Extramedullary relapse of multiple myeloma presenting as space-occupying lesion in liver treated with daratumumab, pomalidomide, dexamethasone and bendamustine

Abstract

Extramedullary relapse in patients with multiple myeloma (MM) is often associated with loss of biochemical response and the appearance of measurable residual disease in the bone marrow. Fever is an unusual presenting manifestation of MM. Treatment of extramedullary relapse in patients progressing on proteasome inhibitors, anti-CD38 monoclonal antibodies and immunomodulatory drugs is challenging, as access to chimeric antigen receptor T-cells and bispecific antibodies is limited. We report a case of relapsed MM who presented with fever and hepatic space-occupying lesion mimicking hepatocellular carcinoma. In this case report, we also present our experience of using a novel combination regimen comprising Dara-Pom-Benda-Dexa (daratumumab, pomalidomide, dexamethasone and bendamustine) for relapsed MM.

Background

Hepatic space-occupying lesions (SOLs) have a broad differential diagnosis. Aetiology of hepatic SOLs includes benign lesions such as cysts, haemangiomas, infective abscesses and various malignant lesions such as hepatocellular carcinoma (HCC), hypervascular metastasis from a gastrointestinal primary and haematolymphoid neoplasms. In the absence of a tissue biopsy, characteristic imaging patterns can point to a specific aetiology such as HCC.

Patients with multiple myeloma (MM) are known to have an increased risk of second malignancy.¹ In patients with MM, extramedullary relapse often occurs concomitantly with marrow relapse.² Therefore, when patients with MM who have attained a stringent complete remission (sCR) and an undetectable measurable residual disease (MRD) state present with a visceral space occupying lesion(SOL), a non-myelomatous second malignancy is often considered as a differential. As fever is not a common manifestation of MM, high-grade fever in patients with MM is often attributed to infections unless proven otherwise. Treatment of patients who have a extramedullary relapse and progression on proteasome inhibitors(PIs), anti-CD38 monoclonal antibodies and immunomodulatory drugs(IMIDs) is often challenging, particularly if access to novel therapies such as chimeric antigen receptor T-cells and bispecific antibodies is limited.

We report a case of relapsed MM who presented with hepatic SOL mimicking a HCC and prolonged fever. In this case report, we also present our experience of using a novel combination regimen comprising Dara-Pom-Benda-Dexa (daratumumab-pomalidomide-bendamustine-dexamethasone) for relapsed MM.

Case presentation

A man in his seventies came to our hospital with generalised body pains. General physical examination revealed pallor and the patient had an Eastern Cooperative Oncology Group(ECOG) performance status (PS) 2. Investigations revealed normocytic normochromic anaemia (Hemoglobin: 84 g/L, Total Leucocyte Count(TLC): 5.4 x 10⁹/L, platelet count: 242 x 10⁹/L, rouleaux formation of red blood cells on blood film with total serum protein: 10.2 g/dL, albumin: 3.2 g/dL). Serum protein electrophoresis revealed a monoclonal protein of 4.2 g/dL. Serum-free light chain(FLC) assay revealed a lambda/kappa ratio of 0.004 (lambda: 16.728 mg/L, kappa: 4182 mg/L), and immunofixation was positive for a monoclonal band in the IgG and kappa region. A Positron Emission Tomography(PET) scan revealed numerous lytic lesions in multiple vertebrae, cranium and scapulae with no other site of extramedullary disease. Bone marrow aspirate revealed 48% clonal plasma cells which were positive for 1q amplification (4 copies), IgH-MAF translocation and TP53 deletion on fluorescence in situ hybridisation. He was diagnosed with MM R-ISS stage 3. He was deemed transplant in-eligible due to age and fraility (Myeloma Fraility Score: 3). He was managed with daratumumab, lenalidomide, bortezomib and dexamethasone (Dara-RVD) regimen and attained a stringent Complete Remission with a normal FLC ratio, undetectable marrow MRD (flow cytometry) and PET-based remission (IMPETUS criterion) at the end of six cycles.³ Following six cycles, he was put on doublet maintenance with bortezomib and lenalidomide. 10 months later, he presented with high-grade fever and a 10 kg weight loss over 1 month. On examination, he had a cachectic appearance with an ECOG PS 3. No hepatomegaly or splenomegaly was noted.

