Allogeneic Stem Cell Transplantation vs. Conventional Therapy as Salvage Therapy for Relapsed / Progressive Patients With Multiple Myeloma After First-line Therapy

Study Overview
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Brief Summary
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Allogeneic stem cell (allo SCT) transplantation for multiple myeloma is a potential curative treatment, but is associated with morbidity and treatment related mortality. Approved drug combinations or another autologous stem cell transplantation (auto-SCT) can be used for relapsed patients resulting in a median progression free survival up to 2-3 years. In the current trial after first-line treatment relapsed or progressed myeloma patients with an HLA compatible donor will be randomized after 3 cycles of salvage therapy to allogeneic stem cell transplantation or to continuous conventional salvage therapy.

Detailed Description
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The primary objective of the present clinical study aims to demonstrate the superiority of allogeneic stem cell transplantation (allo SCT) compared to conventional therapy for the difference in overall survival (OS) at 5 years in patients with multiple myeloma who have relapsed or progressed after first-line autologous hematopoietic stem cell therapy. The secondary objectives are to show an improvement of progression free survival and relapse free survival after allo SCT compared to conventional therapy. In addition, quality of life, toxicities, recurrence rates, non-relapse mortality (NRM), remission rates including minimal residual disease (MRD) and incidence of severe or life-threatening infection between the two arms are compared. Acute and chronic graft-versus-host disease (GvHD) after allo SCT are evaluated.

