Bortezomib + Pembrolizumab +/- Pelareorep for Multiple Myeloma

Recruiting at 1 trial location

Overseen by Kevin R Kelly, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: University of Southern California

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active infection, CNS metastases, Autoimmune disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a combination of chemotherapy drugs, an immunotherapy drug, and a modified virus to treat patients with difficult-to-treat multiple myeloma. The goal is to see if this combination is safe and effective in killing cancer cells and helping the immune system fight the cancer.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor to understand how your current medications might interact with the trial treatments.

How is the drug combination of Bortezomib, Pembrolizumab, and Pelareorep unique for treating multiple myeloma?

This drug combination is unique because it includes Pembrolizumab, an immunotherapy that helps the immune system attack cancer cells, and Pelareorep, a virus-based therapy that can target and kill cancer cells, alongside Bortezomib, a proteasome inhibitor that disrupts cancer cell growth. This combination aims to enhance the body's immune response against multiple myeloma, which is different from traditional chemotherapy approaches. ^{1 2 3 4 5}

Research Team

Kevin R Kelly, MD

Principal Investigator

University of Southern California

Eligibility Criteria

Adults over 18 with relapsed or refractory multiple myeloma, who've had at least three prior treatments, can join this trial. They should be in good physical condition (ECOG 0-1), have normal thyroid and adrenal hormone levels, and a life expectancy of more than 3 months. People with HIV, active autoimmune diseases requiring recent treatment, certain infections or vaccinations, severe allergies to study drugs' ingredients, CNS metastases, another progressing cancer within the last five years or significant heart issues cannot participate.

Inclusion Criteria

I am fully active or can carry out light work.

Willing and able to comply with scheduled visits, the treatment plan, and laboratory tests

Your thyroid and adrenal hormones are at normal levels.

Exclusion Criteria

I have a serious heart condition.

You have had a severe allergic reaction to certain substances in the past.

I have or had lung inflammation that needed steroids.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive bortezomib, dexamethasone, and pembrolizumab with or without pelareorep in 21-day cycles for up to 18 cycles

54 weeks

18 cycles, each with multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 12 weeks or every 6 months depending on disease status

Treatment Details

Interventions

• Bortezomib (Proteasome Inhibitor)
• Dexamethasone (Corticosteroid)
• Pelareorep (Virus Therapy)
• Pembrolizumab (PD-1 Inhibitor)

Trial Overview The AMBUSH trial is testing how safe and effective it is to combine bortezomib and dexamethasone (chemotherapy) with pembrolizumab (an immunotherapy antibody) either with or without pelareorep (a modified virus). The goal is to see if these combinations are better for treating patients whose multiple myeloma has returned after previous treatments or isn't responding anymore.

Participant Groups

Group I: Cohort II (standard therapy, pelareorep) Experimental Treatment 4 Interventions

Patients receive bortezomib SC or IV and dexamethasone either PO, IV, or IM on days 1, 8, and 15 of each cycle. Patients also receive pelareorep IV over 60 minutes on days 1, 2, 8, 9, 15, and 16 and pembrolizumab IV over 30 minutes on day 9 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Cohort I (standard therapy) Experimental Treatment 3 Interventions

Patients receive bortezomib SC) or IV and dexamethasone PO, IV, or IM on days 1, 8, and 15 of each cycle. Patients also receive pembrolizumab IV over 30 minutes on day 9 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

Bortezomib is already approved in Canada, Japan for the following indications:

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?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

Dr. Samir A.

University of Southern California

Chief Executive Officer since 2024

PhD in Molecular Biology from the University of Southern California

Dr. Chung

University of Southern California

Chief Medical Officer since 2016

MD from UC San Diego

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

In a study of 1162 multiple myeloma patients, those treated with the combination of thalidomide, melphalan, and prednisone (MPT) showed significantly better overall survival (OS) rates compared to those treated with melphalan and prednisone (MP) alone, with median OS of 4.2 years for MPT versus 2.2 years for MP in the first line of treatment.

The relative risk of death was reduced by 39% in the MPT group compared to the MP group in the first line of therapy, indicating that MPT is a more effective treatment option for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma--a retrospective population based study of 1162 patients. Lund, J., Uttervall, K., Liwing, J., et al.[2013]

In a study comparing lenalidomide-dexamethasone (len/dex) and melphalan-prednisone-lenalidomide (MPR) in 89 elderly patients with myeloma, both treatments showed similar efficacy in terms of time to progression, progression-free survival, and overall survival, indicating that either regimen can be effective for this patient group.

However, MPR was associated with significantly higher rates of severe hematologic toxicities, such as neutropenia and thrombocytopenia, suggesting that while both treatments are effective, len/dex may be a safer option with fewer severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. Gay, F., Vincent Rajkumar, S., Falco, P., et al.[2018]

In a study of 75 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib and dexamethasone (Kd56) showed a 60% overall response rate and a median progression-free survival (PFS) of 10 months, indicating its efficacy in a real-world clinical setting.

The treatment was well tolerated, with a low rate of adverse events, including no cases of neuropathy and only 10% of patients experiencing cardiovascular events above grade 3, suggesting a favorable safety profile for elderly and heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. Del Giudice, ML., Gozzetti, A., Antonioli, E., et al.[2023]

In the SPIRIT-P2 study, ixekizumab demonstrated significant efficacy in treating active psoriatic arthritis (PsA) compared to placebo, with higher response rates in ACR20, ACR50, and minimal disease activity across different patient subgroups, regardless of whether they were on background conventional synthetic disease-modifying antirheumatic drugs (cDMARDs).

The safety profile of ixekizumab was consistent with the overall study population, showing comparable rates of treatment-emergent adverse events and serious adverse events, indicating that ixekizumab is a safe and effective option for patients with PsA, including those with prior inadequate response to tumor necrosis factor inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixekizumab is efficacious when used alone or when added to conventional synthetic disease-modifying antirheumatic drugs (cDMARDs) in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor inhibitors. Nash, P., Behrens, F., Orbai, AM., et al.[2022]

Biologic DMARDs, particularly TNF inhibitors, have significantly improved outcomes for rheumatoid arthritis patients, but individual responses can vary due to factors like immunogenicity and pharmacogenetics.

Timely detection of immunogenicity can help avoid ineffective treatments and reduce risks, highlighting the need for clinically validated drug level assays to personalize RA therapy, although evidence-based guidelines are still lacking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunogenicity of anti-TNF biologic agents in the treatment of rheumatoid arthritis. Mok, CC., Tsai, WC., Chen, DY., et al.[2022]

References

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

Addition of thalidomide to melphalan and prednisone treatment prolongs survival in multiple myeloma--a retrospective population based study of 1162 patients. [2013]

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

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma. [2018]

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

Carfilzomib plus dexamethasone in patients with relapsed and refractory multiple myeloma: A retro-prospective observational study. [2023]

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

Ixekizumab is efficacious when used alone or when added to conventional synthetic disease-modifying antirheumatic drugs (cDMARDs) in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor inhibitors. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Immunogenicity of anti-TNF biologic agents in the treatment of rheumatoid arthritis. [2022]