Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and autologous stem cell transplantation (ASCT) remain the backbone of multiple myeloma (MM) treatment. However, outcomes in patients with high-risk cytogenetic abnormalities remain poor, particularly in those with ultra–high-risk disease defined by the presence of two or more high-risk cytogenetic abnormalities (HRCAs).
These patients often experience rapid disease progression and short survival despite modern therapies. Improving outcomes in this subgroup remains a major unmet clinical challenge. In recent years, CAR-T cell therapy has emerged as a promising strategy to overcome therapeutic resistance in high-risk MM.
Patient Information
A 53-year-old female presented with progressive fatigue, pallor, and worsening dyspnea over two months. Laboratory evaluation revealed severe anemia (Hb 47 g/L), elevated globulins, and markedly increased serum immunoglobulin A (IgA-κ type).
Bone marrow examination demonstrated:
- Plasma cell infiltration >60% (up to >90% in biopsy)
- Abnormal plasma cell population (43.63% by flow cytometry)
- Monoclonal IgA-κ disease
Cytogenetic analysis revealed multiple high-risk abnormalities:
- t(14;16) positive (51%)
- 1q21 gain
- TP53 deletion
- RB-1/LAMP1 deletion
PET/CT showed diffuse bone marrow involvement with osteolytic lesions.
Final diagnosis:
Ultra–high-risk multiple myeloma
(DS stage IIIA, ISS stage III, R-ISS stage III, R2-ISS stage IV)
Prior Treatment History
The patient received multiple standard regimens:
- VCD (bortezomib + cyclophosphamide + dexamethasone)
- VRD (bortezomib + lenalidomide + dexamethasone)
- Daratumumab-based therapy
Despite achieving an initial complete response (CR), the patient remained at extremely high risk of early relapse due to adverse cytogenetics.
Treatment Strategy: ASCT Combined with BCMA CAR-T Therapy
Given the ultra–high-risk disease profile, a multidisciplinary decision was made to proceed with:
ASCT followed by BCMA-targeted CAR-T cell therapy (Equecabtagene Autoleucel)
This combined strategy aimed to:
- Deepen remission
- Eradicate minimal residual disease (MRD)
- Improve immune reconstitution
- Prolong long-term survival
Treatment Timeline
- April 26, 2024: Peripheral blood stem cell collection
- May–June 2024: Mobilization with cyclophosphamide + G-CSF + plerixafor
- September 3, 2024: Conditioning with melphalan (280 mg over 2 days)
- September 6, 2024: Autologous stem cell infusion (ASCT)
- September 9, 2024: BCMA CAR-T infusion (1 × 10⁶ cells/kg)
Clinical Course and Safety
After CAR-T infusion, the patient developed:
- Grade 1 cytokine release syndrome (CRS)
- Fever (38°C) on day +5
- No hypotension or hypoxia
- ICE score: 10/10
Management included:
- Broad-spectrum antibiotics
- Antipyretics
- Dexamethasone (day +7)
Symptoms resolved rapidly, and no ICANS occurred.
CAR-T cells demonstrated predictable expansion, peaking on day +10 before gradually declining.
Clinical Outcomes
- 1 month post-CAR-T: Stringent complete response (sCR) with MRD negativity
- 3 months post-CAR-T: Sustained sCR with MRD negativity
- 18 months post-ASCT + CAR-T: Continued sCR with ongoing maintenance therapy (bortezomib + lenalidomide)
The patient remains in deep remission with durable disease control.
Expert Commentary
Treating Physician Perspective (Dr. Zhang Yan, Jiangnan University Affiliated Hospital)
This case represents an ultra–high-risk MM patient with multiple adverse cytogenetic lesions, including t(14;16), 1q21 gain, and TP53 deletion, all associated with poor prognosis and early relapse.
Although standard induction therapy achieved initial remission, the risk of recurrence remained extremely high. Therefore, deeper consolidation strategies were required.
Recent evidence supports CAR-T therapy as a highly effective option for high-risk MM, and it has been incorporated into major clinical guidelines such as the 2026 CSCO Plasma Cell Disease Guidelines.
The combination of ASCT and BCMA CAR-T in this patient resulted in:
- Rapid hematologic recovery
- Only grade 1 CRS
- Sustained MRD-negative sCR for 18+ months
This suggests that ASCT combined with CAR-T may effectively overcome the adverse impact of ultra–high-risk cytogenetics.
Expert Review (Dr. Hua Haiying)
Although ASCT remains a cornerstone for transplant-eligible MM patients, relapse is nearly inevitable in ultra–high-risk disease, with expected survival often less than two years.
Even with quadruplet regimens or daratumumab-based therapy, patients with ≥2 HRCAs continue to have poor outcomes.
Emerging data from BCMA CAR-T studies demonstrate promising results, including high MRD negativity rates and prolonged progression-free survival in high-risk populations.
A prospective study combining ASCT with sequential CD19 and BCMA CAR-T consolidation showed:
- ORR: 100%
- MRD negativity >2 years in 70% of patients
- Excellent tolerability with no ICANS
This case further supports the potential of ASCT + CAR-T as a transformative strategy for ultra–high-risk MM.
ASCT combined with BCMA-targeted CAR-T therapy achieved deep and durable remission in a patient with ultra–high-risk multiple myeloma, with sustained sCR and MRD negativity for over 18 months.
This case highlights a promising treatment paradigm that may overcome the historically poor prognosis associated with complex cytogenetic abnormalities in MM.
