; thus, early diagnosis and prompt treatment are crucial. Usual presentation includes non-specific symptoms and can easily be overlooked. This case highlights the importance of diagnosing the condition in unusual settings and attempting treatment by targeting the cause of HLH, HL in our case.

Mantle Cell Lymphoma Relapsing as Disease of Skin, Orbit and CNS: An Extremely Rare Presentation and a Review of Literature.

Mantle cell lymphoma (MCL) is a form of non-Hodgkin's lymphoma originating from mature B cells. The hallmark gene translocation (11:14) results in overexpression of cyclin D1. Affected extranodal sites include bone marrow and gastrointestinal tract, but skin, orbit or CNS are rarely involved. Twenty-four cases have reported involvement of skin by MCL, while orbital MCL is equally rare. Our case is the first to report relapsed MCL with involvement of the skin and orbit simultaneously without disease in the lymphatic system or the bone marrow. A 53-year-old female with stage IV MCL initially presented with pancytopenia, adenopathy and splenomegaly. She achieved complete remission after six cycles of rituximab and bendamustine. Within 4 weeks of treatment, she developed diplopia and a rash of the left breast. Skin biopsy showed lymphoma infiltrates with B-cell markers for MCL. MRI of the orbits and brain suggested orbital lymphoma. CSF cytology further confirmed MCL cells. At time of relapse, she continued to be in hematologic remission. She initiated intrathecal cytarabine and methotrexate along with ibrutinib. R-CHOP was then added to the regimen. Within 2 weeks of starting treatment, her skin disease resolved and she had improvement in vision. MCL commonly presents as a disseminated disease, resulting in high mortality. Involvement of the skin or orbit has been sparingly reported and always suggests aggressive disease. It thus poses a challenge to diagnose and treat the condition as evidenced by resolution of adenopathy and bone marrow disease. Due to the overall poor prognosis of MCL and its unique presentations, as demonstrated by our case, early detection and prompt treatment are crucial to survival.

Correction: Mantle Cell Lymphoma Relapsing as Disease of Skin, Orbit and CNS: An Extremely Rare Presentation and a Review of Literature.

[This corrects the article DOI: 10.14740/jh363w.].

Maintenance therapy in multiple myeloma.

Despite recent advances, multiple myeloma remains an incurable disease. Induction therapy followed by autologous transplantation has become the standard of care. The idea of maintenance therapy in multiple myeloma is not new. Starting with chemotherapy in 1975, to interferon in 1998, to novel agents recently, a multitude of agents have been explored in patients with multiple myeloma. In spite of the novel agents, multiple myeloma continues to be an incurable disease with the progression-free survival after autologous transplant rarely exceeding 3 years. The goal of using maintenance therapy has been to improve the outcomes following autologous transplantation by increasing the progression-free survival, deepening remissions and perhaps increasing overall survival. It has been shown that patients with a stringent complete response (CR) have a better outcome [Kapoor et al. 2013]. It is becoming increasingly common to check minimal residual disease (MRD) as a means of assessing depth of response. It has also been shown that patients with no MRD have not only a better progression-free survival but also a better overall survival compared with patients who are MRD positive. This makes it even more important to find agents for maintenance therapy, which can further deepen and maintain responses. Here, we present a comprehensive review of the agents studied as maintenance for multiple myeloma and their efficacy, both in terms of overall survival, progression-free survival and toxicity.

Hemophagocytic Lymphohistiocytosis Secondary to Bone Marrow Only B-Cell Lymphoma: A Very Rare Entity With an Even Rarer Presentation.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome. It is categorized as familial or acquired, most commonly caused by infections, malignancies, rheumatologic and immunodeficiency disorders. Irrespective of the etiology, the age at the onset is the strongest prognostic factor, hence it is extremely important to have a high suspicion for HLH, diagnose it promptly and initiate treatment without any delay. We encountered a 70-year-old female patient who initially presented with left-sided facial weakness and pancytopenia, secondary to diffuse stage IV B diffuse large B-cell lymphoma with isolated bone marrow involvement with secondary HLH.

Toxic Hemolysis in a Young Healthy Female.

Clostridium perfringes is a gram-positive, rod-shaped, anerobic, spore-forming pathogenic bacterium. C. perfringes is commonly known to cause tissue necrosis and gas gangrene. However, severe life-threatening complications like hemolysis due to clostridium sepsis are rarely encountered. We present a case of a 35-year-old female presenting with endometritis complicated with severe hemolysis in the setting of sepsis secondary to C. perfringes. Her hospital course was complicated with multi-organ involvement, requiring broad-spectrum intravenous antibiotics. Eventually, she made an uneventful recovery by early recognition of these rare complications and prompt institution of appropriate therapy.