Investigations

On investigations, he had an Hb:120g/L, TLC: 7.6 x 10⁹/L, platelet count: 324×10⁹cells/L. He had a normal serum calcium (8.8 mg/dL) and renal functions (urea: 28 mg/dL, creatinine: 0.8g/dL). USG abdomen revealed a hypoechoic lesion of 5×5 cm involving segments 7 and 8 with a radiologic possibility of liver abscess, or a neoplastic SOL. Serum AFP levels were 0.9 ng/mL (normal). Initially, injection piperacillin tazobactum was given on an empirical basis for 7 days, but there was no resolution of fever spikes. Two sets of blood cultures, procalcitonin, echocardiography for vegetations, amoebic, hydatid serology, galactomannan and beta d glucan were negative ruling out common infectious pathogens affecting the liver. Serum ferritin levels were 104 ng/mL (30–150 ng/mL). A repeat serum protein electrophoresis and serum immunofixation was negative. Serum-free light chain assay revealed normal kappa/lambda ratio (1.3) and stable difference in FLC[dFLC] of (12 mg/L). Bone marrow examination did not reveal clonal plasma cells(MRD negative by flowcytometry). A PET scan revealed presence of an 18-Fluoro-Deoxy-Glucose(FDG) avid (Standardised Uptake Value [SUV] max 15.2) SOL in segment 7 of liver (figure 1). PET-guided biopsy from liver SOL showed the presence of an infiltrative tumour arranged in the form of trabeculae, solid nests and islands. The tumour cells were large polygonal with predominantly central and occasional eccentric round nuclei, prominent single centrally placed nucleoli, and abundant clear to pale eosinophilic cytoplasm. There was moderate nuclear pleomorphism with scattered multinucleated cells and no mature-appearing plasma cells were seen. There was no evidence of amyloidosis in the liver biopsy. On immunohistochemistry, these tumour cells were negative for pan-cytokeratin, Heppar-1, Arginase, CD3 and CD20. Further, diffuse strong positivity for CD38, CD138 (membranous), and MUM1 (nuclear) and negativity for CD79a and EBER-ISH was noted. The patient was diagnosed with plasmablastic neoplasm, consistent with plasmablastic lymphoma or anaplastic plasmacytoma on histopathology (figure 2). As the patient was a known case of IgG Kappa MM with characteristic myeloma-associated chromosomal abnormalities previously, therefore, he was managed as a case of relapsed anaplastic myeloma.

Figure 1.

CECT (A, B) and fused PET/CT (C, D) images show FDG avid isodense to hypodense lesions of varying sizes (largest in segment VIII~5.4×5.7×5.0 cm, SUVmax 10.2) in both lobes of the liver.

Figure 2.

(A)Liver core biopsy showing an infiltrative tumour arranged in trabecular and nesting pattern; (B) The tumour cells are large with round eccentric nucleus, prominent nucleoli and abundant basophilic cytoplasmic showing multinucleation as well; (C–J) immunohistochemistry panel showing negativity for pan-cytokeratin, Hepar/Arginase, CD3, CD20/CD79a and postivity for CD38/138 and negative EBER ISH (Left Upper section of Image J)

As the patient had presented with an extramedullary hepatic SOL at relapse, the option of including one of the chemotherapeutic drug, that is, liposomal doxorubicin or bendamustine was considered. The patient was found to have a low ejection fraction (44%) on two-dimensional echocardiography in the current admission. Therefore, bendamustine was favoured over liposomal doxorubicin. The patient had progressed on a bortezomib and lenalidomide maintenance;therefore daratumumab, pomalidomide and dexamethasone were added to bendamustine. The patient received six cycles of Dara-Pom-Benda-Dexa (daratumumab (16 mg/kg dose, 16 doses—8 doses weekly, followed by 8 doses biweekly), pomalidomide (4 mg once daily 21/28days), dexamethasone(40mg weekly) and bendamustine (90 mg/m² for 2 doses, every 28 days)) regimen.

Outcome and follow-up

The patient became afebrile within 2 days after the initiation of anti-myeloma therapy, possibly suggesting a myeloma related fever. He gained weight of around 5 kg after 3 months of reinitiating therapy. After six cycles of this remission, a repeat PET was suggestive of Complete Remission(CR) state (figure 3). Thereafter, he was switched to monthly daratumumab maintenance along with pomalidomide. The patient is currently maintaining CR at 12 months from the first relapse.

Figure 3.

