Inclusion
1.Male or female patients aged 18 years or older.
2.Patient has newly diagnosed treatment naïve MM as per the IMWG criteria and is planned to proceed to high-dose chemotherapy conditioned ASCT as part of first-line treatment.
3.Treatment naïve apart from a limited exposure to corticosteroids and/or radiotherapy for urgent symptom control.
4.No contraindication to the use of any of the study drugs.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
6.Subject has measurable disease at screening, defined as at least one of the following:
- Serum M-protein >= 5 g/L, OR
- Urine M-protein >= 200 mg in 24-hours, OR
- Serum immunoglobulin free light chain (FLC) >= 100 mg/L provided serum FLC ratio abnormal.
7.Subject must meet the following laboratory parameters, per laboratory reference range:
- Absolute neutrophil count (ANC) >= 1 x 10^9/L within 2 weeks prior to starting induction. Subjects may use growth factor support to achieve ANC eligibility criteria.
- Platelet count >= 50 x 109/L, within 2 weeks prior to starting induction. For subjects with > 50% myeloma involvement in the bone marrow, a platelet count of >= 30 x10^9/L within 2 weeks prior to starting induction is allowed. Subjects cannot receive a platelet transfusion within 72 hours prior to the platelet count used for eligibility.
- Haemoglobin >= 80 g/L, within 2 weeks prior to starting induction. Subjects may receive RBC transfusions in accordance with institutional guidelines to meet this criterion.
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <= 3 × upper limit of normal range (ULN).
- Total bilirubin <= 1.5 x ULN (unless bilirubin rise is due to Gilbert syndrome or of non-hepatic origin).
- CrCl >= 30 mL/minute (min), measured by 24-hour urine collection or calculated using Cockcroft-Gault formula:
CrCl = ((140 – age in years) × weight in kg × 0.85 if female) / (72 × serum creatinine in mg/dL)
8.Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures.
9.If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation at least 3 months before study participation, bilateral oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and 90 days after last dose of study drug.
Exclusion
1.Subject has any of the following conditions:
- Non-secretory or oligo-secretory MM.
- Active plasma cell leukemia i.e., either 20% of peripheral white blood cells comprised of plasma cells or > 2.0 × 109/L) circulating plasma cells by standard differential.
- Waldenström's macroglobulinemia.
- Amyloidosis.
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- Subject is known to be positive for Human Immunodeficiency Virus (HIV)
- Significant cardiovascular disease, including uncontrolled angina, severe or uncontrolled arrhythmia, recent myocardial infarction within 6 months of induction, or congestive heart failure New York Heart Association (NYHA) Class >= 3.
- Major surgery within 4 weeks prior to starting induction.
- Uncontrolled and/or active systemic infections (viral, bacterial or fungal).
- Chronic hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
- Peripheral neuropathy >= Grade 3 or >= Grade 2 with pain within 2 weeks prior to starting induction.
- Uncontrolled diabetes or uncontrolled hypertension within 14 days prior to starting induction.
- Any other medical condition that, in the opinion of the Investigator, would adversely affect the subject's participation in the study.
2.Subject has a history of other active malignancies, including myelodysplastic syndrome (MDS), within the past 3 years prior to study entry, with the following exceptions:
- Adequately treated in situ carcinoma of the cervix uteri or the breast
- Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
- Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment
- Previous malignancy with no evidence of disease, confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study
3.Subject has a hypersensitivity or allergy to any of the components of study therapy including Venetoclax, Bortezomib, boron, mannitol, or Dexamethasone.
4.Subject has received any prior anti-MM with the exception of Dexamethasone (total dose not exceeding 160mg) or localized radiotherapy for the emergency management of newly diagnosed MM.
5.Subject has received a strong or moderate CYP3A inhibitor or inducer within 1 week prior to commencing study treatment.
6.Administration or consumption of grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville orange) or star fruit within 3 days prior to the first dose of study drug.