Multiple myeloma (MM) is characterized by a proliferation of plasma cells (PCs) with a strong dependence on the bone marrow (BM) microenvironment. However, in up to one-third of patients with MM, the PC proliferation can escape the cellular microenvironment influences resulting in soft-tissue plasmacytomas. The most frequent mechanism resulting in soft-tissue plasmacytomas is direct growth from skeletal tumors by disruption of the cortical bone, while the remainder result from hematogenous dissemination without involving bony structures (1). Extramedullary involvement or extramedullary disease (EMD) is an aggressive form of multiple myeloma (MM) and it serves as an independent adverse prognostic indicator for MM (2). According to the timing of its occurrence, EMD can be categorized into the following two subtypes: i) Primary EMD (pEMD), which occurs concurrently with the onset of MM; and ii) secondary EMD (sEMD), which occurs in an advanced stage of MM, after relapse or progression (3). The prognosis for EMD is poor, with the median overall survival for patients undergoing extramedullary relapse being <6 months (4). At present, there is an absence of a stratified prognostic system or an ideal treatment strategy backed by evidence-based medical research, as they do not meet clinical requirements. Therefore, it is difficult to recommend one treatment strategy over another (2). The present study reports the case of a patient with extramedullary plasmacytoma at progression, who was treated with a CV-MED regimen (chidamide, bortezomib, mitoxantrone hydrochloride liposome, etoposide and dexamethasone). This protocol may be a promising therapy for obtaining an early response in patients with EMD.

In February 2023, a 59-year-old female patient was referred to Peking University Third Hospital (Beijing, China) due to intermittent bone pain for the past year. The patient reported that the pain was primarily concentrated in the lower and middle sternum, bilateral costal areas, and thoracic and lumbar vertebrae, and worsened after physical activity. Although the patient had been treated with zoledronic acid and calcium carbonate, the bone pain persisted and progressively worsened, which limited mobility. Following the patient's admission to the Peking University Third Hospital, laboratory tests demonstrated the following: White blood count (WBC), 6.15×10⁹/l (normal range, 4.0–10.0×10⁹/l); hemoglobin (Hb) level, 91 g/l (normal range, 110–160 g/l); platelet (PLT) count, 134×10⁹/l (normal range, 100–300×10⁹/l); calcium level, 2.69 mmol/l (normal range, 2.2–2.65 mmol/l); creatinine level, 103 µmol/l (normal range, 60–110 µmol/l); albumin level, 37 g/l (normal range, 40–55 g/l); total protein level, 64.9 g/l (normal range, 65–85 g/l); and β2-microglobulin level, 13.09 ng/ml (normal range, 1–3 ng/ml). Furthermore, electrophoresis of serum immune-fixation (agarose gel electrophoresis; fully automated Hydrasys System; Sebia) demonstrated a light chain monoclonal band indicative of M protein (11.3%; 7.3 g; Table I). Quantitative analysis of serum light chains demonstrated elevated λ chain levels (993 mg/dl; normal range, 269–638 mg/dl) and reduced κ chain levels (190 mg/dl; normal range, 574–1276 mg/dl). Additionally, 24-h urine light chain analysis showed elevated λ chain levels of 33 mg/dl (normal range, <5 mg/dl) and κ chain levels of <1.85 mg/dl (normal range, <1.85 mg/dl). Finally, serum immunoglobulin analysis demonstrated IgG, IgA, IgM and IgE levels of 2.58 g/l (normal range, 6.94–16.18 g/l), 0.084 g/l (normal range, 0.7–3.8 g/l), 0.08 g/l (normal range, 0.6–2.63 g/l) and 0.21 g/l (normal range, ≤100 g/l), respectively. Positron emission tomography-computed tomography (CT) scans demonstrated notable bone erosion in the sacrum, ilium and lumbar vertebrae, accompanied by metabolic activity (Fig. 1). Following bone marrow aspiration and biopsy, hypocellularity with 13% plasma cells was identified, 9% of which were immature (data not shown). Flow cytometric analysis showed 1.53% aberrant plasma cells (Fig. 2), and the patient was diagnosed with MM of the λ light chain type. Furthermore, fluorescence in situ hybridization (FISH) analysis was performed utilizing the IGH/CCND1 Translocation, Dual Fusion Probe from Cytocell on CD138-purified interphase cells according to the manufacturer's instructions, and the results demonstrated that ~80% of the cells (data not shown) carried IgH-CCND1 fusion genes (Fig. 3). Chromosomal karyotype analysis identified a t(11;14)(q13;q32) translocation. The patient was diagnosed with stage IIa MM, according to the Durie-Salmon system (5), stage III MM according to the International Staging System (ISS) and stage II MM according to the revised ISS (6).

Along with supportive treatment (such as gastroprotective agents and calcium additives), the patient was treated between March and May 2023 with two cycles of VRD (2.0 mg bortezomib on days 1, 4, 8 and 11; 40 mg dexamethasone on days 1, 4, 8 and 11; and 25 mg lenalidomide on days 1–21; 28-day cycle) and 100 mg/day aspirin to prevent thromboembolism. Upon reevaluation of the bone marrow, complete remission was achieved in terms of morphology, immunology and cytogenetics. However, a chest CT scan demonstrated a mass in the left chest wall (Fig. 4A) and a CT-guided needle biopsy was performed on the extramedullary mass located beneath the pleura. Immunohistochemical analysis by the Department of Pathology according to standard procedures demonstrated the following results: CD20(−), CD3(−), Ki-67(+, 60%), CD138(+), CD38(+), MUM1(+), CD56(−), CyclinD1(+), κ(−) and λ(+), which verified the diagnosis of EMD (Fig. 5).