CECT (A, B) and fused PET/CT (C, D) images show non FDG avid hypodense lesions of varying sizes (largest in segment VII/VIII~2.2×2.5 cm) in both lobes of liver after 6 cycles

Discussion

The index case was unusual in several aspects. In the current admission, he presented with high-grade prolonged fever with no specific localisation and negative workup for infectious pathogens. The fever responded to the administration of antimyeloma therapy, and this was the key to attributing fever to MM. Fever of unknown origin(FUO) has been described as a presentation of HCC and hepatic haemangiomas; however, it is unusual for patients with MM to present with FUO. In a recently published series consisting of 5523 patients of fever of unknown origin, MM was identified as a cause only in nine patients (0.2%).⁴ Fever in patients with MM has been reported more commonly in patients who present with extramedullary anaplastic plasmacytomas, similar to the current case.⁵

In an autopsy series of MM patients, the involvement of liver was seen in 7.8% of cases.⁶ Commonly reported histological patterns of hepatic involvement due to myeloma include diffuse parenchymal infiltration by plasma cells that present as jaundice and liver dysfunction, amyloidosis that presents as hepatomegaly with elevated alkaline phosphatase, light chain deposition disease and extramedullary plasmacytomas that present as painless hepatic SOLs often detected on imaging.⁷ The appearance of hepatic plasmacytomas on cross-sectional imaging is variable. It can mimic HCC (arterial phase hyperenhancement and delayed portal washout) or haemangioma (peripheral enhancement with gradual filling in towards centre).⁸ The majority of visceral plasmacytomas at relapse are postulated to arise from haematogenous dissemination and this was the likely mechanism of dissemination to liver in the current case as well.⁹

Extramedullary relapse usually is associated with a reappearance of monoclonal protein in the blood and clonal plasma cells in the marrow.⁹ However, in this case, no clonal plasma cells were detectable in the marrow on morphology or flowcytometry, nor was there any evidence of measurable monoclonal protein at the time of relapse. The absence of any light chains and monoclonal protein in serum is suggestive of non-secretory relapse in the current case. The degree of anaplasia visualised on plasma cell morphology in patients with MM is usually not incorporated in most prognostic risk models. However, it carries prognostic significance. In a recent review by Wu et al, atypical pleomorphic, multinucleated morphology of anaplastic myeloma cells having prominent nucleoli and abundant basophilic cytoplasm has been described.¹⁰ Prognosis of such patients is dismal and they usually have adverse risk cytogenetics and an aggressive course.¹⁰ In the index case, the anaplastic plasma cells mimicked an epithelial malignancy such as HCC. Immunohistochemistry studies for pan-cytokeratin and Heppar-1 aided in distinguishing the index case from an epithelial malignancy. This case is unique with the presence of three cytogenetic abnormalities: t(14:16) involving IgH-MAF, 1q amplification and 17p13 (TP53) deletion which occur in frequencies of 5%, 40% and 10%, respectively.¹¹ The presence of three or more than three abnormalities in a single patient is known as triple hit myeloma, which carries a grave prognosis.¹²

The choice of regimen in a patient with relapsed myeloma depends on the baseline cytogenetics, types of previous therapies received with duration and depth of response to previous therapies, fitness of the patient, and the site and aggressiveness of relapse. Combination regimens such as VTD-PACE/VAD (bortezomib, thalidomide, dexamethasone—cisplatin, adriamycin, cyclophosphamide, etoposide/bortezomib, adriamycin, dexamethasone) that include chemotherapy with IMIDs or PIs have been frequently used for high risk soft tissue relapses.^{13 14} Recently, immunochemotherapeutic approaches using Dara KDT PACE (daratumumab, carfilzomib, dexamethasone, thalidomide—cisplatin, adriamycin, cyclophosphamide, etoposide) and Dara DCEP (daratumumab, dexamethasone, cyclophosphamide, etoposide, cisplatin) are being increasingly used for managing these patients.¹⁴ However, age and frailty precluded the use of multiagent chemotherapy in the current case. Bendamustine, when used as a single agent, resulted in a PFS of 7 months and OS of 17 months in a single-centre, retrospective analysis. Overall Response Rate was around 36%, the majority of responders had a partial response.¹⁵ There is scarce literature on the use of bendamustine with other antimyeloma therapies, particularly in combination with daratumumab. There is evidence in the form of some phase 2 studies where bendamustine is used with pomalidomide in cases of extramedullary relapse with an ORR of more than 50%.^{16 17} As bendamustine is partially metabolised in liver, most trials on bendamustine have excluded patients with hepatic dysfunction. Bendamustine was well tolerated in the current case for all six cycles despite the patients age and fraility. This highlights the safety, tolerability, and efficacy of Dara-Pom-Benda-Dexa combination in patients with frail dual refractory relapsed high-risk MM.

Learning points.

• Patients with multiple myeloma can present with extramedullary relapse in the absence of detectable monoclonal protein and measurable residual disease in the marrow.

• Fever can be a presenting manifestation of relapsed multiple myeloma and often responds to antimyeloma therapy.

• Daratumumab-pomalidomide-bendamustine-dexamethasone can be an effective regimen for extramedullary visceral relapse of multiple myeloma.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.