==== Front Intern Med Intern Med Internal Medicine 0918-2918 1349-7235 The Japanese Society of Internal Medicine 35871579 10.2169/internalmedicine.0010-22 Case Report Multiple Myeloma with Hyperammonemia Treated with Novel Agents: A Case Series of Three Patients Nakamura Hajime 1 Takada Kohichi 1 Murase Kazuyuki 1 Ikeda Hiroshi 2 Iyama Satoshi 2 Manabe Tatsuo 3 Kobune Masayoshi 2 1 Department of Medical Oncology, Sapporo Medical University School of Medicine, Japan 2 Department of Hematology, Sapporo Medical University School of Medicine, Japan 3 Department of Neurology, Sapporo Medical University School of Medicine, Japan Correspondence to Dr.　Kohichi Takada, ktakada@sapmed.ac.jp 22 7 2022 1 3 2023 62 5 775778 23 3 2022 10 6 2022 Copyright © 2023 by The Japanese Society of Internal Medicine https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/). Multiple myeloma (MM) is a cancer characterized by the expansion of plasma cells in the bone marrow. Survival times of patients with MM have increased due to the development of novel therapeutic agents. We herein highlight three MM cases that had a poor prognosis despite treatment with novel therapeutic agents. Of note, all patients presented with hyperammonemia that led to a consciousness disorder. The outcome for patients with MM showing high levels of serum ammonia continues to be poor, even with the use of novel therapies. For such patients showing a consciousness disorder, hyperammonemia should be considered as a possible cause. hyperammonemia multiple myeloma ==== Body pmcIntroduction Multiple myeloma (MM) is a cancer characterized by clonal proliferation of plasma cells in the bone marrow. The worldwide incidence of MM amounted to over 176,000 cases and mortality was over 117,000 patients for the year 2020 (1). Therapeutic strategies for MM have changed dramatically in the last 15 years due to the advent of proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Furthermore, in the last 10 years, 7 new drugs carfilzomib, pomalidomide (IMiDs), panobinostat (histone deacetylase inhibitor), ixazomib (proteasome inhibitor), and elotuzumab, daratumumab, and isatuximab (immunostimulatory monoclonal antibodies) have been newly approved for the treatment of this disease. The overall survival has improved for patients with MM, although some still present with a poor prognosis, depending on the presence of genetic abnormalities, including t(4;14), t(14;16), (14;20), del 17p, p53 mutation, and gain 1q (2,3). Patients with MM often present with disease-related complications, including hypercalcemia, renal insufficiency, anemia, and bone lesions (4). However, hyperammonemia is a rarely reported complication of MM and is associated with high mortality (5). Furthermore, knowledge is scarce concerning the treatment effect of newly approved drugs on MM patients with hyperammonemia. We herein report three MM patients who displayed a consciousness disorder evoked by hyperammonemia and who were treated with the aforementioned new therapeutic agents. Case Reports Case 1 A 75-year-old female was referred to our hospital for further treatment of IgG-κ-type MM with t(4;14), gain 1q, and revised international staging system (R-ISS) II. She had previously been treated with bortezomib-melphalan-prednisolone (VMP), lenalidomide-dexamethasone (Ld), pomalidomide-dexamethasone (Pd), bortezomib-dexamethasone (Bd), and panobinostat-bortezomib-dexamethasone, in this order, for two years and six months. However, the disease continued to progress, and we consequently administered carfilzomib-lenalidomide-dexamethasone (KRd) as a sixth treatment. The day after the administration of KRd, the patient presented with a disorder of consciousness. Electroencephalography revealed triphasic waves (Fig. 1), and the level of serum ammonia increased to as high as 268.6 μg/dL. No other causes existed for the consciousness disorder according to a blood examination and computed tomography (CT) of the brain. We therefore deemed the consciousness symptoms to have been caused by hyperammonemia, which was treated using a branched-chain amino acid (BCAA) agent in parallel with KRd treatment. Figure 1. Electroencephalogram findings for Case 1. Electroencephalography revealed triphasic waves that implied metabolic abnormalities, such as hyperammonemia. The level of serum ammonia gradually decreased, and her consciousness improved to a certain extent. However, the patient's general condition deteriorated quickly with the progression of MM, and she ultimately passed away seven days after the administration of KRd (Fig. 2a). Figure 2. Clinical courses for the three patients. a: Case 1, b: Case 2, c: Case 3. BCAA: branched-chain amino acid, EPd: elotuzumab-pomalidomide-dexamethasone, ERd: elotuzumab-lenalidomide-dexamethasone, Kd: carfilzomib-dexamethasone, KRd: carfilzomib-lenalidomide-dexamethasone Case 2 A 61-year-old woman was admitted to our hospital for the further treatment of IgA-λ-MM with del 17p and R-ISS I. At 55 years old, she had undergone an autologous peripheral blood stem cell transplant. Three years and four months later, she relapsed and