Lenalidomide +/- Daratumumab for Multiple Myeloma

(DRAMMATIC Trial)

Recruiting at 814 trial locations

Overseen By Tatjana Kolevska, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: SWOG Cancer Research Network

Must be taking: DVT prophylaxis

Must not be taking: Investigational agents

Disqualifiers: Smoldering myeloma, Plasma cell leukemia, Amyloidosis, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 0

1100 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients are enrolled to screening (Reg Step 1) prior to or after ASCT but prior to Reg Step 2. Patients are followed until they will begin Maintenance and then registered to Reg Step 2 (first randomization). Patients are randomized between Lenalidomide for 2 years and Lenalidomide + Daratumumab/rHuPH20. After 2 years of Maintenance, MRD is assessed to guide further therapy. MRD-positive patients will continue with the assigned treatment. MRD-negative patients will be further randomized (Reg Step 3) to either continue or discontinue the assigned treatment. Patients are treated for up to 7 years from Step 2 reg and followed for up to 15 years.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must not have received any investigational agents within 14 days prior to registration, and you must be able to take DVT prophylaxis (blood clot prevention medication).

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

Research shows that adding daratumumab to lenalidomide and dexamethasone significantly improves outcomes for patients with multiple myeloma, including longer periods without disease progression and higher overall survival rates. In one study, the combination had an 80% response rate, indicating it is effective in treating this condition. ^{1 2 3 4 5}

Is the combination of Lenalidomide and Daratumumab safe for treating multiple myeloma?

The combination of Lenalidomide and Daratumumab has been studied in multiple myeloma patients and is generally considered safe. Common side effects include low blood cell counts (neutropenia, thrombocytopenia, anemia), nerve damage (peripheral sensory neuropathy), and infections. Infusion-related reactions, mostly mild, can occur, especially during the first treatment. ^{4 5 6 7 8}

What makes the drug Lenalidomide combined with Daratumumab unique for treating multiple myeloma?

This drug combination is unique because it pairs lenalidomide, an immunomodulatory drug, with daratumumab, a monoclonal antibody that targets CD38 on myeloma cells, enhancing the immune system's ability to kill these cancer cells. This combination has shown to improve progression-free survival and overall response rates in patients with multiple myeloma. ^{4 5 7 9 10}

Research Team

Parameswaran Hari, MD

Principal Investigator

Medical College of Wisconsin

Amrita Y. Krishnan

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for adults aged 18-75 with symptomatic multiple myeloma who've had induction therapy and a stem cell transplant within the last year. They must be able to take oral meds, have good kidney and liver function, no severe lung issues or uncontrolled infections, and not allergic to study drugs. HIV-positive patients can join if their viral load is undetectable.

Inclusion Criteria

My liver is working well.

I started my initial cancer treatment within the last year and have completed at least two cycles.

I can take and swallow pills whole.

Exclusion Criteria

I haven't had severe asthma in the last 2 years and my asthma is currently under control.

My multiple myeloma has not spread to my brain or spinal cord.

My cancer has not worsened before signing up for this trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Maintenance Treatment

Participants receive Lenalidomide or Lenalidomide + Daratumumab/rHuPH20 for maintenance therapy

2 years

Monthly visits for drug administration

MRD Assessment and Continued Treatment

MRD is assessed to guide further therapy; MRD-positive patients continue treatment, MRD-negative patients are further randomized

Up to 7 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Treatment Details

Interventions

• Daratumumab/rHuPH20
• Lenalidomide

Trial Overview The trial tests Lenalidomide alone versus Lenalidomide plus Daratumumab/rHuPH20 as maintenance therapy post-autologous stem cell transplant (ASCT) in multiple myeloma patients. It uses MRD status after two years of treatment to decide further therapy duration, with possible treatment up to seven years.

