Efficacy of Response-adapted Treatment in Patients With Multiple Myeloma Candidates for Bone Marrow Transplantation
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional

Summary: 
      To assess whether continued treatment to achieve negative Minimal Residual Disease and
      Imaging (MRDI(-)) improves therapeutic outcomes in patients with newly diagnosed Multiple
      Myeloma. The primary endpoints are progression-free survival (PFS) and overall survival (OS).
      The safety evaluation includes the evaluation of adverse events (which are classified
      according to the Common Criteria for Terminology for Adverse Events of the National Cancer
      Institute, version 5.0).
    

Detailed description: 
      Material and methods - Criteria for Enrollment Patients younger than 76 years, diagnosed with
      myeloma since July 1, 2014 until May 31, 2019, without a contraindication for bone marrow
      auto-transplantation are included in the study. Fragile patients with severe senile dementia,
      with another non-treatable neoplasm, or with significant comorbidity in whom the therapeutic
      objective was only palliative are not included in the study. The allocation to each treatment
      group was carried out according to the patient's preferences and his/her responsible
      physician, giving the patient his/her consent for treatment in all cases. In addition to
      other information, before patients gave their consent, patients included in the continued
      treatment group were clarified that it was a non-standard treatment, giving them the choice
      between the most common option of fixed treatment or continuous treatment up to Minimal
      Residual Disease and Image negative (MRDI(-)).

      Material and methods - Study Design and Treatment This is a study of the patients treated in
      real life hematology. It is a cohort study to compare continuous treatment versus
      fixed-duration therapy. The study is conducted in a single hospital, including patients
      diagnosed from July 1, 2014 to May 31, 2019. The autotransplant is considered as a
      therapeutic line more, and all patients who did not receive the transplant were analyzed as
      if they had received it. The patients always receive some of the authorized treatments for
      their therapeutic line, according to the preferences of the responsible hematologist and the
      patient. After the induction phase, all the patients undergo stem-cell mobilization with
      granulocyte colony-stimulating factor.

      The patients of the fixed treatment group (control group) receive up to six cycles of the
      consolidation treatment after transplantation if complete remission has not been achieved.

      In the patients of the MRDI-driven group, patients continue treatment after transplantation
      to achieve complete remission with negative MRD and negative image, changing therapeutic line
      if not achieved with the prescribed treatment. In this group of the patients the treatment is
      stopped only when this degree of deep response is achieved, in whatever the treatment phase
      was.

      Assessments The treatment response and disease progression are assessed according to the
      International Uniform Response Criteria for Multiple Myeloma, except that to consider the
      negative Minimal Residual Disease, a sensitivity level of 10-6 is required. In addition, it
      is considered negative image only if a Positron Emission Tomography/Computed Tomography
      (PET/CT) body and spinal and pelvic Nuclear Magnetic Resonance (NMR), are both negative.

      The work team defined an additional category of relapse: "relapse from MRDI(-)", which
      includes any of the relapse criteria of negative Minimal Residual Disease, and/or positive
      image. To evaluate the Positron Emission Tomography/Computed Tomography (PET/CT) the criteria
      of Elena Zamagni et al. (6) are used. In Nuclear Magnetic Resonance studies, all lesions with
      a size equal to or greater than 5 mm are considered positive if they are hypointense signal
      in T1, hyperintense in Fat Suppression (FS) T2 signal, and in the studies of diffusion
      hyperintense signal in b1000 with apparent diffusion coefficient (ADC) between 0.4 and 1. In
      perfusion studies, type 4-curve lesions are considered positive. The adverse events are
      assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
      of the National Cancer Institute. It is considered as an Adverse Event (AE) any unfavorable
      and unintended sign (including an abnormal laboratory finding), symptom, or disease
      temporally associated with the use of a medical treatment or procedure that may or may not be
      considered related to the medical treatment or procedure.

      Among all the patients, bone marrow samples are obtained at diagnostic for cytogenetic
      evaluation.

      Among the patients of the MRDI-driven group who are a complete response, bone marrow samples
      are obtained for minimal residual disease evaluation by means of seven-color flow cytometry
      (which has a sensitivity level of 10-6, indicating that it can detect 1 malignant plasma cell
      within 1,000,000 bone marrow cells). If the patient achieve a Complete Remission (CR)
      according to the International Uniform Response Criteria for Multiple Myeloma, Minimal
      Residual Disease (MRD) and imaging studies are performed before transplantation, after
      transplantation, and after every six cycles of treatment in cases with CR where previous MRD
      or imaging studies are positive.

      In the control group, the MRD and imaging only occasionally is it evaluated. In all patients
      who achieve a negative MRD and negative image, MRD and imaging tests are performed at 6
      months and annually.

      The response obtained, progression-free survival, overall survival, and the incidence of
      adverse effects are valued.

      Statistical Analysis Progression-free survival is defined as the time from start of treatment
      until either the first documentation of disease progression or death owing to myeloma or not.
      Overall survival is defined as the time from start of treatment until death from any cause.

      Duration of PFS and OS is estimated by means of the test of the long rank Kaplan-Meier method
      with Cox analysis. Analyses are performed with the use of "IBM SPSS Statistics software,
      version 23.0"; the data cutoff date is December 31, 2022.
    

Intervention name(s): Continued treatment adapted to the response
Intervention type(s): Other
Intervention description(s): Instead of receiving a pre-specified number of treatment cycles, regardless of the result obtained, in the MRDI-driven treatment group patients continue receiving treatment until reaching a complete remission with negative MRD and Image, changing the therapeutic line if it is not obtained with the line current therapy. In this group of the patients the treatment was stopped only when this degree of deep response was achieved.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, no randomized. It is a cohort study to compare MRDI(-) driven treatment adapted to the response versus fixed-duration therapy.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Minimal Residual Disease; Therapeutics; Multiple Myeloma