AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical suspicion to detect unexplained manifestations in the appropriate clinical setting. Early detection and treatment are crucial as the degree of cardiac involvement emerges as a primary prognostic predictor of survival in a patient with AL amyloidosis. Following the diagnosis of AL amyloidosis with appropriate tissue biopsies, prompt treatment with a bortezomib, cyclophosphamide and dexamethasone-based first-line induction with or without daratumumab should be initiated. The goal of treatment is to achieve the best haematologic response possible, ideally with involved free light chain <20 mg/L, as it offers the best chance of organ function improvement. Treatment should be changed if patients do not achieve a partial response within 2 cycles of treatment or very good partial response after 4 cycles or after autologous stem cell transplant, as achievement of profound and prolonged clonal responses translates to better organ response and long-term outcomes. Early involvement of multidisciplinary subspecialists such as renal physicians, cardiologists, neurologists, and gastroenterologists for optimal maintenance and support of involved organs is recommended for optimal management of patients with AL amyloidosis.
Existing literature on daratumumab, a fully human IgG1κ monoclonal antibody directed against CD38, in POEMS syndrome is limited. POEMS syndrome is a plasma cell disorder presenting typically with polyradiculoneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal plasma cell disorder (M), and skin changes (S). Other manifestations include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis–erythrocytosis, elevated vascular endothelial growth factor (VEGF) levels, a predisposition toward thrombosis, and abnormal pulmonary function tests. The median survival of patients with POEMS is 13.7 years while those with extravascular volume overload have a poorer prognosis with a median survival of 6.6 years.1 We report a patient with POEMS syndrome refractory to lenalidomide and dexamethasone that responded remarkably to single-agent daratumumab. A 59-year-old woman presented 6 years ago with gradual weakness of the lower limb bilaterally. The power of proximal and distal lower limb muscles was graded as 4 and 3, respectively. She required a walking stick for ambulation and had frequent episodes of falls. She also experienced reduced sensation below the knee bilaterally. She did not have urinary or bowel incontinence, diplopia, dysarthria, dysphagia, or trauma to the back. Initial full blood count showed normal hemoglobin and white cells with thrombocytosis. (HB 14.9 g/dL; WBC 8.8 × 109/L; PLT 567 × 109/L). Brain imaging was unremarkable, and the lumbar puncture showed normal biochemical, microbiological, and cytological findings. Subsequently, a nerve conduction study confirmed the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). A myeloma panel showed monoclonal IgA lambda on serum immunofixation with a total serum IgA level of 4.8 g/L (1.2–4.4 g/L). The patient was started on azathioprine, prednisolone, and intravenous immunoglobulin (IVIG) for 6 cycles for CIDP by neurology. Two years into the treatment, her lower limb weakness persisted, and she was referred to hematology for therapeutic plasma exchange. Repeat myeloma panel showed a persistent monoclonal IgA lambda band, with a total IgA level of 3.5 g/L. Free light chain kappa and lambda levels were normal at 7.2 mg/L (6.7–22.4 mg/L) and 18.0 mg/L (8.3–27.0 mg/L), respectively. Full body skeletal survey performed did not show any bony lesion, however, pan body computed tomography scan showed absent organomegaly but a moderate pericardial effusion without tamponade and a new sclerotic focus with periosteal reaction along the lateral aspect of the left fifth rib. A baseline echocardiogram performed 2 months later found a normal left ventricular ejection fraction of 60% and there was no regional wall motion abnormality; however, there was a grade 1 left ventricular diastolic dysfunction with trivial pericardial effusion, without any features of cardiac amyloidosis. Bone marrow examination was offered to diagnose possible multiple myeloma or amyloidosis, but the patient declined. As the patient did not have features of constipation, renal failure, anemia, and bone disease, a presumptive diagnosis of IgA lambda monoclonal gammopathy of unknown significance was made. A year later, the patient's lower limb symptoms remained stable on steroid therapy. There were no constitutional symptoms like fever, fatigue, musculoskeletal pain, loss of weight, or loss of appetite, however, she started to complain of blurring of vision bilaterally. Ophthalmological examination confirmed bilateral optic disk swelling. Magnetic resonance imaging (MRI) brain showed normal optic nerves and chiasm with no evidence of major dural venous sinus thrombosis. Opening pressure for lumbar puncture was normal and cerebrospinal fluid showed normal biochemistry and cytology with no oligoclonal bands detected. An autoimmune workup, including anti-nuclear antibody, P-antineutrophilic cytoplasmic antibodies , C-antineutrophilic cytoplasmic antibodies, Anti-Ro, Anti-La, Aquaporin 4 antibody, and anti-myelin oligodendrocyte glycoprotein, was found to be negative. She also complained of nonitchy erythematous dome-shaped papules over the right upper limb, chest wall, and right thigh. A shave biopsy of the skin lesion confirmed the diagnosis of glomeruloid hemangioma, which is a cutaneous vascular neoplasm associated with POEMS syndrome. The patient subsequently agreed to undergo a bone marrow aspirate, which showed a hypercellular marrow with an increase in erythropoiesis and megakaryopoiesis, with 9% plasma cells with negative Congo red staining of the trephine. Further investigations showed full blood count of HB 11.3 g/dL; WBC 13.4 × 109/L; PLT 406 × 109/L; a VEGF concentration of 381 pg/mL (reference range < 96.2 pg/mL), serum IgA paraprotein level of 4 g/L, and free light chain lambda level of 67.9 mg/L. Given the fulfillment of mandatory criteria of peripheral neuropathy with evidence of a monoclonal plasma cell proliferative disorder, with major criteria of the presence of an osteosclerotic lesion, elevated VEGF levels, together with minor criteria of papilledema, skin changes (glomeruloid haemangioma) extravascular