Clinical and Histopathological Analyses of Anaplastic Myeloma

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Clinical and Histopathological Analyses of Anaplastic Myeloma

Anaplastic myeloma (AM), recognized as a rare and aggressive morphological subtype of multiple myeloma (MM), encompasses both anaplastic multiple myeloma and anaplastic plasmacytoma. Characterized by rapid progression, chemotherapy resistance, and poor prognosis, AM represents a clinical challenge with limited therapeutic success. This article synthesizes findings from a retrospective analysis of four AM cases, providing insights into the clinical presentation, histopathological features, genetic abnormalities, and treatment outcomes of this understudied disease.

Clinical Presentation and Demographics

The four AM patients (three females, one male) ranged in age from 36 to 58 years, highlighting the propensity of AM to affect younger individuals compared to conventional MM. Common presenting symptoms included bone pain (three patients), neurological deficits such as lower limb weakness (two patients), and palpable masses (one patient with a skull lesion). All patients exhibited anemia (hemoglobin levels: 78–99 g/L) and extramedullary tumor involvement, with imaging revealing osteolytic lesions, spinal masses (T1–T8 vertebral involvement), and intraperitoneal or spinal canal tumors. Notably, three patients developed effusions secondary to tumor infiltration.

Laboratory findings demonstrated consistent abnormalities: elevated lactate dehydrogenase (LDH) levels (444–1,429 U/L), increased β2-microglobulin (6.89–9.46 mg/L), and reduced immunoglobulin (Ig) levels in three cases. Immunofixation electrophoresis identified monoclonal proteins in all patients: one IgG-κ, one IgG-λ, and two λ light chain-restricted cases. Serum free light chain analysis in the first patient showed a markedly elevated λ chain (1,429 mg/L), consistent with aggressive disease biology.

Histopathological and Immunophenotypic Features

Definitive diagnosis required histopathological examination of bone marrow and extramedullary tumor biopsies. Common morphological features included:

  1. Cellular pleomorphism: Large, irregular cells with abundant cytoplasm, vesicular nuclei, and prominent nucleoli.
  2. High mitotic activity: Frequent atypical mitotic figures.
  3. Anaplastic morphology: Multinucleated cells, nuclear vacuolization, and immunoblast-like appearance mimicking sarcoma or lymphoma.

Immunohistochemistry confirmed plasma cell origin across all cases, with uniform expression of CD38 and CD138. Three cases showed MUM1 positivity, while CD56 expression was observed in only one patient. Light chain restriction (κ or λ) confirmed clonality. Notably, Ki-67 proliferation indices ranged from 25% to 90%, correlating with disease aggressiveness. The third patient’s abdominal mass biopsy revealed Ki-67 positivity in 85% of cells, alongside anaplastic features such as nuclear hyperchromasia and discohesive growth patterns [Figure 1].

Genetic and Cytogenetic Abnormalities

Fluorescence in situ hybridization (FISH) and karyotyping revealed high-risk genetic profiles:

  • 1q21 amplification: Detected in the first patient, associated with drug resistance and disease progression.
  • del(13q14.3): Identified in two patients, a known poor prognostic marker in MM.
  • del(TP53): Observed in the fourth patient, linked to genomic instability and treatment resistance.
  • IGH rearrangements: Present in the first case, indicative of clonal evolution.

Karyotypic abnormalities in the first patient included del(1q25), monosomy 13 (−13), and monosomy 14 (−14), reflecting complex chromosomal instability. These findings align with prior reports of AM harboring multiple high-risk genetic lesions.

Treatment Response and Outcomes

Therapeutic regimens combined proteasome inhibitors (bortezomib), immunomodulatory agents (thalidomide), and chemotherapy, with variable outcomes:

  1. Case 1: Initial VTD (bortezomib, thalidomide, dexamethasone) and VDD (bortezomib, liposomal doxorubicin, dexamethasone) regimens failed. Partial remission (PR) was achieved with V-DECP (bortezomib, cisplatin, cyclophosphamide, etoposide, dexamethasone), but the patient succumbed to infection and bone marrow suppression within 5 months.
  2. Case 2: No response to VAD (vindesine, epirubicin, dexamethasone). Rapid progression led to death from infection at 3 months.
  3. Case 3: Initial response to nine VTD cycles was followed by aggressive relapse with intraperitoneal masses. Thalidomide-VAD and radiotherapy failed; survival was 3 months post-AM diagnosis.
  4. Case 4: Skull plasmacytoma initially responded to VCD (bortezomib, cyclophosphamide, dexamethasone), but spinal canal recurrence required surgery. Subsequent V-DECP and thalidomide-VAD achieved PR, with survival exceeding 9 months at manuscript submission.

Notably, intensified regimens like V-DECP showed transient efficacy in two patients, suggesting a potential role for alkylator-based combinations. However, treatment-related toxicity, particularly myelosuppression, limited durability of responses.

Diagnostic Challenges and Differential Diagnosis

Distinguishing AM from other malignancies requires integration of clinical, morphological, and immunophenotypic data. Key differentials include:

  1. Plasmablastic lymphoma (PBL): Shares CD138/MUM1 positivity but typically occurs in HIV-positive patients without osteolytic lesions.
  2. Sarcoma: Lacks plasma cell markers (CD38/CD138) and monoclonal protein expression.
  3. Metastatic carcinoma: Expresses epithelial markers (EMA, cytokeratins) absent in AM.

In this series, AM cells were negative for CD20, CD3, CD79a, and PAX5, excluding lymphoid malignancies. Light chain restriction further supported clonal plasma cell origin.

Prognostic Implications and Therapeutic Perspectives

The median survival of 3–5 months in three cases underscores AM’s aggressive biology. Poor prognostic factors included:

  • Extramedullary disease at diagnosis
  • Elevated LDH and β2-microglobulin
  • High Ki-67 indices (>80%)
  • TP53 deletions and 1q21 amplifications

While conventional MM therapies showed limited efficacy, the fourth patient’s prolonged survival with surgical debulking and V-DECP suggests multidisciplinary approaches may improve outcomes. Emerging strategies such as anti-CD38 monoclonal antibodies (daratumumab), BCMA-directed CAR T-cell therapy, and venetoclax (targeting BCL-2 in t(11;14) cases) warrant investigation in AM.

Conclusion

Anaplastic myeloma represents a distinct clinicopathological entity within the plasma cell dyscrasia spectrum. Early recognition of its anaplastic morphology, extramedullary tropism, and high-risk genetic profile is critical for timely intervention. While current therapies remain inadequate, intensified regimens and novel immunotherapies offer cautious optimism. Collaborative efforts to standardize diagnostic criteria and expand therapeutic research are essential to improve outcomes for this rare and lethal malignancy.

doi.org/10.1097/CM9.0000000000000902

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