Study to Compare VMP With HDM Followed by VRD Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma (HO95)

Stichting Hemato-Oncologie voor Volwassenen Nederland

Status and phase: Completed; Phase 3

Conditions: Multiple Myeloma

Treatments: Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD); Drug: Bortezomib, Melphalan, Prednisone (VMP); Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT01208766

EMN02 (Other Identifier)

HOVON 95 MM

2009-017903-28 (EudraCT Number)

Details and patient eligibility

About

Study phase: phase III

Study objective:

• Comparison of Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed autologous stem cell transplantation (ASCT)
• Comparison of Bortezomib, Lenalidomide, Dexamethasone(VRD) as consolidation versus no consolidation
• Comparison of single versus tandem high dose Melphalan with ASCT

Patient population: Patients with symptomatic multiple myeloma,previously untreated, ISS stages 1-3, age 18-65 years inclusive

Study design: Prospective, multicenter, intergroup, randomized

Duration of treatment: Expected duration of induction, stem cell collection and intensification is 6 - 9 months. Consolidation with VRD will last 2 months Maintenance therapy with Lenalidomide will be given until relapse. All patients will be followed until 10 years after registration.

Enrollment: 1,503 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS (see appendix A), i.e. at least one of the CRAB criteria should be present;
• Measurable disease as defined by the presence of M-protein in serum or urine (serum M-protein> 10 g/l or urine M-protein > 200 mg/24 hours), or abnormal free light chain ratio;
• Age 18-65 years inclusive;
• WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by comorbid conditions);
• Negative pregnancy test at inclusion if applicable;
• Written informed consent.

Inclusion for randomisation 1:

• WHO performance 0-2;
• Bilirubin and transaminases < 2.5 times the upper limit of normal values;
• A suitable stem cell graft containing at least 4 x 106 CD34+ cells/kg (or according to national guidelines).

Inclusion for randomisation 2:

• Bilirubin and transaminases < 2.5 times the upper limit of normal values;
• ANC >= 0.5 x 109/l and platelets > 20 x 10^9/l;
• Patient is able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.

Exclusion criteria

• Known intolerance of Boron;
• Systemic AL amyloidosis;
• Primary Plasmacell Leukemia;
• Non-secretory MM;
• Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
• Severe cardiac dysfunction (NYHA classification II-IV);
• Significant hepatic dysfunction, unless related to myeloma;
• Patients with GFR <15 ml/min,
• Patients known to be HIV-positive;
• Patients with active, uncontrolled infections;
• Patients with neuropathy, CTC grade 2 or higher;
• Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
• Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women);
• Lactating women.

Exclusion for randomisation 1:

• Severe pulmonary, neurologic, or psychiatric disease;
• CTCAE grade 3-4 polyneuropathy during Bortezomib treatment;
• Allogeneic Stem Cell Transplantation (Allo SCT) planned;
• Progressive disease.'

Exclusion for randomisation 2:

• Progressive disease;
• Neuropathy, except CTCAE grade 1;
• CTCAE grade 3-4 polyneuropathy during Bortezomib treatment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,503 participants in 4 patient groups

R1: 4 cycles Bortezomib, Melphalan, Prednisone (VMP)

Active Comparator group

Description:

All patients randomized to VMP treatment, will be treated with Bortezomib, Melphalan, Prednisone(VMP, 4 cycles) and will start intensification with VMP between 4 and 6 weeks after stem cell collection.

Treatment:

Drug: Bortezomib, Melphalan, Prednisone (VMP)

R1: 1 (2) cycle(s) HDM

Experimental group

Description:

All patients randomized to intensification with High Dose Melphalan will start intensification with HDM (in hospitals with a policy of double intensification, patients will be randomized between VMP, 1 HDM and 2 HDM) between 4 and 6 weeks after stem cell collection.

Treatment:

Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)

R2: none

No Intervention group

Description:

No consolidation, patients will continue to Lenalidomide maintenance.

R2: 2 cycles of VRD

Experimental group

Description:

In patients randomized to consolidation treatment, 2 cycles of Bortezomib, Lenalidomide,Dexamethasone (VRD) will start at 8 weeks after the end of the last course of VMP or HDM.

Treatment:

Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)