volume overload (pericardial effusion), and thrombocytosis, a diagnosis of POEMS syndrome was made. The patient was started on lenalidomide 25 mg daily and dexamethasone 20 mg weekly for 3 weeks in a 4-weekly cycle. Three months after the initiation of lenalidomide and dexamethasone, the patient developed breathlessness and the MRI heart showed a global increase in T1 values without late gadolinium enhancement (LGE) over the left ventricle suggesting an early cardiac infiltrative process with a left ventricular ejection fraction of 35%. This was complicated by a complete heart block, intermittent ventricular standstill, and moderate pericardial effusion. Coronary angiogram revealed moderate disease in the left anterior descending artery. A dual-chamber permanent pacemaker was inserted in view of persistent AV nodal disease. Concurrently, her lower limb weakness and sensory deficits did not improve, and the biochemical markers continue to rise (Figure 1) despite the treatment. In view of the poor clinical response to lenalidomide and dexamethasone, the patient was treated with single-agent daratumumab 16 mg/kg with dexamethasone. She underwent a regime of 8 weekly doses of daratumumab, and a further additional 8 doses fortnightly before switching to monthly maintenance of daratumumab. A month after the commencement of single-agent daratumumab, the patient's lower limb neurological deficit improved. With physiotherapy, she was able to ambulate around with a walking stick and the power of bilateral proximal and distal lower limb muscles improved to 5 and 4, respectively. Follow-up pacemaker interrogation revealed 100% intrinsic rhythm indicating a complete recovery of AV nodal function. Troponin T and pro NT-BNP levels done post daratumumab were normal. Biochemical evaluation of her free light chain, IgA, and VEGF concentration showed a decreasing trend with normalization of VEGF levels and no serum IgA paraprotein levels detected at the latest assessment. She remained clinically stable for 18 months while on maintenance daratumumab and she was offered an autologous stem cell transplant, which she is still considering. For POEMS syndrome, there is no standard of care established,1 with a single randomized control trial describing treatment with thalidomide and dexamethasone for transplant noneligible patients with a primary endpoint of VEGF levels, with a reduced rate of 0·39 (SD 0·34) in the thalidomide group compared with −0·02 (0·54) in the placebo group, with no deaths reported in both arms.2 Several phase II trials evaluating lenalidomide and dexamethasone were performed, with the largest study by Li et al having a 3-year overall survival of 90% and progression-free survival of 75%. Dose-reduced bortezomib, cyclophosphamide, and dexamethasone have also been evaluated in single case reports with good clinical response. The principle of treatment for POEMS syndrome is a directed therapy at the underlying clonal plasma cell disorder rather than solely targeting VEGF with anti-VEGF antibodies.1 Upfront daratumumab has been used in two cases, one with daratumumab with lenalidomide and dexamethasone and another combining daratumumab with lenalidomide, bortezomib, and dexamethasone.3 In addition, daratumumab and lenalidomide were used as a third-line option in a patient that had an upfront melphalan-based autologous stem cell transplant, where prior lenalidomide and dexamethasone salvage therapy showed poor response.4 In our patient, single-agent daratumumab was used as salvage therapy with significant biochemical and clinical improvement of the patient's neuropathy and cardiomyopathy. While cardiomyopathy, pericardial effusion, and complete heart block are not preexisting features of the major or minor criteria for POEMS syndrome, excessive VEGF production is known to cause interstitial edema in tissues and can result in left ventricular systolic dysfunction as evidenced by early cardiac infiltration on the cardiac T1 MRI5 and in rare cases, complete heart block.6 An important differential to exclude would be concurrent AL amyloidosis with cardiac infiltration; however, the patient was too unwell to undergo a cardiac biopsy for confirmation. There was no evidence of chamber enlargement, ventricular hypertrophy, or pseudo-infarct pattern on the 12-lead electrocardiogram, which is commonly seen in cardiac amyloidosis. Transthoracic echocardiogram did not show signs of restrictive filling physiology, biatrial enlargement, or "speckled" pattern. The lack of LGE in our patient suggests cardiac amyloidosis is unlikely, as cardiac MRI has a high diagnostic accuracy of LGE for cardiac amyloidosis with a sensitivity of 85% and specificity of 92%.7 Daratumumab has multiple mechanisms of action on clonal plasma cells: first, antibody-mediated cellular cytotoxicity (complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity), second, killing of immunosuppressive populations of T-regulatory and B-regulatory lymphocytes, and myeloid-derived suppressor cells that express CD38 and lastly immunomodulation mediated by decreased adenosine in the tumor microenvironment. These mechanisms would account for the improved response and clinical recovery of our patients. While the existing evidence for use of daratumumab in the upfront and relapsed setting for POEMS syndrome is limited, single-agent daratumumab seems a reasonable salvage option in patients with POEMS syndrome who are refractory to the upfront lenalidomide dexamethasone. Results from clinical trials such as the ongoing single-arm combination daratumumab and lenalidomide on patients with newly diagnosed and relapsed POEMS syndrome (NCT04396496) are eagerly awaited. The authors declare that they have no conflict of interest. Bingwen Eugene Fan conceived the study. Bingwen Eugene Fan and Han Wei Tiew wrote the first draft of the manuscript. All authors contributed substantially to the acquisition, analysis, and interpretation of data, critical revision of the manuscript for important intellectual content. The data that support the findings of this study are available from the corresponding author upon reasonable request. Informed consent was obtained from the patient. The data that support the findings of this study are available from the corresponding author upon reasonable request.
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