Quadruple Drug Therapy for Multiple Myeloma

Overseen By Larysa Sanchez

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Larysa Sanchez

Must not be taking: NSAIDs, Aminoglycosides

Disqualifiers: Peripheral neuropathy, Kidney failure, Cardiac disease, Hepatitis, 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: 13

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single center, open-label, phase 2 study in elderly (age ≥ 70) subjects with newly diagnosed multiple myeloma who are transplant ineligible. Subjects will receive subcutaneous daratumumab, dose-attenuated bortezomib, revlimid, and dexamethasone until confirmed disease progression, discontinuation of study treatment due to unacceptable drug toxicity, or other reasons. Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and clinical response.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you should avoid NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of enrollment, except aspirin. It's best to discuss your current medications with the study team.

What evidence supports the effectiveness of the quadruple drug therapy for multiple myeloma?

Research shows that combinations of drugs like bortezomib, lenalidomide, and dexamethasone are effective in treating multiple myeloma, with studies indicating improved response rates and prolonged survival. Adding daratumumab to similar regimens has shown promise in achieving deeper responses, suggesting that the quadruple drug therapy could be effective. ^{1 2 3 4 5}

What safety data exists for the combination of lenalidomide and dexamethasone in treating multiple myeloma?

Lenalidomide combined with dexamethasone is generally well tolerated in patients with multiple myeloma, though common side effects include low blood cell counts, fatigue, muscle cramps, rash, infections, trouble sleeping, and blood clots. This combination has been approved by health authorities for use in patients who have had previous treatments, and strategies are in place to manage these side effects effectively. ^{6 7 8 9 10}

How is the quadruple drug therapy for multiple myeloma unique?

The quadruple drug therapy for multiple myeloma is unique because it combines four drugs—Bortezomib, Daratumumab, Dexamethasone, and Lenalidomide—each with different mechanisms to target the cancer more effectively. This combination aims to improve treatment outcomes by using a broader approach compared to the more common three-drug regimens. ^{1 2 5 11 12}

Research Team

Larysa Sanchez

Principal Investigator

Icahn School of Medicine at Mount Sinai

Sundar Jagannath, MBBS

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for people aged 70 or older with newly diagnosed multiple myeloma who can't have a stem cell transplant. They should be able to perform daily activities (ECOG ≤ 2) and have measurable disease indicators. Men must use contraception if sexually active with women of childbearing potential. People are excluded if they have certain heart, lung, kidney diseases, infections, severe allergies to the drugs being tested, or other health conditions that could affect drug absorption or pose risks.

Inclusion Criteria

I am 70 or older, ineligible for a specific stem cell transplant, and can care for myself despite my myeloma.

You have a measurable amount of M-protein in your blood or urine, or abnormal results in a serum free light chain assay.

I have been newly diagnosed with multiple myeloma and have not received treatment.

Exclusion Criteria

You have tested positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

Your platelet count is less than 75,000 cells per cubic millimeter.

I haven't had any cancer treatment in the last 3 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Initial Treatment

Participants receive 12 cycles of daratumumab in combination with dose-attenuated VRd

48 weeks

12 visits (in-person, monthly)

Maintenance Therapy

Participants receive maintenance therapy with daratumumab and either lenalidomide or ixazomib based on cytogenetic risk status

Up to 2 years

Monthly visits (in-person)

Long-term Follow-up

Participants are monitored for safety and effectiveness after treatment

At least 1 year

Periodic visits (in-person or virtual)

Treatment Details

Interventions

• Bortezomib
• Daratumumab
• Dexamethasone
• Lenalidomide

Trial Overview The study tests a combination of subcutaneous daratumumab with lower doses of bortezomib, lenalidomide (revlimid), and dexamethasone in elderly patients who cannot undergo transplantation. The treatment continues until disease progression or unacceptable side effects occur while monitoring for safety and effectiveness.

Participant Groups

Group I: Daratumumab with dose-attenuated VRd Experimental Treatment 5 Interventions

SubQ Daratumumab with Dose-Attenuated VRd

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

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Larysa Sanchez

Lead Sponsor

Trials

2

Recruited

40+

Ajai Chari

Lead Sponsor

Trials

5

Recruited

100+

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

Findings from Research

In a phase II study involving 31 patients under 65 years old with newly diagnosed multiple myeloma, the combination therapy of lenalidomide, bortezomib, and dexamethasone (RVD) led to high response rates, with 87% of patients achieving a very good partial response or better after consolidation therapy.