Sexual health in hematopoietic stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) plays a central role in patients with malignant and, increasingly, nonmalignant conditions. As the number of transplants increases and the survival rate improves, long-term complications are important to recognize and treat to maintain quality of life. Sexual dysfunction is a commonly described but relatively often underestimated complication after HSCT. Conditioning regimens, generalized or genital graft-versus-host disease, medications, and cardiovascular complications as well as psychosocial problems are known to contribute significantly to physical and psychological sexual dysfunction. Moreover, it is often a difficult topic for patients, their significant others, and health care providers to discuss. Early recognition and management of sexual dysfunction after HSCT can lead to improved quality of life and outcomes for patients and their partners. This review focuses on the risk factors for and treatment of sexual dysfunction after transplantation and provides guidance concerning how to approach and manage a patient with sexual dysfunction after HSCT.

Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by a highly variable clinical course. In the past decade, several prognostic risk factors have been identified facilitating the classification of CLL into various risk groups. Patients with poor risk disease, such as poor cytogenetics or relapsing after purine-based analogues, had limited therapeutic options, with allogeneic hematopoietic cell transplantation (allo-SCT) the only known therapy with curative potential. More recently, the introduction of novel agents inhibiting the B-cell receptor pathway, and the early success with chimeric antigen receptor T cells offers an effective and relatively safe option for this poor prognostic group which holds promise in the future. Alternatively, the use of reduced intensity conditioning regimens in the allo-SCT setting has led to a significant decrease in nonrelapse mortality to 16-23%, making it an attractive therapeutic option. No recent guidelines have been developed since these novel therapies became available regarding the optimal time to allo-SCT in this patient population. The advent of these novel and highly active therapeutic agents, therefore, warrants a reappraisal of the role and timing of allo-SCT in patients with CLL. In this article, we summarize the literature regarding the novel therapeutic agents available today as well as focus on the efficacy and safety of allo-SCT.

Multiple myeloma and its therapies: to what extent do they contribute to the increased incidence of second malignant neoplasms?

BACKGROUND: The high risk of another cancer once one has been diagnosed is well known. Furthermore, a clear association exists between the use of some cytotoxic agents and chemotherapy-induced malignancies. METHODS: This review is set to explore the relationship between multiple myeloma, its modern therapies and the development of second cancers due to various genetic, immune, and environmental (including iatrogenic) factors. Most relevant publications were identified through the PubMed database and by reviewing the drug information released by the US Federal Drug Administration. FINDINGS: Our comprehensive analysis identified several retrospective population studies, cohort group analyses and a number of case reports linking myeloma with other cancers in the world literature. A majority of these studies suggest that incidence of second solid and hematologic malignancies is significantly increased in patients with multiple myeloma and its precursor lesion, monoclonal gammopathy of unknown significance. In addition, incidence of second malignancies has been found increased in the family members of these individuals, especially in their first-degree relatives. CONCLUSIONS: Analysis of the existing literature cohorts does not discriminate between the burden of second cancers in treated myeloma patients as opposed to the patients followed with the wait-and-watch approach. Notably, the rate of second malignant neoplasms in multiple myeloma may be further increased by certain myeloma therapies. These cancers include, for the most part, hematologic malignancies such as acute leukemias and certain lymphomas. While there is no question about the role of alkylating agents and topoisomerase II inhibitors in this regard, further research is necessary to determine whether the excess of second cancers represents a direct consequence of lenalidomide use.

Refractory DKA as first presentation of acromegaly and a potential role for continuous venovenous hemofiltration in its successful management.

Diabetic ketoacidosis is rarely encountered in acromegaly. We present a unique patient with refractory diabetic ketoacidosis (DKA) as a first presentation of acromegaly. In addition to an insulin drip and intravenous fluids, our patient was managed with octreotide therapy. As he developed acute renal failure in the context of renal hypoperfusion, continuous venovenous hemofiltration (CVVH) was instituted. After only three days of therapy, the growth hormone (GH) level dropped circa fourfold and insulin growth factor 1 (IGF-1) level dropped ninefold. We postulate a hypothetical role of CVVH in removal of plasma GH and IGF-1, similar to the clearance of other medium size molecules such as brain natriuretic peptide and procalcitonin. If this is confirmed in future studies, CVVH may have therapeutic implications for the above category of patients.