Lenalidomide-Dexamethasone-DLI for Multiple Myeloma

Overseen By Nathalie Lachapelle, B.Sc. INF

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ciusss de L'Est de l'Île de Montréal

Must be taking: Lenalidomide, Dexamethasone

Disqualifiers: Acute GVHD, Chronic GVHD, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: 24 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

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. 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. 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.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss your specific situation with the trial investigators.

What data supports the effectiveness of the drug combination Lenalidomide and Dexamethasone for treating multiple myeloma?

Research shows that the combination of Lenalidomide and Dexamethasone is effective for treating multiple myeloma, with studies indicating improved survival and response rates in patients who have relapsed after previous treatments. This combination has been shown to be superior to Dexamethasone alone in terms of response and survival, and is considered a standard treatment for relapsed multiple myeloma. ^{1 2 3 4 5}

Is the combination of lenalidomide and dexamethasone safe for humans?

The combination of lenalidomide and dexamethasone is generally considered safe for humans, but it can cause side effects like fatigue, muscle cramps, rash, infections, and blood-related issues. Serious side effects may include pneumonia and blood clots, so monitoring by healthcare professionals is important. ^{4 6 7 8 9}

What makes the lenalidomide-dexamethasone drug combination unique for treating multiple myeloma?

The lenalidomide-dexamethasone combination is unique because it is an oral treatment specifically approved for multiple myeloma patients who have already undergone at least one prior therapy. It significantly improves response rates and survival compared to dexamethasone alone, and is part of a restricted distribution program to ensure safe use. ^{2 3 9 10 11}

Research Team

Jean Roy, MD

Principal Investigator

Ciusss de L'Est de l'Île de Montréal

Eligibility Criteria

This trial is for adults aged 18-65 with multiple myeloma in first relapse post-allogeneic stem cell transplant. Participants must not be pregnant, planning pregnancy, or breastfeeding and must follow strict contraception guidelines. They should have measurable disease but no recent participation in other drug trials, no early post-transplant relapse, no Lenalidomide resistance or active severe infections.

Inclusion Criteria

I am between 18 and 65 years old.

My myeloma has returned after my first stem cell transplant.

You have a detectable disease based on specific criteria at the time of a relapse.

Exclusion Criteria

Your bilirubin, AST and ALT levels are too high, unless it's due to a condition called Gilbert's disease or hemolysis. Your alkaline phosphatase level is also too high.

I do not have an active infection with HIV, HTLV-1 or 2, hepatitis B, or hepatitis C.

You are currently struggling with drug or alcohol abuse.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Lenalidomide and Dexamethasone daily for 21 days with Dexamethasone 40 mg once weekly for 6 cycles of 28 days each

24 weeks

6 visits (in-person) for each cycle

Donor Lymphocyte Infusions (DLIs)

Participants receive 3 donor lymphocyte infusions at specified doses

3 months

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including bone marrow aspirates and PET scans

5 years

Every 3 months for 1 year, then yearly

Treatment Details

Interventions

• Dexamethasone
• DLI
• Lenalidomide

Trial Overview The study tests a two-step treatment combining Lenalidomide (Len) and Dexamethasone (Dex), followed by Donor Leukocytes Infusions (DLIs). This aims to control the disease after relapse from stem cell transplant by creating an environment that allows DLIs to work better while reducing the risk of graft-versus-host disease.

Participant Groups

Group I: Lenalidomide-Dexamethasone-DLI Experimental Treatment 1 Intervention

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.

Dexamethasone is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Ciusss de L'Est de l'Île de Montréal

Lead Sponsor

Trials

81

Recruited

6,400+

C3i Center Inc.

Collaborator

Trials

1

Recruited

10+

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Findings from Research

In a study involving 98 relapsed refractory multiple myeloma patients, treatment with lenalidomide plus dexamethasone resulted in a 52% overall response rate, with 49% achieving partial remission and 3% achieving complete remission, despite patients having undergone a median of 5 prior treatments.

The combination therapy not only provided rapid responses but also extended overall survival by nearly six months, demonstrating its efficacy and safety regardless of previous treatments with thalidomide and bortezomib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium. Delforge, M., Michiels, A., Doyen, C., et al.[2018]

Lenalidomide, when combined with dexamethasone, has shown superior efficacy in treating relapsed multiple myeloma compared to dexamethasone alone, as demonstrated in two large phase III studies that reported improved response rates, progression-free survival, and overall survival.

