The TG01 Study With TG01/QS-21 Vaccine in Patients With High-risk Smouldering Multiple Myeloma and Multiple Myeloma

Inclusion Criteria:

• Male or female patients ≥ 18 years of age
• RAS mutation (KRAS/NRAS codon 12/13 mutation) detected on archival or fresh bonemarrow material with VariantPlex Myeloid Panel
• Confirmed diagnosis of high-risk smoldering multiple myeloma (SMM) according to IMWGcriteria (30) and high-risk criteria as listed up below OR confirmed diagnosis ofmultiple myeloma (MM) according to IMWG criteria and measurable disease following ≥ 1 line of treatment
• In patients with high-risk SMM at least 2 of 3 following abnormalities, based onlaboratory data obtained at screening must be fulfilled:

1. Serum M-protein >20 g/L.
2. Serum involved/uninvolved FLC ratio >20.
3. BMPC >20%. OR presence of ≥10% BMPC and at least one of the following based onlaboratory data obtained at screening:

• Serum M-protein ≥30 g/L (If IgA, IgA ≥20g/L)
• Serum involved/uninvolved FLC ratio ≥8 (but <100)
• Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1uninvolved Ig isotype (Only IgG, IgA and IgM will be considered)
• Progressive increase in Serum M-protein level (evolving type of SMM) definedas an increase of Serum M-protein ≥10% in the last 12 months beforeenrolment in the study. This increase must be consistent from one to anothersample (i.e., no decrease observed between 2 increased Serum M-proteinvalues)
• Both high-risk SMM and MM patients must have evidence of measurable disease inaccordance with IMWG criteria
• If patient with MM was eligible for ASCT, ASCT must have been performed, and patientscannot be enrolled until 3 months after ASCT
• Patient should not be expected to require immediate, subsequent line of treatment forat least 2 months
• Patient has not had reduction of clonal plasma cell markers for last two cycles (lasttwo months if off treatment). If a patient had no reduction during the last two cyclesof induction before ASCT, the patient can be enrolled, provided 3 months after ASCT
• Following ASCT, the patient cannot be enrolled without having tried lenalidomidemaintenance given at standard doses for at least two cycles, if the clonal markers hada reduction during the last 2 cycles of induction treatment. Lenalidomide will bestopped when entering the study
• ECOG performance status 0-1
• Female patients of child-bearing potential (FCBP) must have negative serum pregnancytest at Screening and agree to use a highly effective method of contraception duringtreatment and for 3 months following last dose of drug.
• Male patients must use an effective barrier method of contraception during treatmentand for 3 months following the last dose if sexually active with a FCBP.
• Ability to provide written informed consent and can understand and comply with therequirements of the study

Exclusion Criteria:

• Pregnant or lactating women or women without a pregnancy test at baseline (postmenopausal women must have been amenorrhoeic for at least 12 months to beconsidered of non-childbearing potential)
• Medical conditions such as but not limited to:

1. Any uncontrolled infection
2. Uncontrolled cardiac failure classification III or IV (NYHA)
3. Uncontrolled systemic and gastro-intestinal inflammatory conditions
4. History of adverse reactions to vaccines

• Active malignancy with worse prognosis than multiple myeloma
• Likely to require treatment intervention for multiple myeloma within two months ofstart of treatment with TG01/QS-21
• Known history of positive tests for HIV/AIDS, hepatitis B or C
• Planned to receive yellow fever or other live (attenuated) vaccines during the courseof study
• Known hypersensitivity to QS-21.
• Only participants who are able to consent will be included in the study.