As the patient was diagnosed with sEMD, treatment with three cycles of the CV-MED chemotherapy regimen was administered. Each cycle of CV-MED therapy consisted of 10 mg chidamide three times a week on days 1–21, 1.3 mg/m² bortezomib on days 1, 4, 8 and 11, 12 mg/m² mitoxantrone hydrochloride liposome on day 1, 50 mg/m² etoposide on days 1–3 and 20 mg dexamethasone on days 1, 4, 8 and 11 of a 28-day cycle. The most severe adverse event was hematological toxicity, and the patient developed febrile and grade IV myelosuppression, with a WBC count of 0.7×10⁹/l, an Hb level of 105 g/l and a PLT count of 24×10⁹/l. The symptoms resolved after systemic treatment (such as platelet transfusions, rehydration therapy and intravenous antibiotics). No obvious mucositis, neuropathy or other complications were observed. After three cycles of CV-MED chemotherapy, further chest CT scans demonstrated that the mass in the left chest wall was notably reduced in size, thus demonstrating the beneficial effects of the CV-MED regimen (Fig. 4B). Following autologous hematopoietic stem cell harvesting and a maintenance regimen incorporating daratumumab, the patient has been followed up at intervals of 1–2 months. To date, there has been no recurrence of the extramedullary lesion.

The incidence of sEMD ranges from 6–20%, and resistance to chemotherapy and poor patient prognosis has been reported (7). He et al (8) reported that multiple extramedullary bone-related and/or extramedullary extraosseous lesions are independent factors for a poor prognosis in patients with MM. Even in the era of novel drugs, there are currently no universally accepted international or domestic guidelines for sEMD. To the best of our knowledge, no prospective therapeutic studies on patients with sEMD have specifically been reported. Consequently, it is difficult to recommend a particular treatment strategy for EMD over another. Nonetheless, EMD is regarded as a high-risk disease and aggressive treatment approaches, if feasible, are typically recommended (1).

Since a large proportion of patients with EMD would have already received bortezomib-based front-line therapy, which is commonly combined with immunomodulatory drugs (IMiDs), effective treatment strategies for relapse commonly include lymphoma-like regimens, such as cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE), dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP), or dexamethasone, carmustine, etoposide, doxorubicin or 1iposomal doxorubicin and melphalan (Dexa-BEAM) (9). Alkylating agents and cytotoxic therapies are potent frontline treatments for extramedullary involvement in MM, especially for para-skeletal (PS) involvement. Wu et al (10) reported a partial remission rate of 50.0% with plasmacytomas in patients who received initial conventional therapy. According to the Mayo Stratification for Myeloma and Risk-Adapted Therapy guidelines, patients with MM who are eligible for autologous stem cell transplant with EMD are recommended to undergo two cycles of VDT-PACE therapy followed by sequential autologous hematopoietic stem cell transplantation (11).

Doxorubicin is recommended as a first-line therapy for patients with MM and is also widely used to treat extramedullary plasmacytoma (EMP) (2). A review of 40 patients with relapsed and refractory MM, who were treated with a median of 5 courses (range, 3–9 courses) of liposomal doxorubicin chemotherapy after developing sEMD, showed a short-term efficacy of 68.0 and 46.7% in the PS plasmacytoma and EMD groups, respectively (12). Mitoxantrone hydrochloride liposomes belong to the anthracene class of antitumor compounds, which is similar to liposomal doxorubicin. The high accumulation of the liposomes in tumor tissues is considered a key characteristic in preclinical investigations (13). Previous clinical trials have shown promising results for mitoxantrone in patients with relapsed and refractory peripheral T-cell lymphoma (14) and solid tumors (15). Therefore, mitoxantrone hydrochloride liposomes were selected as a substitute for doxorubicin in the present study due to their high accumulation in tumor tissues in lymphoma, resulting in the establishment of the MED-based regimen.

According to a pilot study presented at the 65th American Society of Hematology meeting, 15 patients with EMPs underwent a median of two cycles of liposomal mitoxantrone-based therapy. The specific regimens administered included the following: The mitoxantrone hydrochloride liposome-bortezomib-dexamethasone (MVD) triplet regimen (3/15 patients; 20.0%), the MVD plus lenalidomide regimen (M-VRD) (3/15 patients; 20.0%), the MVD plus IMiDs and etoposide regimen (6/15 patients; 40.0%), and the MVD plus other cytotoxic agents (cyclophosphamide or cisplatin) regimen (3/15 patients; 20.0%). The overall response rate for EMP was 53.3%. The study showed promising results regarding the early response and efficacy of the MVD-based regimen in MM with EMP (16). Additionally, previous in vitro research has shown that chidamide could have antimyeloma effects by inhibiting the proliferation and invasion of MM cells, as well as by inducing apoptosis (17). Clinically, the successful treatment of relapsed or refractory MM with a regimen of chidamide, bortezomib and dexamethasone has been previously reported (18). For the present study, it was thus sought to integrate chidamide with an MVD-based protocol, and the CV-MED regimen was ultimately selected as the preferred treatment approach. Moreover, due to the significant hematological toxicity associated with the chemotherapy protocol, and the development of grade IV myelosuppression and febrile neutropenia after treatment, it was anticipated that the patient might not tolerate weekly administrations of the CD38 monoclonal antibody (mAb). As a result, the chemotherapy regimen temporarily excluded the CD38 mAbs.

In conclusion, the present case report indicated that a chemotherapy regimen based on mitoxantrone hydrochloride liposomes, bortezomib and chidamide could be an effective approach for treating patients with EMD. However, further studies are required to evaluate the efficacy and safety of this treatment.