This study will assess whether the combination of daratumumab and carfilzomib-based Induction/Consolidation/Maintenance Therapy with ASCT improves the outcome of patients with ultra high-risk, newly diagnosed multiple myeloma

Survival outcomes for patients with newly diagnosed multiple myeloma (MM) have improved substantially in the past decades, due to the introduction of novel therapeutic strategies. Unfortunately, patients with ultra-high-risk MM, including "double-hit" MM, extramedullary MM (EMM), and primary plasma cell leukemia (pPCL), have a significantly worse prognosis and benefit less from current therapeutic strategies. This study aims to investigate whether a treatment regimen combining daratumumab and carfilzomib-based Induction/Consolidation/Maintenance Therapy with autologous stem cell transplantation (ASCT) can improve the survival outcomes of newly diagnosed, transplant-eligible, ultra high-risk multiple myeloma patients. In the study, participants will receive induction therapy with 2-4 cycles of Dara-KRd-PACE, followed by ASCT, 4 cycles of Dara-KRd consolidation, and then maintenance with 12 cycles of Dara-Kd.

Inclusion Criteria:

1. Patients must have newly diagnosed ultra high-risk disease, as defined by one of the following:1)"Double hit"Multiple Myeloma (≥2 adverse markers: t(4;14), t(14;16), t(14;20), 1q21+, del(17p),p53 mutation) ,2)Extramedullary Multiple Myeloma, 3) primary plasma cell leukemia.
2. Patients must be either untreated or have not received systemic MM therapy. Prior bisphosphonates and localized radiation are allowed.
3. Aged 18 years to 70 years.
4. Fit for intensive chemotherapy and autologous stem cell transplant (at clinician's discretion).
5. Eastern Cooperative Oncology Group (ECOG) score ≤2 before induction chemotherapy.

Exclusion Criteria:

1. No evidence of high-risk disease.
2. Primary diagnosis of Waldenstrom's disease/POEMS syndrome/light chain amyloidosis.
3. Received therapy for multiple myeloma.
4. Prior or concurrent invasive malignancies.
5. Eastern Cooperative Oncology Group (ECOG) score >2 before induction chemotherapy.
6. Clinically significant allergies or intolerance to daratumumab,carfilzomib,lenalidomide, dexamethasone, cisPlatin, epirubicin, cyclophosphamide,melphalan, and etoposide.
7. Participants with contraindication to thromboprophylaxis.
8. Any uncontrolled or severe cardiovascular or pulmonary disease.
9. Platelet count < 50,000/μL, absolute neutrophil count <1000/μL, and haemoglobin <60 g/L before induction chemotherapy.
10. Calculated creatinine clearance <30 mL/min, alanine transaminase (ALT) or aspertate aminotransferase (AST) >3 times upper limit of normal (ULN). Bilirubin >2 times ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin >2.0 times ULN).
11. Known to be seropositive for history of HIV or known to have active hepatitis B or hepatitis C.
12. Ejection fraction by echocardiogram (ECHO) ≥ 45%, pulmonary function studies <50% of predicted on mechanical aspects (Forced Expiratory Volume 1 (FEV1), Forced Vital Capacity (FVC) and diffusion capacity (DLCO) < 50% of predicted.
13. Uncontrolled or severe cardiovascular or pulmonary disease, clinically significant cardiac disease, uncontrolled diabetes mellitus, or other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
14. Known/underlying medical conditions that, in the investigator's opinion, would make the administration of the study drug hazardous.
15. Participant is a woman who is pregnant, or breast feeding, or planning to become pregnant while enrolled in this trial or within at least 6 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial or within at least 6 months after the last dose of trial treatment.
16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study.
17. Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
18. Known or suspected of not being able to comply with the study protocol.