Bortezomib + Pembrolizumab +/- Pelareorep for Multiple Myeloma

Not currently recruiting at 1 trial location

Overseen By Christine Duran

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Southern California

Must not be taking: Immunosuppressants, Steroids

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

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

Compensation: Varies

Number of Visits: 30

Duration: 54 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for people with multiple myeloma, a type of blood cancer that has returned or isn't responding to existing treatments. Researchers are studying the safety and effectiveness of combining chemotherapy drugs (bortezomib and dexamethasone), an immune therapy (pembrolizumab), and a lab-modified virus (pelareorep) to kill cancer cells. The trial includes two groups: one receives standard therapy with pembrolizumab, while the other adds pelareorep. People who have tried at least three different treatments for multiple myeloma might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that combining bortezomib and pembrolizumab is generally well-tolerated in patients with multiple myeloma. Previous research indicated that patients experienced common side effects like tiredness and nausea, typical of cancer treatments. However, most effects were manageable.

Adding pelareorep keeps safety a key focus. Ongoing research aims to fully understand the safety of this combination. Pelareorep, a lab-modified virus, targets cancer cells without harming normal cells. As this approach is still under study, detailed safety information is not yet fully available.

Overall, since this trial is in early stages (Phase 1 and Phase 2), it closely monitors safety and manages any risks. Participants will be carefully observed for side effects to ensure the treatment remains as safe as possible. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple myeloma because they combine powerful drugs in a new way. Bortezomib and dexamethasone are standard treatments, but adding pembrolizumab and pelareorep brings something new to the table. Pembrolizumab is an immunotherapy that helps the immune system fight cancer more effectively, while pelareorep is a virus-based therapy that can attack cancer cells. This combo could enhance the body's natural defenses and directly target the cancer, offering a potentially more effective approach than traditional therapies alone.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

This trial compares two treatment approaches for multiple myeloma. In one arm, participants receive a combination of bortezomib, dexamethasone, and pembrolizumab. Research shows that these drugs together may help treat multiple myeloma by stopping cancer cells from growing and spreading. Early research suggests that pembrolizumab, a type of immunotherapy, might enhance the body's ability to fight cancer.

In the other arm, participants receive the same combination with the addition of pelareorep, a modified virus that targets cancer cells without harming normal ones. Although limited human data exists on pelareorep, it is thought to boost the immune system's response to cancer. The trial aims to determine if adding pelareorep makes the treatment more effective than the standard combination alone. ^{3 4 5 6 7}

Who Is on the Research Team?

Kevin R Kelly, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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.

I have or had lung inflammation that needed steroids.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Dexamethasone
• Pelareorep
• Pembrolizumab

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.

How Is the Trial Designed?

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 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?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4560339/

Promising therapies in multiple myeloma - PMC Randomized trials are now underway comparing KRd to lenalidomide/bortezomib/dexamethasone in newly diagnosed patients, and results of these studies are awaited ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05514990?rank=1&term=NCT05514990

Bortezomib and Pembrolizumab With or Without ... Giving the combination of bortezomib, dexamethasone, and pembrolizumab with pelareorep may work better in treating patient with multiple myeloma. Detailed ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10821908/

harnessing the immune system to battle multiple myeloma Although this study showed an acceptable safety and efficacy of pembrolizumab in combination with lenalidomide and low-dose dexamethasone for R/ ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2312054

Daratumumab, Bortezomib, Lenalidomide, and ... An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients

5. nature.com nature.com/articles/s41408-023-00804-y

Clinical evidence for immune-based strategies in early-line ... We discuss the current treatment landscape for early-line treatment of MM, with a focus on immune-based agents, and associated clinical investigations.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4646042/

Pembrolizumab (MK-3475) in combination with ... An open-label, Phase I, multicenter, nonrandomized, dose-escalation trial will evaluate the safety, tolerability, and efficacy of pembrolizumab in combination ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02036502

NCT02036502 | A Study of Pembrolizumab (MK-3475) in ... This is a study of pembrolizumab (MK-3475) in combination with lenalidomide and low-dose dexamethasone in participants with refractory or relapsed and ...