was treated with Ld, Pd, and daratumumab-bortezomib-dexamethasone, in that order. The disease continued to progress despite treatment, and we subsequently administered carfilzomib-dexamethasone. However, the serum IgA-λ level continued to increase, so we administered elotuzumab-pomalidomide-dexamethasone (EPd) as a fifth-line treatment. The patient presented with strange behavior five days after the administration of EPd. Blood examinations revealed hyperammonemia, with levels as high as 212.1 μg/dL. There were no other possible causes of the strange behavior besides hyperammonemia, according to a blood examination, so we administered BCAA agents. The serum ammonia levels subsequently decreased to 56.7 μg/dL at 11 days after the confirmation of hyperammonemia, resulting in an improvement in the patient's strange behavior. Furthermore, serum λ-light chain decreased with EPd, which was continued for two cycles. However, the patient's general condition gradually deteriorated, mainly because of infectious complications such as bacterial pneumonia, and it became difficult to continue the chemotherapy for MM. She ultimately passed away four months after the determination of hyperammonemia (Fig. 2b). Case 3 A 48-year-old woman was admitted to our hospital for further treatment of IgA-λ-MM with R-ISS 1. She had previously been treated with Bd, Ld, and Pd, in that order. Despite this, the disease continued to progress, so we consequently proceeded to administer elotuzumab-lenalidomide-dexamethasone (ERd). One day before administering ERd, the patient presented with strange behavior, and the serum level of ammonia increased to 67.7 μg/dL. Treatment with ERd was started as planned, with the patient simultaneously being treated with BCAA agents for hyperammonemia. The serum ammonia level decreased two days after administering BCAA agents, and the patient's unusual behavior improved accordingly. Furthermore, the serum λ-light chain level decreased from 661.0 mg/L to 216.0 mg/L with ERd treatment. However, the patient presented with abdominal bloating after a cycle of ERd; CT revealed massive ascites and multiple liver metastases. Plasma cells were found in the ascites after a pathological evaluation. The patient's general condition deteriorated quickly, mainly due to the refractory ascites. She ultimately passed away 32 days after hyperammonemia was diagnosed (Fig. 2c). Discussion Hyperammonemia, characterized by excessive levels of ammonia in the blood, is a life-threatening metabolic condition that can cause brain injury and consciousness disorder. The most common causes of hyperammonemia are severe liver dysfunction and congenital disorders of urea metabolism (6). Notably, several representative MM cell lines reportedly produce a high amount of ammonia compared to non-MM cell lines, including human hepatic carcinoma (7). In practice, the hyperammonemia of our three cases was thought to have been caused by MM cells, as no evidence of liver disease was found by blood or imaging examinations. All three cases were classified as relapsed refractory MM that was treated with several regimens. However, a case with hyperammonemic encephalopathy as a presenting symptom of newly diagnosed MM was also reported in the literature (8). Consciousness disorder in MM is often related to hypercalcemia and hyperviscosity. Although hyperammonemia is a rare condition of MM, it should always be ruled out in patients who present with a consciousness disorder during all stages of the disease. Hyperammonemia in MM is reportedly associated with a high mortality rate (5,9,10). Recently, various novel therapeutic agents, including monoclonal antibodies, proteasome inhibitors, and IMiDs, have been introduced and have extended the survival in patients with MM. However, the clinical impact of these new therapeutic agents on MM with hyperammonemia remains uncertain. We administered new drugs, including carfilzomib, lenalidomide, pomalidomide, and elotuzumab, to the patients as outlined here. All patients received BCAA agents simultaneously and presented with a decreased level of serum ammonia. In addition, treatments elicited responses and were of benefit in cases 2 and 3, as evidenced by a decrease in the serum λ-light chain level after the administration of chemotherapy. However, the general condition of all patients deteriorated despite treatments. Clinicians should be aware of the high mortality rate of patients with MM presenting with hyperammonemia even after treatment with novel therapeutic agents. Recently, more intensive treatment strategies, including daratumumab-VMP and daratumumab plus lenalidomide, bortezomib, and dexamethasone, have been introduced clinically for untreated MM (11,12). Furthermore, B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy has also induced frequent and intense responses in patients with relapsed and refractory MM (13). These new treatment strategies should be considered when MM patients present with hyperammonemia. In summary, MM should be included in the differential diagnosis of hyperammonemia. 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