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

• Sponsor: Universitätsklinikum Hamburg-Eppendorf (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05675319
• Collaborator: Gemeinsamer Bundesausschuss (G-BA) (Other), Staburo GmbH (Other)
• Enrollment: 482
• Locations: 32
• Arms: 2
• Anticipated Duration (Months): 64
• Patients Per Site: 15.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	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	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 482 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Stem Cell Transplantation vs. Conventional Therapy as Salvage Therapy for Relapsed / Progressive Patients With Multiple Myeloma After First-line Therapy
• Anticipated Study Start Date: Jan 1, 2023
• Anticipated Primary Completion Date: Jul 1, 2027
• Anticipated Study Completion Date: May 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (allo SCT) Allogeneic stem cell transplantation	Drug: Allogeneic Stem Cells; Allogeneic Stem Cell Transplantation
Active Comparator: Arm B (conventional therapy) 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); triple regimen for first relapse should be applied according to latest Summary of Product Characteristics (SmPC) version; Drug: elotuzumab/lenalidomide/dexamethasone (ERD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: daratumumab/bortezomib/dexamethasone (DVD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: daratumumab/lenalidomide/dexamethasone (DRD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: ixazomib/lenalidomide/dexamethasone (IRD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: pomalidomide/bortezomib/dexamethasone (PVD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: carfilzomib/daratumumab/dexamethasone (KDD); triple regimen for first relapse should be applied according to latest SmPC version; Drug: Autologous Stem Cells; Autologous Stem Cell Transplantation

Outcome Measures

Primary Outcome Measures

1. Overall survival at five years after randomization [at 5 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.

Secondary Outcome Measures

1. Event-free survival at 1 year after randomization [from randomization to 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

2. Event-free survival at 3 years after randomization [from randomization to 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

3. Event-free survival at 5 years after randomization [from randomization to 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

4. Change from baseline in total EORTC score 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]

   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.

5. Change from baseline in total EORTC score 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]

   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.

6. Change from baseline in total EORTC score 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]

   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.

7. Time to first occurrence of remission after randomization [at 30 days, 100 days, 6 months, 1 and 2 years 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.

8. Non-relapse mortality (NRM) at 1 year after randomization [from randomization to 1 year after randomization, an average of 1 year]

   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.

9. Non-relapse mortality (NRM) at 3 years after randomization [from randomization to 3 years after randomization, an average of 3 years]

   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.

10. Non-relapse mortality (NRM) at 5 years after randomization [from randomization to 5 years after randomization, an average of 5 years]

    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.

11. Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 1 year after randomization [at 30 days, 100 days, 6 months and 1 year after randomization, an average of 1 year]

    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

12. Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 3 years after randomization [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]

    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

13. Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 5 years after randomization [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]

    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.

14. Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 1 year after randomization [at 30 days, 100 days, 6 months and 1 year after randomization, an average of 1 year]

    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.

15. Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 3 years after randomization [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]

    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.

16. Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 5 years after randomization [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]

    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.

17. Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 1 year after randomization [from randomization to 1 year after randomization, an average of 1 year]

    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.

18. Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 3 years after randomization [from randomization to 3 years after randomization, an average of 3 years]

    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.

19. Time to first occurrence of infection reported as cumulative incidence of infection with CTCAE grade 3 - 5 at 5 years after randomization [from randomization to 5 years after randomization, an average of 5 years]

    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.

Other Outcome Measures

1. Event-free survival at 3 and 5 years after randomization [from randomization to 3 and 5 years after randomization]

   Patients will be observed from randomization until database lock for interim analysis and the event-free survival (EFS) rate is calculated at 3 and 5 years after randomization. Events are defined as: Progression or Relapse or Engraftment Failure or Death of any cause

2. Change from baseline in total EORTC score (Summary Score) at 3 and 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, an average at 3 and 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 interim analysis and adjusted mean is calculated at 3 and 5 years after randomization.

3. Non-relapse mortality at 1, 3 and 5 years after randomization [from randomization to 1, 3 and 5 years after randomization, an average of 1, 3 and 5 years]

   Patients will be observed from randomization until database lock for interim analysis and cumulative incidence of death before any relapse at 1, 3 and 5 years after randomization is reported

4. Cumulative incidence of acute GvHD after allogeneic stem cell transplantation at 1, 3 and 5 years after randomization [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 1, 3 and 5 years]

   Patients will be observed from randomization until database lock for interim analysis and cumulative incidence of any acute GvHD (according to Przepiorka et al.) at 1, 3 and 5 years after randomization is reported

5. Cumulative incidence of chronic GvHD after allogeneic stem cell transplantation at 1, 3 and 5 years after randomization [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 1, 3 and 5 years]

   Patients will be observed from randomization until database lock for interim analysis and cumulative incidence of any chronic GvHD (according to Jagasia et al.) at 1, 3 and 5 years after randomization is reported

6. Time to first occurrence of Minimal Residual Disease (MRD) [at 30 days, 100 days, 6 months, 1 and 2 years after randomization, rate of occurence at 6 months, 1 and 2 years after randomization]

   Patient observed from randomization until database lock for interim analysis and until database lock for final and rate of occurrence calculated at 6 months, 1 year and 2 years after randomization

7. Time to first occurrence of progression [from randomization to 1, 3, and 5 years after randomization]

   Patients will be observed from randomization until database lock for interim analysis and rates at 3 and 5 years after randomization are calculated; and patients will be observed from randomization until database lock for final analysis and rates at 1, 3, and 5 years after randomization are calculated

8. Time to first recurrence of relapse [at 1, 3, and 5 years after randomization]

   Patients will be followed from randomization to database lock for interim analysis and rates at 3 and 5 years after randomization are calculated; and patients will be followed from randomization to database lock for final analysis and rates at 1, 3, and 5 years after randomization are calculated.

