Daratumumab for First Line Treatment of Transplant-ineligible Myeloma Patients Followed by Daratumumab Re-treatment at First Relapse

Inclusion Criteria:

1. Signed Written Informed Consent 1.1 Study participants must have signed and dated anIEC approved written informed consent form in accordance with regulatory andinstitutional guidelines. This must be obtained before the performance of anyprotocol-related procedures that are not part of normal study participant care. 1.2 Study participants must be willing and able to comply with scheduled visits,treatment schedule, laboratory tests and other requirements of the study.
2. Target Population 2.1. Untreated patients with multiple myeloma diagnosis to the IMWGdiagnostic criteria 2.2. Subject must have documented multiple myeloma as defined bythe criteria below:

• Monoclonal plasma cells in the bone marrow ≥10% at some point in their diseasehistory or presence of a biopsy proven plasmacytoma.
• Measurable disease as defined by any of the following:
• IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL orurine M-protein level ≥200 mg/24 hours; or
• IgA, IgD, IgE, IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urineM-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma without measurable disease in the serum or theurine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serumImmunoglobulin kappa lambda free light chain ratio.

3. ECOG ≤2
4. Not eligible for autologous transplantation
5. Age 18 years or above
6. Reproductive Status

• Women of childbearing potential (WOCBP) must use appropriate method(s) ofcontraception and must agree to use adequate method to avoid pregnancy for 5months (30 days plus the time required for durvalumab to undergo five half-lives)after the last dose of study drug.
• Appropriate methods of contraception are:
• female sterilization or tubal ligation (at least 6 weeks prior to thestart of the study treatment),
• male sterilization (at least 6 months prior to the start of the studytreatment) and/or
• a combination of a hormonal method of contraception with a barriermethod or/and
• an intrauterine device or system
• Women of childbearing potential must have a negative serum or urine pregnancytest (minimum sensitivity 25 IU/L or equivalent units of β-HCG) within one untiltwo weeks prior to the start of durvalumab at time of neoadjuvant treatment andafter surgery before starting adjuvant treatment.
• Women will be not be considered to be of childbearing potential if they arepost-menopausal and/or underwent surgical sterilization (bilateral oophorectomy,bilateral salpingectomy or hysterectomy). To be considered post-menopausal theappropriate age-specific requirements have to be met:
• Women < 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulating hormonelevels in the post-menopausal range for the institution.
• Women ≥ 50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses > 1 year ago, hadchemotherapy-induced menopause with last menses > 1 year ago.
• Women must not be breastfeeding. Men who are sexually active with WOCBP must useany contraceptive method with a failure rate of less than 1% per year. Menreceiving durvalumab and who are sexually active with WOCBP must be willing toadhere to contraception for a period of 7 month post treatment completion.

Exclusion Criteria:

• Subject has received any multiple myeloma therapy previously except dexamethasone to amaximum cumulative dose of 160mg, emergency radiotherapy or surgery for symptomcontrol
• Participation in other interventional clinial trials
• Subject has known meningeal involvement of multiple myeloma.
• Subject has a history of malignancy (other than multiple myeloma) within 3 yearsbefore the date of Screening. Subject has either of the following:

1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required forsubjects suspected of having COPD and subjects must be excluded if FEV1 is <50% ofpredicted normal.
2. Known moderate or severe persistent asthma, within the past 2 years, uncontrolledasthma of any classification. Note that subjects who currently have controlledintermittent asthma or controlled mild persistent asthma are allowed to participate inthe study.

• Use of drugs with significant interaction with or intolerance to theinvestigational product
• Subject is known to be seropositive for human immunodeficiency virus (HIV)
• active hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or positive HBV DNA)
• Subject has any concurrent medical condition or disease (eg, active systemicinfection) that is likely to interfere with study procedures or results, or thatin the opinion of the investigator would constitute a hazard for participating inthis study.
• Patients has known current symptomatic congestive heart failure (New York HeartAssociation Class III-IV), unstable angina pectoris, or cardiac arrhythmia
• Subject has any of the following laboratory test results during the ScreeningPhase:
• Absolute neutrophil count ≤1.0 × 109/L;
• Platelet count <50 × 109/L
• Aspartate aminotransferase (AST) or alanine aminotransferase level (ALT) ≥2.5 times the upper limit of normal (ULN)
• Alkaline phosphatase level ≥2.5 × ULN
• Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct × ULN)
• Pregnant women and nursing mothers, or a women who is planning to become pregnantwhile enrolled in this study or within 3 month after the last dose of daratumumab
• Failure to use highly-effective contraceptive methods. The followingcontraceptive methods with a Pearl Index lower than 1% are regarded ashighly-effective:
• Oral hormonal contraception ('pill')
• Dermal hormonal contraception
• Vaginal hormonal contraception (NuvaRing®)
• Contraceptive plaster
• Long-acting injectable contraceptives
• Implants that release progesterone (Implanon®)
• Tubal ligation (female sterilisation)
• Intrauterine devices that release hormones (hormone spiral)
• Double barrier methods This means that the following are not regarded assafe: condom plus spermicide, simple barrier methods (vaginal pessaries,condom, female condoms), copper spirals, the rhythm method, basaltemperature method, and the withdrawal method (coitus interruptus).
• Persons with any kind of dependency on the principal investigator or employed bythe sponsor or principal investigator
• Legally incapictated persons
• Subject is known or suspected of not being able to comply with the studyprotocol(eg, because of alcoholism, drug dependency, or psychological disorder)or the subject has any condition for which, in the opinion of the investigator,participation would not be in the best interest of the subject (eg, compromisetheir well-being) or that could prevent, limit, or confound theprotocol-specified assessments.
• Persons held in an institution by legal or official order