Len/Dex/DLI in Relapsed Multiple Myeloma After Allogeneic Stem Cell Transplant
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03413800|
Recruitment Status : Recruiting
First Posted : January 29, 2018
Last Update Posted : January 31, 2019
Multiple Myeloma (MM) is a morbid disease which can only be cured with an allogeneic hematopoietic stem cell transplant (HSCT). Approximately 50% of allotransplanted patients will relapse, with a median survival of 5 years. Better approaches to improve disease control at relapse, while decreasing toxicity, are urgently needed.
Relapse after allogeneic transplant is a failure of the graft versus MM effect (GvMM). DLIs can be used to control disease following relapse, but the optimal dose, schedule of administration and drug association remain elusive, while the immunosuppression found in MM patients can compromise their effect. One reason for immunotherapy failure relates to the immunological environment: as much as myeloma cells depend on their microenvironment to survive and proliferate, the immunotherapeutic effect of allogeneic HSCT depends on both systemic and local immunological status to be efficacious. Immunomodulatory drugs such as Lenalidomide (Len) have been tried in various settings after allogeneic transplantation with the aim to reverse immunosuppression and stimulate the GvMM, but if and how Len influences a GvMM and thereby promotes an immunotherapeutic success remained uncharacterized. Therefore, a deeper understanding of the immunological environment in MM patients is needed in order to establish and / or restore a potent GvMM effect.
This study proposes the powerful combination of the two following goals, one clinical and one biological :
- Clinical: The investigators propose a two-step treatment using first Len in association with Dexamethasone (Dex), followed by Donor Leukocytes Infusions (DLIs) to offer an optimal disease control strategy in relapsed patients. The cytoreductive and immunomodulatory effects of Len is expected to induce a permissive immunological environment for the immunotherapeutic activity of DLIs to develop, while the association with Dex will lessen the risk of graft-versus-host disease (GVHD). This treatment combination has the potential to further improve depth of myeloma response, delay myeloma progression and improve patient survival.
- Biological: In an attempt to gain knowledge on how the GvMM behaves in MM patients post-relapse after having received a combined treatment of Len/Dex/DLIs, the investigators propose to characterize the immune environment of their bone marrow (BM) using both minimal residual disease (MRD) assessement by flow cytometry and an unbiased analysis of the transcriptome at various time points.
|Condition or disease||Intervention/treatment||Phase|
|Relapsed Hematologic Malignancy Multiple Myeloma||Drug: Lenalidomide-Dexamethasone-DLI||Phase 2|
Myeloma patients in first relapse after sibling or unrelated donor allogeneic transplant willing to participate in this study will be screened for eligibility.
- After baseline evaluation including BM aspirate for plasma cell count, minimal residual disease using 8-color multiparameter flow cytometry, transcriptome sequencing and a positron emission tomography (PET scan), patients will receive Len- Dex daily x 21 days with Dex 40 mg once weekly for a total of 6 cycles of 28 days each
- Patients will then be evaluated clinically for acute and chronic GVHD before each cycle and a PET scan will be performed at the end of Len/Dex treatment
- Sibling and unrelated donor transplant recipients will receive 3 DLIs
Disease and immune evaluation using serum and urine electrophoresis/immunofixation in addition to measurement of serum-free light chains, BM aspirate for plasma cell count and minimal residual disease using 8-color multiparameter flow cytometry, transcriptome sequencing and a PET scan will be performed
- A BM aspirate will be performed before each DLI for plasma cell count, MRD evaluation by flow cytometry and transcriptome sequencing
- Patients will be followed with a BM aspirate every 3 months x 1 year, then yearly and at progression for plasma cell count and evaluation
- Transcriptome sequencing will be done on BM aspirates at time of relapse, after Len/Dex cycles, 6m, 12m, 18m and 24m after the last-DLI.
- A PET scan will be performed after the last DLI and at progression.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||15 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II, Open-label Study of Lenalidomide and Dexamethasone Followed by Donor Lymphocyte Infusions in Relapsed Multiple Myeloma Following Allogeneic Stem Cell Transplant|
|Actual Study Start Date :||February 12, 2018|
|Estimated Primary Completion Date :||January 29, 2021|
|Estimated Study Completion Date :||January 29, 2023|
Lenalidomide (Len) and Dexamethasone (Dex) for 6 months followed by three donor lymphocyte infusions (DLIs)
- Efficacy of Len-Dex-DLI in patients with relapsed myeloma measured by progression-free survival [ Time Frame: 2 years ]To determine the as efficacy of Len and Dex followed by DLIs, measured by progression-free survival at 2 years after the last DLI
- Incidence of grade ≥III non hematologic toxicity and incidence of grade ≥IV hematologic toxicity [ Time Frame: 5 years ]Patients will be evaluated according to protocol and adverse events will be monitored continuously, documented and collected in database
- Incidence of acute GVHD [ Time Frame: 1 years ]GVHD will be evaluated according to protocol, documented and collected in database. Analysis will be done by cumulative incidence.
- Incidence of chronic GVHD [ Time Frame: 2 years ]GVHD will be evaluated according to protocol, documented and collected in database. Analysis will be done by cumulative incidence.
- Maximum grades of acute and chronic GVHD [ Time Frame: 2 years ]GVHD will be evaluated according to protocol, documented and collected in database
- Response to treatment [ Time Frame: 3 years ]International Myeloma Working Group (IMWG) response after Len/Dex and after DLIs, best response achieved
- Non-relapse mortality after DLIs [ Time Frame: 3 years ]Analysis by cumulative incidence
- Overall survival at 2 years [ Time Frame: 2 years ]Kaplan Meier analysis
- Incidence of progression at 2 years [ Time Frame: 2 years ]Kaplan Meier analysis
- Disease status assessment by flow cytometry [ Time Frame: 5 years ]BM evaluation of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) analysis
- Disease status assessment by PET scan [ Time Frame: 5 years ]Evaluation of extramedullary disease by positron emission tomography (PET) scan
- Evaluation of quality of life (QoL) during treatment [ Time Frame: 5 years ]QoL questionnaire will be given to patients according to protocol
- Evaluation of the BM microenvironment by transcriptome analysis before and after treatments [ Time Frame: 3 years ]Both mononucleated celles and extracellular compartment will be analyzed by RNAseq
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03413800
|Contact: Jean Roy, MDemail@example.com|
|Contact: Séverine Landais, PhD||514-252-3400 ext firstname.lastname@example.org|
|CIUSSS de l'Est-de-l'île-de-Montréal, Installation Hôpital Maisonneuve Rosemond||Recruiting|
|Montréal, Quebec, Canada, H1T2M4|
|Contact: Séverine Landais, PhD 514-252-3400 ext 3609 email@example.com|
|Contact: Jean Roy, MD 514-252-3400 firstname.lastname@example.org|
|Principal Investigator:||Jean Roy, MD||Ciusss de L'Est de l'Île de Montréal|