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

• ClinicalTrials.gov Identifier: NCT01208766
• Recruitment Status: Active, not recruiting
• First Posted: September 24, 2010
• Last Update Posted: August 22, 2023
• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Collaborators: Stichting European Myeloma Network; Gruppo Italiano Malattie EMatologiche dell'Adulto; DSMM (Deutsche Studiengruppe Multiples Myelom); NMSG (Nordic Myeloma Study Group); Central European Myeloma Study Group
• Information provided by (Responsible Party): Stichting Hemato-Oncologie voor Volwassenen Nederland

Tracking Information

• First Submitted Date: September 23, 2010
• First Posted Date: September 24, 2010
• Last Update Posted Date: August 22, 2023
• Actual Study Start Date: January 2011
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 17, 2023)

• For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first). [ Time Frame: end of trial (last patient last visit) ]
  For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first).
• For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first [ Time Frame: end of trial (last patient last visit) ]
  For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first
• For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first [ Time Frame: end of trial (last patient last visit) ]
  For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first

Original Primary Outcome Measures (submitted: September 23, 2010)

• For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first). [ Time Frame: end of trial ]
• For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first [ Time Frame: end of trial ]
• For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first [ Time Frame: end of trial ]

Current Secondary Outcome Measures (submitted: August 17, 2023)

• Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive. [ Time Frame: end of trial (last patient last visit) ]
  Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive.
• Toxicity [ Time Frame: End of trial (last patient last visit) ]
  Toxicity
• Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment. [ Time Frame: end of trial (last patient last visit) ]
  Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment.

Original Secondary Outcome Measures (submitted: September 23, 2010)

• Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment [ Time Frame: end of trial ]
• Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive. [ Time Frame: end of trial ]
• Toxicity [ Time Frame: End of trial ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Compare VMP With HDM Followed by VRD Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma
• Official Title: A Randomized Phase III Study to Compare Bortezomib, Melphalan, Prednisone (VMP) With High Dose Melphalan Followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Bortezomib, Melphalan, Prednisone (VMP)
  • Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11,22,25,29,32
  • Melphalan _ 9 mg/m² _ p.o. _ days 1-4
  • Prednisone _ 60 mg/m² _ p.o. _ days 1-4
• Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)

  - Melphalan _ 100 mg/m² _ i.v. rapid infusion _ -3, -2*

  *Patients with renal insufficiency 100 mg/m2 only at day -3

  If a patient is randomized to receive 2 x HDM a second course of High Dose Melphalan may be administered between 2 and 3 months after the first course when the patient achieved at least PR.

• Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)
  • Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11
  • Lenalidomide _ 25 mg _ p.o. _ days 1-21
  • Dexamethasone _ 20 mg _ p.o. _ days 1,2,4,5,8,9,11,12

Study Arms

• Active Comparator: R1: 4 cycles Bortezomib, Melphalan, Prednisone (VMP)
  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.
  Intervention: Drug: Bortezomib, Melphalan, Prednisone (VMP)
• Experimental: R1: 1 (2) cycle(s) HDM
  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.
  Intervention: Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)
• No Intervention: R2: none
  No consolidation, patients will continue to Lenalidomide maintenance.
• Experimental: R2: 2 cycles of VRD
  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.
  Intervention: Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)

Publications *

• Schmitz A, Brondum RF, Johnsen HE, Mellqvist UH, Waage A, Gimsing P, Op Bruinink DH, van der Velden V, van der Holt B, Hansson M, Andersen NF, Frolund UC, Helleberg C, Schjesvold FH, Ahlberg L, Gulbrandsen N, Andreasson B, Lauri B, Haukas E, Bodker JS, Roug AS, Bogsted M, Severinsen MT, Gregersen H, Abildgaard N, Sonneveld P, Dybkaer K. Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial. BMC Cancer. 2022 Feb 5;22(1):147. doi: 10.1186/s12885-022-09184-1.
• Sonneveld P, Dimopoulos MA, Beksac M, van der Holt B, Aquino S, Ludwig H, Zweegman S, Zander T, Zamagni E, Wester R, Hajek R, Pantani L, Dozza L, Gay F, Cafro A, De Rosa L, Morelli A, Gregersen H, Gulbrandsen N, Cornelisse P, Troia R, Oliva S, van de Velden V, Wu K, Ypma PF, Bos G, Levin MD, Pour L, Driessen C, Broijl A, Croockewit A, Minnema MC, Waage A, Hveding C, van de Donk NWCJ, Offidani M, Palumbo GA, Spencer A, Boccadoro M, Cavo M. Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2021 Nov 10;39(32):3613-3622. doi: 10.1200/JCO.21.01045. Epub 2021 Sep 14.
• Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, Dozza L, van der Holt B, Zweegman S, Oliva S, van der Velden VHJ, Zamagni E, Palumbo GA, Patriarca F, Montefusco V, Galli M, Maisnar V, Gamberi B, Hansson M, Belotti A, Pour L, Ypma P, Grasso M, Croockewit A, Ballanti S, Offidani M, Vincelli ID, Zambello R, Liberati AM, Andersen NF, Broijl A, Troia R, Pascarella A, Benevolo G, Levin MD, Bos G, Ludwig H, Aquino S, Morelli AM, Wu KL, Boersma R, Hajek R, Durian M, von dem Borne PA, Caravita di Toritto T, Zander T, Driessen C, Specchia G, Waage A, Gimsing P, Mellqvist UH, van Marwijk Kooy M, Minnema M, Mandigers C, Cafro AM, Palmas A, Carvalho S, Spencer A, Boccadoro M, Sonneveld P. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020 Jun;7(6):e456-e468. doi: 10.1016/S2352-3026(20)30099-5. Epub 2020 Apr 30. Erratum In: Lancet Haematol. 2020 Jun;7(6):e443. Lancet Haematol. 2020 Nov;7(11):e785.
• Gambella M, Omede P, Spada S, Muccio VE, Gilestro M, Saraci E, Grammatico S, Larocca A, Conticello C, Bernardini A, Gamberi B, Troia R, Liberati AM, Offidani M, Rocci A, Palumbo A, Cavo M, Sonneveld P, Boccadoro M, Oliva S. Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: A pooled analysis. Cancer. 2019 Mar 1;125(5):750-760. doi: 10.1002/cncr.31854. Epub 2018 Dec 18.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 22, 2021): 1503
• Original Estimated Enrollment (submitted: September 23, 2010): 1500
• Estimated Study Completion Date: April 2024
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Czechia, Denmark, Finland, Greece, Hungary, Italy, Luxembourg, Netherlands, Norway, Portugal, Sweden, Switzerland, Turkey

Administrative Information

• NCT Number: NCT01208766
• Other Study ID Numbers: HOVON 95 MM; 2009-017903-28 ( EudraCT Number ); EMN02 ( Other Identifier: European Myeloma Network )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Original Responsible Party: Prof. P. Sonneveld, HOVON
• Current Study Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Original Study Sponsor: Same as current

Collaborators

• Stichting European Myeloma Network
• Gruppo Italiano Malattie EMatologiche dell'Adulto
• DSMM (Deutsche Studiengruppe Multiples Myelom)
• NMSG (Nordic Myeloma Study Group)
• Central European Myeloma Study Group

Investigators

• Principal Investigator: Pieter Sonneveld, Prof.; Stichting Hemato-Oncologie voor Volwassenen Nederland

• PRS Account: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Verification Date: August 2023