Trial in patients with newly diagnosed myeloma to evaluate the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy.

Investigational Medicinal Products: Isatuximab, Lenalidomide

1. Randomization: Patients are randomized in one of 2 study arms (IA or IB) before induction therapy. Patients randomized in arm IA will receive 3 cycles RVd (Bortezomib (Velcade®), Lenalidomide (Revlimid®, each cycle is 42 days), Dexamethasone). Patients in arm IB will additionally receive the monoclonal antibody Isatuximab in the 3 cycles RVd. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation).
2. Randomization: Before maintenance treatment patients are randomized in one of 2 study arms (IIA and IIB): Patients in arm IIA receive Lenalidomide maintenance therapy for three years, patients in arm IIB receive additional Isatuximab.

There are two primary objectives:

1. to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity at least 1e-5)
2. to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first.

The duration of the trial for each patients is expected to be 45-48 months (induction and intensification treatment: 6-9 months, 3 months rest between intensification and start of maintenance phase 36 months).

Inclusion Criteria:

1. Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.)

2. Patient is eligible for high dose therapy and autologous stem cell transplantation.

3. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2

   • Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l)
   • Urine light-chain (M-protein) of ≥ 200 mg/24 hours
   • Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal

4. Age 18 - 70 years inclusive

5. WHO performance status 0-2

6. Negative pregnancy test at inclusion (females of childbearing potential)

7. All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.

8. All patients must

   • agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
   • agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist

9. Ability of patient to understand character and individual consequences of the clinical trial

10. Provide written informed consent (must be available before enrolment in the trial)

Exclusion Criteria

1. Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
2. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
3. Plasma cell leukemia
4. Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion
5. Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%
6. Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert's disease), unless related to myeloma.
7. Patients with active or history of hepatitis B or C
8. HIV positivity
9. Patients with active, uncontrolled infections
10. Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
11. Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
12. Patients with a history of active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy
13. Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
14. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
15. Platelet count < 75 x 109/l
16. Haemoglobin < 8.0 g/dl, unless related to myeloma
17. Absolute neutrophil count (ANC) < 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed)
18. Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
19. Unable or unwilling to undergo thromboprophylaxis
20. Pregnancy and lactation
21. Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
22. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

No patients will be allowed to enrol in this trial more than once.

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