Establishment of patient-derived xenograft models in Chinese patients with multiple myeloma: Insights into therapeutic responsiveness and molecular subtyping

Abstract

Multiple myeloma (MM), a malignant hematologic tumor characterized by the proliferation of monoclonal plasma cells, remains incurable with high relapse rates despite advances in treatment. Patient-derived xenograft (PDX) models have emerged as a promising tool for understanding MM's complex pathophysiology and testing therapeutic responses. In this study, we successfully developed PDX models from three patients with MM by subcutaneously engrafting their tumor cells into immunodeficient NCG mice. These models accurately mirrored the clinical drug responses of their corresponding patient cases, exhibiting similar drug sensitivities and resistance patterns. Omics profiling facilitated the alignment of PDX models with specific molecular subgroups identified in current MM research, enhancing the models' clinical relevance. The concordance between PDX models and clinical data confirms the utility of these models in simulating patient-specific responses and advancing personalized treatment strategies. This study validates the effectiveness of PDX models established by subcutaneous engraftment of tumor cells in replicating human disease and treatment responses, thus providing a robust platform for future personalized treatments and development of targeted interventions in Chinese MM patients.

Keywords: Drug responsiveness; Molecular subgroups therapeutic innovations; Multiple myeloma; Omics profiling; Patient-derived xenograft; Subcutaneous engraftment.

Fig. 1

Imaging and Cytological Results of the Patients. (A) A representative computed tomography (CT) image of Case 1, displaying extensive bone destruction in the thoracic vertebrae and sternum. (B) A representative ascites smear from Case 2, illustrating large abnormal plasma cells with foamy cytoplasm, vacuoles, fine chromatin, and visible nucleoli; binucleate plasma cells are also noted. (C) Representative CT images from Case 3 showing extensive destruction of multiple pelvic bones (left panel) and multiple ribs and thoracic vertebrae (right panel). (D) FISH analysis image depicting a normal karyotype, with no deletions of 1q21 or TP53.

Fig. 2

Establishment of Three PDX Models and In Vivo Drug Sensitivity Testing. (A1) Photographs of mice bearing tumors, treated with either vehicle control or the BCD regimen (bortezomib (Bortezomib), dexamethasone, and cyclophosphamide). (A2) Images of tumors harvested from mice treated with either vehicle control or the BCD regimen. (A3) Graph depicting the growth of xenograft tumors in vehicle and BCD treatment groups; data presented as mean ± SE for n = 4 mice per group. **P < 0.01 versus the vehicle group. (B1) Photographs of mice bearing tumors treated with vehicle control or BCD regimen (bortezomib (Bortezomib), dexamethasone, and cyclophosphamide). (B2) Images of tumors collected from subcutaneous xenografts treated with vehicle control or BCD regimen. (B3) Volume growth of xenograft tumors in vehicle and BCD groups. Data are mean ± SE, n = 5 mice per group. (C1) Photographs of tumor-bearing mice treated with vehicle control, BCD regimen (bortezomib (Bortezomib), dexamethasone, and cyclophosphamide), MPT regimen (melphalan, prednisone, and thalidomide), or ILD regimen (ixazomib, lenalidomide, and dexamethasone). (C2) Photos of tumors collected from subcutaneous xenografts treated with vehicle, BCD, MPT, or ILD regimens. (C3) Volume growth of xenograft tumors in vehicle, BCD, MPT, and ILD groups. Data are mean ± SE, n = 3 or 4 mice per group. P < 0.01 vs. the vehicle group.

Fig. 3

Immunohistochemical and Morphological Characterization of Three PDX Models. (A) Immunohistochemical staining of the PDX model from Case 1 showing strong positivity for CD138 (++) and very strong positivity for MUM1 (+++). Hematoxylin and eosin (HE) staining illustrates morphological features characteristic of multiple myeloma. (B) Immunohistochemical staining of the PDX model from Case 2 displaying strong positivity for CD138 (++) and moderate positivity for MUM1 (++). HE staining shows morphological features consistent with multiple myeloma characteristics. (C) Immunohistochemical staining of the PDX model from Case 3 revealing strong positivity for CD138 (++) and very strong positivity for MUM1 (+++). HE staining shows morphological features consistent with multiple myeloma characteristics. (D) Negative control. Liver tissue staining with CD138 and MUM1 was negative, ruling out false positives.

Fig. 4

Omics Data Analysis of Three PDX Models. (A) Case 1 PDX: Omics data analysis revealed multiple copy number variations (CNVs), including notable amplification of the q arm on chromosome 1 and deletion of the q arm on chromosome 13. (B) Case 2 PDX: Abundant CNVs observed, including amplification of the q arm on chromosome 1 and deletion of the q arm on chromosome 13. Additionally, a well-established translocation between chromosome 4 and 14 was identified, supported by fusion data. (C) Case 3 PDX: Sequencing results indicate a solitary deletion on chromosome 6.