Participant Groups

Group I: Arm 2: Lenalidomide + Daratumumab/rHuPH20 Experimental Treatment 2 Interventions

Lenalidomide 10 mg/day, D1-28, q28 days for 3 cycles, then 15 mg/day, D1-28 for up to 2 years from starting treatment. Plus Daratumumab/rHuPH20 1800 mg/30,000 units D1, 8, 15, 22 q 28 days for 2 cycles, then D 1 and 15 q 28 days for cycles 3-6 then D1 q 28 days for subsequent cycles for up to 2 years from starting treatment.

Group II: Arm 2b: Stop Lenalidomide + Daratumumab/rHuPH20 Active Control 1 Intervention

MRD- and randomized to Arm 2b: Discontinue protocol therapy.

Group III: Arm 1a: Continue Lenalidomide Active Control 1 Intervention

MRD+ or MRD- and randomized to Arm 1a: Lenalidomide 10 mg/day, D1-28, q28 days for 3 cycles, then 15 mg/day, D1-28 for up to 7 years from starting treatment.

Group IV: Arm 1b: Stop Lenalidomide Active Control 1 Intervention

MRD- and randomized to Arm 1b: Discontinue protocol therapy.

Group V: Study Entry / Screening Active Control 1 Intervention

Study entry/screening to follow patient until Maintenance.

Group VI: Arm 1: Lenalidomide Active Control 1 Intervention

Lenalidomide 10 mg/day, D1-28, q28 days for 3 cycles, then 15 mg/day, D1-28 for up to 2 years from starting treatment.

Group VII: Arm 2a: Continue Lenalidomide + Daratumumab/rHuPH20 Active Control 2 Interventions

MRD+ or MRD- and randomized to Arm 2a: Lenalidomide 10 mg/day, D1-28, q28 days for 3 cycles, then 15 mg/day, D1-28 for up to 7 years from starting treatment. Plus Daratumumab/rHuPH20 1800 mg/30,000 units D1, 8, 15, 22 q 28 days for 2 cycles, then D 1 and 15 q 28 days for cycles 3-6 then D1 q 28 days for subsequent cycles for up to 7 years from starting treatment.

Lenalidomide is already approved in European Union, United States for the following indications:

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Who Is Running the Clinical Trial?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

Janssen, LP

Industry Sponsor

Trials

169

Recruited

329,000+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Mental Health Therapies

Top Products

Imodium, Remicade, Invega, Procrit

Joaquin Duato

Janssen, LP

Chief Executive Officer since 2022

MBA from ESADE Business School

Biljana Naumovic

Janssen, LP

Chief Medical Officer since 2023

MD from Belgrade University Medical School

Adaptive

Collaborator

Trials

1

Recruited

1,100+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination therapy of carfilzomib, lenalidomide, dexamethasone, and daratumumab achieved a high minimal residual disease (MRD) negativity rate of 71% in newly diagnosed multiple myeloma patients, indicating effective treatment without the need for high-dose melphalan chemotherapy or autologous transplant.

The treatment demonstrated excellent safety and tolerability, with a 1-year progression-free survival rate of 98% and no reported deaths, although some patients experienced grade 3 or 4 adverse events like neutropenia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. Landgren, O., Hultcrantz, M., Diamond, B., et al.[2022]

A systematic review of seven randomized controlled trials involving 4268 patients with multiple myeloma showed that combination regimens containing daratumumab significantly improved overall response rates compared to control groups.

While daratumumab enhanced treatment efficacy in both standard-risk and high-risk patients, it was associated with a higher incidence of severe neutropenia and pneumonia, indicating a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of daratumumab in the treatment of multiple myeloma: a systematic review and meta-analysis. Wang, Y., Li, Y., Chai, Y.[2021]

In a study of 178 multiple myeloma patients who progressed after daratumumab treatment, the median progression-free survival (PFS) was only 4.5 months and overall survival (OS) was 14.2 months, indicating limited effectiveness of subsequent therapies.

Patients receiving pomalidomide-based therapy had a slightly better median PFS and OS (5.2 months and 21.7 months, respectively) compared to those on carfilzomib-based therapy, highlighting the need for new treatment options for patients previously treated with daratumumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis. LeBlanc, R., Mian, H., Reece, D., et al.[2023]

In a study of 737 patients with newly diagnosed multiple myeloma, the addition of daratumumab to lenalidomide and dexamethasone significantly reduced the risk of disease progression or death, with a hazard ratio of 0.56, indicating a 44% lower risk compared to the control group.

