Len/Dex/DLI in Relapsed Multiple Myeloma After Allogeneic Stem Cell Transplant

NCT03413800 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: HMR003
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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 :

1. 1.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.
2. 2.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.

Conditions

Relapsed Hematologic Malignancy; Multiple Myeloma

Keywords

hematopoietic stem cell transplant; lenalidomide; DLI

Outcome Measures

Primary Outcomes (1)

• Efficacy of Len-Dex-DLI in patients with relapsed myeloma measured by progression-free survival

  To determine the as efficacy of Len and Dex followed by DLIs, measured by progression-free survival at 2 years after the last DLI

  2 years

Secondary Outcomes (12)

• Incidence of grade ≥III non hematologic toxicity and incidence of grade ≥IV hematologic toxicity

  5 years

• Incidence of acute GVHD

  1 years

• Incidence of chronic GVHD

  2 years

• Maximum grades of acute and chronic GVHD

  2 years

• Response to treatment

  3 years

Study Arms (1)

Lenalidomide-Dexamethasone-DLI

EXPERIMENTAL

1. Patients will receive Len (10 mg in the presence of ≤ grade I acute GVHD or absence of chronic GVHD; 5 mg in presence of controlled mild or moderate chronic GVHD) daily x 21 days with Dex 40 mg once weekly for a total of 6 cycles of 28 days each 1. For grade ≥III non hematologic or grade IV hematologic toxicity, Len can be reduced to 5 mg 2. In absence of these toxicities, acute GVHD (using Glucksberg modified criteria) or severe chronic GVHD (using NIH criteria), Len dose can be increased by 5 mg per cycle to a maximum of 25 mg 2. If eligibility is confirmed, sibling and unrelated donor transplant recipients will both receive 3 donor lymphocyte infusions (DLIs) at the following doses: 5 x 106 CD3+/kg; 1 x 107 CD3+/kg; 5 x 107 CD3+/kg 3. Patient will be followed for 5 years post relapse.

Drug: Lenalidomide-Dexamethasone-DLI

Interventions

Lenalidomide-Dexamethasone-DLI DRUG

Lenalidomide (Len) and Dexamethasone (Dex) for 6 months followed by three donor lymphocyte infusions (DLIs)

Lenalidomide-Dexamethasone-DLI

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65 years
• Myeloma patients in first relapse after a sibling or unrelated allogeneic stem cell transplantation
• Patients with measurable disease at time of relapse based on the IMWG criteria
• All study participants must comply with the Revlimid Pregnancy Prevention Plan.
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid Pregnancy Prevention Plan.

You may not qualify if:

• Relapse occurred within 180 days post allograft
• Refractory to Len at any given time before allogeneic transplantation
• Presence of ≥ grade II or uncontrolled acute GVHD
• Presence of severe or uncontrolled chronic GVHD
• Karnofsky score \< 70%
• Bilirubin \> 50 μmol/L unless felt to be related to Gilbert's disease or hemolysis; AST and ALT \> 5 x upper limit of normal (ULN); alkaline phosphatase \> 5 x ULN
• Known hypersensitivity to Len or Dex
• Active infection with any of the following viruses: HIV, HTLV-1 or 2, hepatitis B (defined as HBsAg positivity) or hepatitis C (defined as anti-HCV positivity or HCV-RNA positivity)
• Positive beta-human chorionic gonadotropin pregnancy test, to be performed in all women of childbearing potential at screening and baseline. Female study participants who are surgically sterile (hysterectomy) or who have been postmenopausal for at least 12 consecutive months are automatically eligible for this criterion
• Females of child-bearing potential not agreeing to remain abstinent or to use 2 simultaneous effective methods of contraception from at least 4 weeks before, to at least 4 weeks following discontinuation of Len. Males not agreeing to use a condom during any sexual contact with females of child-bearing potential from at least 4 weeks before, to at least 4 weeks following discontinuation of Len
• Women who are lactating
• Female of child-bearing potential who are planning to become pregnant while enrolled in this study up to 4 weeks after the last Len dose
• Participation in a trial with an investigational agent within 30 days prior to entry in the study
• Inability to provide written informed consent prior to initiation of any study-related procedures, or inability, in the opinion of investigators, to comply with all requirements of the study
• Estimated probability to survive less than 6 months after initiation of Len and Dex

Sponsors & Collaborators

• Ciusss de L'Est de l'Île de Montréal: lead
• Celgene: collaborator
• C3i Center Inc.: collaborator

Study Sites (1)

CIUSSS de l'Est-de-l'île-de-Montréal, Installation Hôpital Maisonneuve Rosemond

Montreal, Quebec, H1T2M4, Canada

Location

MeSH Terms

Conditions

Hematologic Neoplasms; Multiple Myeloma

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Jean Roy, MD

  Ciusss de L'Est de l'Île de Montréal

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: January 15, 2018
• First Posted: January 29, 2018
• Study Start: February 12, 2018
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: August 21, 2024

Record last verified: 2024-08

Locations

CA (1)