The drug is administered orally in a 21-day cycle and has manageable side effects, such as neutropenia and venous thrombotic events, making it a viable treatment option for patients who have undergone at least one prior therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

United Kingdom myeloma forum position statement on the use of lenalidomide in multiple myeloma. Davies, F., Morris, C., Bird, J., et al.[2018]

In a phase 2 trial and extended access program involving Chinese patients with relapsed/refractory multiple myeloma, lenalidomide plus low-dose dexamethasone (Rd) demonstrated a manageable safety profile, with 60% of patients experiencing Grade 3-4 adverse events, but no patients discontinued treatment due to these adverse effects.

Rd provided sustained efficacy, with a median duration of response of 35.1 months, median time to progression of 36.9 months, and median progression-free survival of 36.0 months, indicating that long-term treatment can be effective for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term use of lenalidomide and low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: MM-024 Extended Access Program. Du, X., Jin, J., Cai, Z., et al.[2018]

In a study involving 792 patients with relapsed multiple myeloma, the combination of carfilzomib with lenalidomide and dexamethasone significantly improved progression-free survival, with a median of 26.3 months compared to 17.6 months for the control group.

The carfilzomib group also showed a higher overall response rate (87.1% vs. 66.7%) and better health-related quality of life, indicating a favorable risk-benefit profile despite similar rates of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Stewart, AK., Rajkumar, SV., Dimopoulos, MA., et al.[2022]

Lenalidomide combined with dexamethasone has been shown to be effective for treating relapsed/refractory multiple myeloma, and it has received approval from both the FDA and EMA for patients who have undergone at least one prior therapy.

The most common serious side effects include cytopenias and infections, but an expert panel has provided management strategies to minimize these risks, ensuring that patients can receive the full benefits of the treatment without unnecessary dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Palumbo, A., Dimopoulos, M., San Miguel, J., et al.[2018]

In a large observational study of 2150 patients with relapsed/refractory multiple myeloma, lenalidomide plus dexamethasone demonstrated a favorable safety profile, with lower incidence rates of neuropathy and infections compared to other treatments like bortezomib and thalidomide.

The study confirmed that lenalidomide's safety profile in a real-world setting is consistent with previous clinical trial data, with no new safety concerns identified, although it did show a higher incidence of neutropenia compared to bortezomib and thalidomide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. Gamberi, B., Berthou, C., Hernandez, M., et al.[2021]

Lenalidomide, in combination with dexamethasone, was administered to 1438 patients with relapsed or refractory multiple myeloma, showing a median treatment duration of 15.4 weeks and confirming its efficacy in this patient population.

The most common adverse events included hematological issues (49%), gastrointestinal problems (59%), and fatigue (55%), with serious adverse events like pneumonia occurring in 8% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Chen, C., Reece, DE., Siegel, D., et al.[2021]

Lenalidomide, when combined with dexamethasone, significantly improves time to progression in patients with multiple myeloma compared to placebo, as shown in two randomized, double-blind studies.

However, the treatment is associated with serious side effects, including increased risks of neutropenia, thrombocytopenia, and thromboembolic events, leading to its restricted distribution under the RevAssist program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. Hazarika, M., Rock, E., Williams, G., et al.[2020]

Lenalidomide, when combined with dexamethasone, significantly improves response rates and survival in patients with relapsed/refractory multiple myeloma, showing a response rate of 60% compared to 20% with placebo in Phase III trials.

While lenalidomide is effective, it is associated with common adverse events such as hematologic toxicity and venous thromboembolism, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. Larocca, A., Cavallo, F., Mina, R., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium. [2018]

2. England pubmed.ncbi.nlm.nih.gov

United Kingdom myeloma forum position statement on the use of lenalidomide in multiple myeloma. [2018]

3. England pubmed.ncbi.nlm.nih.gov

A multiple myeloma patient who developed ischemic colitis during lenalidomide treatment: A rare case report. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Long-term use of lenalidomide and low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: MM-024 Extended Access Program. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Current treatment strategies with lenalidomide in multiple myeloma and future perspectives. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Adherence to and effectiveness of lenalidomide after 1 year of treatment in a real world setting. [2021]