Official Title
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Allogeneic Stem Cell Transplantation vs. Conventional Therapy as Salvage Therapy for Relapsed / Progressive Patients With Multiple Myeloma After First-line Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Allogeneic Stem Cells
* Drug: carfilzomib/lenalidomide/dexamethasone (KRD)
* Drug: elotuzumab/lenalidomide/dexamethasone (ERD)
* Drug: daratumumab/bortezomib/dexamethasone (DVD)
* Drug: daratumumab/lenalidomide/dexamethasone (DRD)
* Drug: ixazomib/lenalidomide/dexamethasone (IRD)
* Drug: pomalidomide/bortezomib/dexamethasone (PVD)
* Drug: carfilzomib/daratumumab/dexamethasone (KDD)
* Drug: Autologous Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for study inclusion must meet criteria 1- 7 at registration and all of the following criteria before randomization: Multiple Myeloma Age 18 - 65 years A signed informed consent form must be obtained before participation in the study Age 66 - 70 years, if comorbidity index according to Sorror score = 0 and ECOG ≤ 1 1st relapse/ progression according to IMWG criteria after first-line therapy (consisting of induction therapy followed by autologous transplantation once or twice and maintenance therapy), Additionally: meeting the need for treatment based on the SLiM criteria Negative pregnancy test in female patients Maximum of 1 cycle salvage therapy prior to study inclusion Availability of a fully compatible stem cell donor (HLA-ident. Sibling or 10/10 MUD or 9/10 MMUD if mismatch affects DQB) after 3 cycles salvage therapy CR/PR or SD according to IMWG-criteria after 3 cycles salvage therapy within the study Exclusion Criteria: Patients are excluded from the study if any one of criteria 1-6 are met at registration and if criterion 7 is met before randomization: Non-sufficient organ function defined as: Bilirubin (in the absence of Meulengracht's disease), SGPT or SGOT ≥3 higher than normal values Cardiac ejection fraction ≤ 50% GFR < 30 ml/min DLCO < 50% and/or continuous oxygen dependency Active hepatitis B or C infection or uncontrolled HIV infection Other, active malignant disease Prior treatment with allogeneic stem cells Participation in a clinical trial or taking an IMP within 30 days or five times the half-life of the IMP, whichever is longer, prior to registration Positive serum pregnancy test at screening and before first treatment or breastfeeding PD under salvage therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (allo SCT)<br>Allogeneic stem cell transplantation | Drug: Allogeneic Stem Cells<br>* Allogeneic Stem Cell Transplantation<br>|
| Active Comparator: Arm B (conventional therapy)<br>Currently approved triple regimens for first relapse: carfilzomib/lenalidomide/dexamethasone (KRD) or elotuzumab/lenalidomide/dexamethasone (ERD) or daratumumab/bortezomib/dexamethasone DVD) or daratumumab/lenalidomide/dexamethasone (DRD) or ixazomib/lenalidomide/dexamethasone (IRD) or pomalidomide/bortezomib/dexamethasone (PVD) or carfilzomib/daratumumab/dexamethasone (KDD) Alternatively, autologous stem cell transplantation may also be performed, if sufficient stem cells are still cryopreserved. | Drug: carfilzomib/lenalidomide/dexamethasone (KRD)<br>* triple regimen for first relapse should be applied according to latest Summary of Product Characteristics (SmPC) version<br>Drug: elotuzumab/lenalidomide/dexamethasone (ERD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: daratumumab/bortezomib/dexamethasone (DVD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: daratumumab/lenalidomide/dexamethasone (DRD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: ixazomib/lenalidomide/dexamethasone (IRD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: pomalidomide/bortezomib/dexamethasone (PVD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: carfilzomib/daratumumab/dexamethasone (KDD)<br>* triple regimen for first relapse should be applied according to latest SmPC version<br>Drug: Autologous Stem Cells<br>* Autologous Stem Cell Transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at five years after randomization | The present clinical study aims to demonstrate the superiority of allogeneic stem cell transplantation compared to conventional therapy for the difference in overall survival at 5 years in patients with multiple myeloma who have relapsed or progressed after first-line autologous hematopoietic stem cell therapy. | at 5 years after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival at 1 year after randomization | A secondary objective is to show an improvement of progress free survival and relapse free survival after allogeneic stem cell transplantation compared to conventional therapy. Events are defined as: Progression or Relapse or Engraftment Failure or Death of any cause | from randomization to 1 year after randomization | 
| Event-free survival at 3 years after randomization | A further secondary objective is to show an improvement of progress free survival and relapse free survival after allogeneic stem cell transplantation compared to conventional therapy. Events are defined as: Progression or Relapse or Engraftment Failure or Death of any cause | from randomization to 3 years after randomization | 
| Event-free survival at 5 years after randomization | A secondary objective is to show an improvement of progress free survival and relapse free survival after allogeneic stem cell transplantation compared to conventional therapy. Events are defined as: Progression or Relapse or Engraftment Failure or Death of any cause | from randomization to 5 years after randomization | 
| Change from baseline in total EORTC score at 1 year after randomization | The aim of the quality of life questionnaires (QLQ) is to provide a comparison between the two treatment arms. Quality of life according EORTC (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) & Quality of Life Questionnaire - Multiple Myeloma Module (EORTC QLQ-MY20)) will be assessed in both groups.. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology/ sickness. Patients will be observed from baseline until database lock for final analysis and adjusted mean calculated at 1 year after randomization. | at visit Screening, at the end of cycle 3 (84 days, each cycle is 28 days) of salvage therapy, 6 months and 12 months after randomization | 
| Change from baseline in total EORTC score at 3 years after randomization | The aim of the quality of life questionnaires (QLQ) is to provide a comparison between the two treatment arms. Quality of life according EORTC (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) & Quality of Life Questionnaire - Multiple Myeloma Module (EORTC QLQ-MY20)) will be assessed in both groups. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology/ sickness. Patients will be observed from baseline until database lock for final analysis and adjusted mean calculated at 3 years after randomization. | at visit Screening, at the end of cycle 3 (84 days, each cycle is 28 days) of salvage therapy, 6 months, 1 year, 2 years and 3 years after randomization | 
| Change from baseline in total EORTC score at 5 years after randomization | The aim of the quality of life questionnaires (QLQ) is to provide a comparison between the two treatment arms. Quality of life according EORTC (European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) & Quality of Life Questionnaire - Multiple Myeloma Module (EORTC QLQ-MY20)) will be assessed in both groups. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology/ sickness. Patients will be observed from baseline until database lock for final analysis and adjusted mean calculated at 5 years after randomization. | at visit Screening, at the end of cycle 3 (84 days, each cycle is 28 days) of salvage therapy, 6 months, 1, 2, 3, 4 and 5 years after randomization | 
| Time to first occurrence of remission after randomization | Patients will be followed from randomization until database lock for final analysis and cumulative incidence of first remission (partial or complete), at 2 years after randomization, is reported. | at 30 days, 100 days, 6 months, 1 and 2 years after randomization | 
| Non-relapse mortality (NRM) at 1 year after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of death before any relapse at 1 year after randomization was reported. | from randomization to 1 year after randomization, an average of 1 year | 
| Non-relapse mortality (NRM) at 3 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of death before any relapse at 3 years after randomization was reported. | from randomization to 3 years after randomization, an average of 3 years | 
| Non-relapse mortality (NRM) at 5 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of death before any relapse at 5 years after randomization was reported. | from randomization to 5 years after randomization, an average of 5 years | 
| Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 1 year after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any acute Graft-versus-Host Disease (GvHD, according to Przepiorka et al.) at 1 year after randomization is reported | at 30 days, 100 days, 6 months and 1 year after randomization, an average of 1 year | 
| Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 3 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any acute GvHD (according to Przepiorka et al.) at 3 years after randomization is reported | at 30 days, 100 days, 6 months, 1 year, 18 months and 2 years, 30 months and 3 years after randomization, an average of 3 years | 
| Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 5 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any acute GvHD (according to Przepiorka et al.) at 5 years after randomization is repoted. | at 30 days, 100 days, 6 months, 1 year, 18 months and 2 years, 30 months, 3, 4 and 5 years after randomization, an average of 5 years | 
| Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 1 year after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any chronic GvHD (according to Jagasia et al.) at 1 year after randomization is reported. | at 30 days, 100 days, 6 months and 1 year after randomization, an average of 1 year | 
| Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 3 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any chronic GvHD (according to Jagasia et al.) at 3 years after randomization is reported. | at 30 days, 100 days, 6 months, 1 year, 18 months and 2 years, 30 months and 3 years after randomization, an average of 3 years | 
| Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 5 years after randomization | Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any chronic GvHD (according to Jagasia et al.) at 5 years after randomization is reported. | at 30 days, 100 days, 6 months, 1 year, 18 months and 2 years, 30 months, 3, 4 and 5 years after randomization, an average of 5 years | 
| Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 1 year after randomization | The severity and/or intensity of an adverse event will be graded based upon the patient's symptoms according to the current active version of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any infectious complication with CTCAE grade 3 - 5 at 1 year after randomization is reported. | from randomization to 1 year after randomization, an average of 1 year | 
| Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 3 years after randomization | The severity and/or intensity of an adverse event will be graded based upon the patient's symptoms according to the current active version of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any infectious complication with CTCAE grade 3 - 5 at 3 years after randomization is reported. | from randomization to 3 years after randomization, an average of 3 years | 
| Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 5 years after randomization | The severity and/or intensity of an adverse event will be graded based upon the patient's symptoms according to the current active version of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Patients will be observed from randomization until database lock for final analysis and cumulative incidence of any infectious complication with CTCAE grade 3 - 5 at 5 years after randomization is reported. | from randomization to 5 years after randomization, an average of 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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first relapse/progression after first-line therapy, allogeneic stem cell transplantation, salvage therapy