MRD-guided treatment for high-risk newly diagnosed multiple myeloma

Inclusion Criteria:

1. patients with newly diagnosed multiple myeloma（may receive up to one course of a bortezomib-containing regimen for the urgent relief of bone pain, renal insufficiency, and hypercalcemia）;
2. age ≥ 18 years;
3. have an evaluable lesion; serum M protein ≥ 10 g/L, or urinary light chain ≥ 200 mg/24h, or involved serum free light chain (FLC) ≥ 100 mg/L, and an extramedullary measurable tumor SPD: The diameter of cutaneous nodules can be measured with a manual tape, and extramedullary tumor SPD of extramedullary tumors is measured on a CT scan as the product of the largest dimension of the largest pendulous diameter of the lesion (minimum diameter of 5mm or more), parosteal lesions need to be in soft tissue outside the bone cavity to meet the above criteria. MRI measures the size of an extramedullary tumor as the product of the maximum pendulous diameter at the level of the largest area of the tumor (minimum diameter of 5mm or more)
4. ECOG physical status score ≤ 2
5. or have a high-risk karyotype abnormality recognized in mSMART or NCCN guidelines: t(4;14), t(14;16), t(14;20), Del(17p) or -17 and/or TP53 mutation, Del(1p32), 1q21 gain(amp), the coexistence of two adverse karyotypes as a double hit,and triple hit similarly defined
6. or R-ISS stage 3
7. or combined plasma cell leukemia (defined as peripheral blood sorted clonal plasma cells ≥ 5%)
8. bone marrow function: neutrophils ≥ 1.0 x 109 /L, platelets ≥ 70 x 109 /L (if bone marrow plasma cells ≥ 50%, platelets ≥ 50 x 109 /L)
9. AST, ALT, ALP ≤ 3 × upper limit of normal value, serum bilirubin ≤ 2 times upper limit of normal value;
10. serum creatinine clearance ≥ 40mL/min
11. negative pregnancy test for women of childbearing age; patients and their spouses must agree to use effective contraception during the treatment period and the following one-year period;
12. Signed informed consent for chemotherapy. A legal representative will sign the informed consent form if the subject is unable to sign it due to impaired consciousness, paralysis of the subject's upper limbs, or inability to write.

Exclusion Criteria:

1. monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, primary light chain amyloidosis with organ involvement.
2. diagnosed or treated for another malignancy prior to pre-registration ≤ 1 year or previously diagnosed with another malignancy with evidence of any residual disease being treated.
3. other co-morbidities that would interfere with the subject's ability to participate in the trial, e.g., uncontrolled infections, uncompensated cardiac or pulmonary disease, other synchronized chemotherapy or any adjuvant therapy considered investigational.
4. peripheral neuropathy ≥ grade 1-2 with pain on clinical examination within 30 days prior to pre-registration
5. major surgery within 14 days prior to pre-registration
6. evidence of current uncontrolled cardiovascular disease, including uncontrolled hypertension (hypertension defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg on 3 non-same day office measurements without antihypertensive medication), arrhythmias (prolonged QT interval, ventricular tachycardia, ventricular flutter, ventricular fibrillation, frequent ventricular premature beats (24 h ventricular premature load ≥ 15% of the total number of heart beats, atrioventricular block, heart rate \<30-40 bpm), congestive heart failure, unstable angina or myocardial infarction. New York Heart Association (NYHA) Class III, IV heart failure.
7. Participants with known chronic obstructive pulmonary disease (COPD) (defined as exertional expiratory volume in 1 second \[FEV1\] \<50% of predicted normal volume), persistent asthma, or a history of asthma within the past 2 years (controlled intermittent asthma or mild persistent asthma is permitted). Participants with known or suspected COPD must have FEV1 testing during screening.
8. moderate/severe renal insufficiency: creatinine clearance \< 40mL/min.
9. known human immunodeficiency virus (HIV) positivity.
10. Hepatitis B seropositivity (defined as a positive Hepatitis B surface antigen \[HBsAg\] test). Subjects whose infection has resolved (i.e., subjects who are HBsAg negative but positive for Hepatitis B Core Antigen Antibody \[anti-HBc\] and/or Hepatitis B Surface Antigen Antibody \[anti-HBs\]) must be screened for Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) levels using real-time Polymerase Chain Reaction (PCR). PCR-positive subjects will be excluded. Exception:Subjects with serologic results suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR.
11. known or suspected active hepatitis C infection.
12. any medical or psychiatric condition that, in the opinion of the investigator, may interfere with the completion of treatment under this protocol.
13. known allergy or intolerance to the test drug.
14. inability to comply with the protocol/procedure.
15. Subjects will be ineligible to participate in the trial because the genotoxic, mutagenic, and teratogenic effects of the investigational drug(s) involved in this trial on the developing fetus and neonate are unknown if any of the following conditions are present at the time of screening: Pregnant women, lactating mothers, males or females of childbearing potential who refuse adequate contraception (as per protocol).