This protocol is a phase II multi­center, ran­dom­ized, open label study designed to assess the efficacy and safety of dara­tu­mu­mab com­bined with bor­tez­o­mib, cyclophosphamide and dexa­meth­a­sone (Dara-VCd) versus the association of bor­tez­o­mib, thalido­mide and dexa­meth­a­sone (VTd) as pre trans­plant induction and post trans­plant consolidation, followed by main­te­nance with ixazomib alone or in com­bi­na­tion with dara­tu­mu­mab, in newly diag­nosed multiple myeloma (MM) patients eli­gible for au­tol­o­gous stem cell trans­plan­ta­tion.

Patients enrolled in the Dara-VCd arm will receive: 4 cycles of dara­tu­mu­mab-bortezomib-cyclophosphamide-dexamethasone induction, followed by trans­plan­ta­tion and 2 cycles of dara­tu­mu­mab-bortezomib-cyclophosphamide-dexamethasone consolidation. The choice of cyclophosphamide in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone is suggested by the better safety profile of cyclophosphamide, in comparison with thalido­mide and the efficacy of the alkylator agent, when com­bined with bor­tez­o­mib.

Once-weekly bor­tez­o­mib seems to be equally effective and better tolerated than the standard twice weekly schedule. The out­comes and response rate did not appear to be affected by the bor­tez­o­mib dosing schedule.

Patients enrolled in the VTd arm will receive: 4 cycles of bor­tez­o­mib-thalidomide-dexamethasone induction, followed by au­tol­o­gous trans­plan­ta­tion and 2 cycles of bor­tez­o­mib-thalidomide dexa­meth­a­sone as consolidation. The VTd drug association is the current standard first line induction ther­apy for multiple myeloma patients who are eli­gible to stem cell trans­plan­ta­tion.

At the end of consolidation phase patients with at least a partial response (≥ PR) will be rerandomized (assigned by chance) to one of 2 treat­ment groups to receive main­te­nance treat­ment with ixazomib alone or in com­bi­na­tion with dara­tu­mu­mab. Patients will receive treat­ment until any sign of pro­gres­sion or intolerance, up to 24 months.

Enrollment status: Not yet recruiting.
Estimated start date: April 1, 2019

Countries with trial sites (# of sites): Czechia (1), Greece (1), Ireland (1), Italy (1)

Trial IDs: NCT03896737 and EMN18.

Criteria for participating in the trial:

Inclusion Criteria:

• Patient at least 18 years of age and ≤ 65 years.
• Patient eli­gible for au­tol­o­gous stem cell trans­plan­ta­tion (ASCT).
• LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not avail­able.
• Newly diag­nosed multiple myeloma patient.
• Patient has given voluntary written informed consent before per­for­mance of any study related procedure not part of standard medical care, with the under­stand­ing that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Patient with documented multiple myeloma and measurable disease as defined by:
  • Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
  • Measurable disease as defined by at least one of the fol­low­ing:Serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma: Serum immuno­glob­u­lin free light chain ≥10 mg/dL and ab­nor­mal serum immuno­glob­u­lin kappa lambda free light chain ratio.
• Evidence of end organ damage/presence of bio­markers of malig­nan­cies, specifically:
  • Hypercalcaemia: serum cal­cium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
  • Renal insufficiency: creatinine clearance (CLcr)177 μmol/L (>2 mg/dL)
  • Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value
  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT.
  • If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
• Any one or more of the fol­low­ing bio­markers of malig­nan­cy:
  • Clonal bone marrow plasma cell per­cent­age ≥ 60% (clonality should be estab­lish­ed by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence.
  • Bone marrow plasma cell per­cent­age should preferably be esti­mated from a core biopsy specimen; in case of a disparity be­tween the aspirate and core biopsy, the highest value should be used)
  • Involved:uninvolved serum free light chain ration ≥ 100 (values based on the serum Freelite assay. The involved free light chain must be ≥100 mg/L)
  • > 1 focal lesion on MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size)
• Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.
• Women of childbearing poten­tial must commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously. This in­cludes one highly effective form of con­tra­cep­tion (tubal ligation, intrauterine device, hormonal [birth control pills, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one addi­tional effective con­tra­cep­tive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing through 90 days after the last dose of study drug. Reliable con­tra­cep­tion is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral ophorectomy.
• Male patient agrees to use an acceptable method for con­tra­cep­tion (i.e., condom or abstinence) during study drug ther­apy (including dose inter­rup­tion) and for 90 days after the last dose of study drug.
• Patient with an ECOG per­for­mance status score of 0, 1, or 2 or Karnofsky per­for­mance status ≥ 60%.
• Pretreatment clin­i­cal laboratory values within 30 days of enrolment:
• Platelet count ≥75 x 109/L;
• Absolute neu­tro­phil count (ANC) ≥ 1 x 109/L (G-CSF use is permitted);
• Corrected serum cal­cium 3 months.

Exclusion Criteria:

• Patient with a diag­nosis of pri­mary amyloidosis, mono­clonal gam­mop­athy of undetermined sig­nif­i­cance, smol­der­ing MM or PCL. Monoclonal gam­mop­athy of undetermined sig­nif­i­cance is defined by presence of serum M-protein 2×109/L in periph­eral blood or a periph­eral blood plasmacytosis >20%
• Patient with a diag­nosis of Waldenström's disease, or other con­di­tions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
• Patient has prior or current systemic ther­apy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexa­meth­a­sone 40 mg/day for a maximum 4 days) of corticosteroids before treat­ment.
• Patient has periph­eral neu­rop­athy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0.
• Patient is exhibiting clin­i­cal signs of meningeal involvement of multiple myeloma.
• Clinical active infectious hepatitis type A, B, C or HIV.
• Subject has known chronic obstructive pul­mo­nary disease (COPD) (defined as a forced expiratory volume in 1 second [FEV1] <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. Subjects with known or sus­pected COPD or asthma must have a FEV1 test during screen­ing.
• Evidence of current uncontrolled cardiovascular con­di­tions, in­­clud­ing uncontrolled hyper­tension, uncontrolled cardiac arrhythmias, symp­tomatic congestive heart failure, unstable angina, or myo­cardial infarction within the past 6 months.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
• Contraindication to any of the required concomitant drugs or sup­port­ive treat­ments.
• Pregnant or lactating females.

Trial locations:

Czechia

University Hospital Ostrava (not yet recruiting)
Ostrava, Czechia, 708 52

Greece

General Hospital of Athens "Alexandra" (not yet recruiting)
Athens, Greece, 115 28

Ireland

University Hospital Galway (not yet recruiting)
Galway, Ireland, H91 YR71

Italy

A.O.U. Maggiore della Carità di Novara (not yet recruiting)
Novara, Italy, 28100

For addi­tional in­for­ma­tion about this trial, see its page at ClinicalTrials.Gov.