The treatment showed favorable safety, with no treatment-related mortality and a 100% overall survival rate at 3 years; importantly, 68% of patients achieved minimal residual disease (MRD) negativity, and none of these patients relapsed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. Roussel, M., Lauwers-Cances, V., Robillard, N., et al.[2022]

The introduction of bortezomib and lenalidomide, especially in combination with dexamethasone, has significantly improved treatment outcomes for multiple myeloma, leading to better response rates and longer durations of response compared to older therapies.

Triplet regimens like lenalidomide, bortezomib, and dexamethasone (RVD) have shown enhanced efficacy and good tolerability in both newly diagnosed and relapsed/refractory multiple myeloma patients, indicating a promising approach for improving patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of multiple myeloma with lenalidomide and bortezomib combination therapy]. Takeda, Y., Sakaida, E., Nakaseko, C.[2018]

Thalidomide, when used as a first-line treatment combined with conventional chemotherapy, has been shown to improve survival rates in patients over 65, despite its potential toxicity to the peripheral nervous system.

Bortezomib and lenalidomide, both effective in treating myeloma relapse, can be used in combination with dexamethasone and each other, indicating a shift towards using these agents to manage myeloma as a chronic disease rather than relying solely on traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drugs for myeloma]. Moreau, P.[2019]

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]

In a study comparing two induction therapies for newly diagnosed multiple myeloma, the quadruplet regimen (D-VTd) showed significantly better response rates after treatment, with 90.5% achieving complete remission (CR) or stringent complete remission (sCR) compared to 68.6% in the triplet regimen (VRd).

The quadruplet regimen (D-VTd) also resulted in a higher rate of very good partial response (VGPR or better) at 93%, compared to 67.6% in the triplet regimen (VRd), although VRd was associated with a higher incidence of skin rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. Byun, JM., Park, SS., Yoon, SS., et al.[2023]

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 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 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 of 68 older patients (70 years and above) with bortezomib-resistant multiple myeloma, treatment with lenalidomide and low-dose dexamethasone resulted in a positive response in all patients over a median duration of 12 months.

Despite significant renal dysfunction at the start of treatment, all patients showed improvement in renal function by the end, indicating that this combination therapy is both effective and safe for older patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-adjusted Lenalidomide Combined with Low-dose Dexamethasone Rescues Older Patients with Bortezomib-resistant Multiple Myeloma. Yamasaki, S., Kohno, K., Kadowaki, M., 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]

In a study of 78 patients with relapsed or refractory multiple myeloma, the combination of bortezomib, bendamustine, and prednisone showed a 69% response rate, indicating significant efficacy in treating this condition.

Patients without severe prior hematological toxicities had a median progression-free survival (PFS) of 11 months and overall survival (OS) of 50 months, while those with severe toxicities had much poorer outcomes, highlighting the importance of patient health status in treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. Pönisch, W., Bourgeois, M., Moll, B., et al.[2021]

Bortezomib is recommended for use in both newly diagnosed and relapsed/refractory multiple myeloma patients, whether they are eligible for autologous stem cell transplantation or not, based on a systematic review of evidence.

The guidelines also emphasize the importance of monitoring and managing potential toxicities associated with bortezomib treatment, such as the risk of herpes zoster reactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. Kouroukis, CT., Baldassarre, FG., Haynes, AE., et al.[2015]

References

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

Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

[Treatment of multiple myeloma with lenalidomide and bortezomib combination therapy]. [2018]

3. France pubmed.ncbi.nlm.nih.gov

[New drugs for myeloma]. [2019]

4. 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]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study. [2023]

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

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

7. England pubmed.ncbi.nlm.nih.gov

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

8. 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]

9. Japan pubmed.ncbi.nlm.nih.gov

Dose-adjusted Lenalidomide Combined with Low-dose Dexamethasone Rescues Older Patients with Bortezomib-resistant Multiple Myeloma. [2018]

10. 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]

11. Germany pubmed.ncbi.nlm.nih.gov

Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. [2015]