9. Time to first occurrence of graft failure after stem cell transplatation [at day 30 after after randomization]

   Patients are followed from randomization until database lock for interim analysis and rates at 3 and 5 years post-randomization are calculated; and patients are followed from randomization until database lock for final analysis and rates at 1, 3, and 5 years post-randomization are calculated. A graft failure is defined as no stable neutrophil count > 0.5 x 10^9/l at day 28 post-SCT.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients eligible for study inclusion must meet criteria 1- 7 at registration and all of the following criteria before randomization:

1. Multiple Myeloma

2. Age 18 - 65 years

3. A signed informed consent form must be obtained before participation in the study

4. Age 66 - 70 years, if comorbidity index according to Sorror score = 0 and ECOG ≤ 1

5. 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

6. Negative pregnancy test in female patients

7. Maximum of 1 cycle salvage therapy prior to study inclusion

8. 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

9. 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:

1. 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

1. Active hepatitis B or C infection or uncontrolled HIV infection

2. Other, active malignant disease

3. Prior treatment with allogeneic stem cells

4. 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

5. Positive serum pregnancy test at screening and before first treatment or breastfeeding

6. PD under salvage therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital of Freiburg	Freiburg	Baden-Württemberg	Germany	79106
2	University Hospital Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
3	Robert-Bosch Hospital Stuttgart	Stuttgart	Baden-Württemberg	Germany	70376
4	University Hospital Tübingen	Tübingen	Baden-Württemberg	Germany	72076
5	University Hospital of Ulm	Ulm	Baden-Württemberg	Germany	89081
6	University Hospital Augsburg	Augsburg	Bayern	Germany	86156
7	University Hospital Munich ( LMU)	München	Bayern	Germany	80336
8	Munich Hospital Schwabing	München	Bayern	Germany	80804
9	University Hospital of the Technical University Munich rechts der Isar	München	Bayern	Germany	81675
10	Hospital North Nürnberg	Nürnberg	Bayern	Germany	90419
11	University Hospital Regensburg	Regensburg	Bayern	Germany	93053
12	University Hospital of Würzburg	Würzburg	Bayern	Germany	97070
13	University Hospital Frankfurt/ Main	Frankfurt am Main	Hessen	Germany	60590
14	Philipps University Marburg	Marburg	Hessen	Germany	35037
15	University Medical Center Göttingen	Göttingen	Niedersachsen	Germany	37075
16	University Hospital RWTH Aachen	Aachen	Nordrhein-Westfalen	Germany	52074
17	University Hospital Bonn	Bonn	Nordrhein-Westfalen	Germany	53127
18	University Hospital Düsseldorf	Düsseldorf	Nordrhein-Westfalen	Germany	40225
19	University Hospital Essen	Essen	Nordrhein-Westfalen	Germany	45147
20	University Hospital Münster	Münster	Nordrhein-Westfalen	Germany	48149
21	University Medical Center Mainz	Mainz	Rheinland-Pfalz	Germany	55131
22	University Hospital Halle (Saale)	Halle (Saale)	Sachsen-Anhalt	Germany	06120
23	Hospital of Chemnitz gGmbH	Chemnitz	Sachsen	Germany	09116
24	University Hospital Carl Gustav Carus	Dresden	Sachsen	Germany	01307
25	University Hospital of Leipzig	Leipzig	Sachsen	Germany	04103
26	University Hospital of Schleswig-Holstein (Campus Kiel)	Kiel	Schleswig-Holstein	Germany	24105
27	University Hospital Jena	Jena	Thüringen	Germany	07743
28	Charité - University of Medicine Berlin	Berlin		Germany	10117
29	Helios Hospital Berlin-Buch	Berlin		Germany	13125
30	Asklepios Hospital Hamburg St. Georg	Hamburg		Germany	20099
31	University Medical Center Hamburg-Eppendorf	Hamburg		Germany	20246
32	Hospital Oldenburg (AöR)	Oldenburg		Germany	26133

Sponsors and Collaborators

• Universitätsklinikum Hamburg-Eppendorf
• Gemeinsamer Bundesausschuss (G-BA)
• Staburo GmbH

Investigators

• Principal Investigator: Nicolaus Kröger, Prof. Dr., University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Universitätsklinikum Hamburg-Eppendorf
• ClinicalTrials.gov Identifier: NCT05675319
• Other Study ID Numbers: AlloRelapseMMStudy
• First Posted: Jan 9, 2023
• Last Update Posted: Jan 9, 2023
• Last Verified: Dec 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Universitätsklinikum Hamburg-Eppendorf: first relapse/progression after first-line therapy; allogeneic stem cell transplantation; salvage therapy
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Dexamethasone acetate; Lenalidomide; Bortezomib; Daratumumab; Pomalidomide; Ixazomib; Elotuzumab; BB 1101; Antibodies, Monoclonal

Study Results

No Results Posted as of Jan 9, 2023