Patients receiving daratumumab had a higher rate of complete response (47.6% vs. 24.9%) and a greater percentage achieving minimal residual disease status (24.2% vs. 7.3%), although they also experienced more severe side effects like neutropenia and pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. Facon, T., Kumar, S., Plesner, T., et al.[2023]

Daratumumab, when combined with lenalidomide and dexamethasone (DRd) or bortezomib and dexamethasone (DVd), showed an overall response rate of 80% in 171 heavily treated patients with relapsed/refractory multiple myeloma, indicating its efficacy in this challenging patient population.

Patients receiving the DRd combination experienced better progression-free survival (PFS) compared to those on DVd, with PFS rates of 84% and 77%, respectively, while the treatment was generally safe, with common side effects including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. Fazio, F., Franceschini, L., Tomarchio, V., et al.[2022]

In the POLLUX study, after 25.4 months of follow-up, the combination of daratumumab with lenalidomide and dexamethasone significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma, with a hazard ratio of 0.41 compared to lenalidomide/dexamethasone alone.

The overall response rate was notably higher with the daratumumab combination (92.9%) compared to the control (76.4%), and a significant proportion of patients achieved minimal residual disease negativity (26.2% vs 6.4%), indicating a deeper response without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Dimopoulos, MA., San-Miguel, J., Belch, A., et al.[2019]

Daratumumab combined with lenalidomide and dexamethasone showed an impressive overall response rate of 81% in patients with relapsed/refractory multiple myeloma, indicating its efficacy in this challenging patient population.

The treatment was well tolerated, with no dose-limiting toxicities observed and manageable infusion-related reactions, suggesting a favorable safety profile consistent with previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Plesner, T., Arkenau, HT., Gimsing, P., et al.[2022]

Daratumumab, an anti-CD38 monoclonal antibody, has significantly improved treatment outcomes for multiple myeloma (MM), showing enhanced progression-free survival and response rates in relapsed/refractory cases when combined with other therapies, as demonstrated in several key clinical trials.

In newly diagnosed patients, daratumumab has also shown an overall survival benefit when added to frontline treatment regimens, indicating its effectiveness in both early and advanced stages of MM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations. Arnall, JR., Maples, KT., Harvey, RD., et al.[2022]

In a phase 3 trial with 569 patients, the addition of daratumumab to lenalidomide and dexamethasone significantly improved progression-free survival, with only 18.5% of patients experiencing disease progression compared to 41.0% in the control group.

Daratumumab also resulted in a higher overall response rate (92.9% vs. 76.4%) and a greater percentage of patients achieving minimal residual disease status (22.4% vs. 4.6%), although it was associated with a higher incidence of neutropenia and infusion-related reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. Dimopoulos, MA., Oriol, A., Nahi, H., et al.[2022]

Combining lenalidomide with daratumumab significantly enhances the ability of the immune system to kill multiple myeloma cells, as shown in assays using both cell lines and primary patient cells.

The synergy between lenalidomide and daratumumab was particularly evident in the bone marrow environment of multiple myeloma patients, suggesting that this combination could be a powerful treatment strategy in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. van der Veer, MS., de Weers, M., van Kessel, B., et al.[2021]

References

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

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. [2022]

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

Efficacy and safety of daratumumab in the treatment of multiple myeloma: a systematic review and meta-analysis. [2021]

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

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis. [2023]

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

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. [2023]

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

Daratumumab combined with dexamethasone and lenalidomide or bortezomib in relapsed/refractory multiple myeloma (RRMM) patients: Report from the multiple myeloma GIMEMA Lazio group. [2022]

6. Italy pubmed.ncbi.nlm.nih.gov

Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. [2019]

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

Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. [2022]

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

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations. [2022]

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

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. [2021]