Iberdomide + Bortezomib + Dexamethasone + Isatuximab for Multiple Myeloma

(BOREALIS Trial)

Recruiting at 4 trial locations

Overseen By Vanessa Huntley

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Canadian Myeloma Research Group

Must not be taking: Steroids, Immunosuppressants, CYP3A4/5 drugs

Disqualifiers: Unstable cardiac disease, Renal failure, 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: 8

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to test a combination of four drugs—iberdomide, bortezomib (Velcade), dexamethasone, and isatuximab—to evaluate their effectiveness and tolerability in people with multiple myeloma. This trial targets those newly diagnosed with this blood cancer who are not eligible for a transplant. It seeks participants who have not yet received treatment and experience symptoms affecting daily life, such as bone pain or fatigue from anemia. Joining the trial could help researchers learn more about these treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require strong inhibitors or inducers of CYP3A4/5, which are certain types of drugs that affect how your body processes medications.

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

Research has shown that using iberdomide with other treatments is generally safe. Patients who took iberdomide with dexamethasone (a steroid that helps reduce swelling) tolerated it well. Some studies also tested iberdomide with bortezomib (a drug that helps control cancer growth) and found it effective and safe.

Bortezomib has treated multiple myeloma for some time. Various studies confirm its general safety for patients, even those with kidney problems. However, concerns exist when bortezomib is used after certain transplants, so discussing health conditions with a doctor is important.

Dexamethasone is commonly used in multiple myeloma treatment. Past research shows that lowering the dose does not affect patient outcomes. Some studies noted serious side effects, but these were uncommon.

Overall, patients with multiple myeloma have generally tolerated these treatments well. Always consult healthcare providers for personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Iberdomide, Bortezomib, Dexamethasone, and Isatuximab for treating multiple myeloma because it introduces Iberdomide, a novel cereblon E3 ligase modulator (CELMoD). Unlike existing treatments that primarily rely on proteasome inhibitors or immunomodulatory drugs, Iberdomide offers a new mechanism by modulating protein degradation pathways, potentially enhancing the immune response against cancer cells. This combination aims to improve efficacy and overcome resistance seen with current therapies, offering hope for better patient outcomes.

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

Previous studies have shown promising results for treating multiple myeloma with the combination of iberdomide, bortezomib, and dexamethasone. Iberdomide, when used with other drugs, has helped 93.1% of patients who cannot undergo a transplant. Bortezomib has controlled the disease and increased survival rates, with some studies showing an 80% survival rate. Dexamethasone alone has been effective in about 50-60% of patients. Together, these treatments appear to manage multiple myeloma effectively and improve patient outcomes. ^{2 3 4 6 7}

Who Is on the Research Team?

Martha Louzada, MD, MSc

Principal Investigator

London Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for individuals aged 65 or older with newly diagnosed multiple myeloma, who haven't been treated yet. They must have certain levels of monoclonal proteins in their blood or urine and signs of organ damage related to the disease. Participants need to understand the study and agree to follow its schedule.

Inclusion Criteria

I am 65 years old or older.

My myeloma is causing organ problems.

i. [C] Calcium elevation in the blood (serum calcium >2.75 mmol/L or >0.25 mmol/L higher than the upper limit of normal) ii. [R] Renal insufficiency (serum creatinine >177 µmol/L) iii. [A] Anemia (hemoglobin <100 g/l or 2 g < laboratory normal) iv. [B] Lytic bone lesions or osteoporosis

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive Iberdomide, Bortezomib, and Dexamethasone for upfront treatment. Isatuximab is added for those not achieving VGPR or MRD negativity after 4 cycles.

16 weeks

4 cycles (each cycle is 28 days)

Intensification

Continued treatment with Iberdomide, Bortezomib, and Dexamethasone for cycles 5-8.

16 weeks

4 cycles (each cycle is 28 days)

Maintenance

Ongoing treatment with Iberdomide, Bortezomib, and Dexamethasone from cycle 9 onwards.

Ongoing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Dexamethasone
• Iberdomide

Trial Overview The study tests a combination treatment using Iberdomide, Bortezomib, Dexamethasone, and Isatuximab added as needed. It aims to see how effective this regimen is for treating multiple myeloma and how well patients tolerate it.

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?

Canadian Myeloma Research Group

Lead Sponsor

Trials

7

Recruited

500+

Published Research Related to This Trial

In a phase 3 study involving 307 patients with relapsed and refractory multiple myeloma, the combination of isatuximab, pomalidomide, and dexamethasone significantly improved progression-free survival (11.5 months) compared to pomalidomide and dexamethasone alone (6.5 months).

The most common side effects included infusion reactions and upper respiratory infections, with a low incidence of treatment-related deaths, indicating that isatuximab is a relatively safe and effective treatment option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal, M., Richardson, PG., Rajkumar, SV., et al.[2020]

In two phase 2 studies involving 256 patients with relapsed or refractory multiple myeloma, adding dexamethasone to bortezomib improved treatment responses, with 18% of patients in the SUMMIT study and 33% in the CREST study showing better outcomes.

The combination therapy did not significantly increase the type or number of adverse events, indicating that dexamethasone can enhance efficacy without adding prohibitive toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Jagannath, S., Richardson, PG., Barlogie, B., et al.[2022]

In a study of 24 patients with relapsed/refractory multiple myeloma (RRMM) showing only biochemical progression, the combination of isatuximab and dexamethasone with methylprednisolone resulted in a 63% overall response rate and a 79% clinical benefit rate, indicating its efficacy.

The treatment was well tolerated, with only 5 instances of Grade ≥3 adverse events, primarily lymphocytopenia, and no severe complications related to respiratory infections, anemia, or thrombocytopenia, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of isatuximab in combination with steroids for the treatment of relapsed/refractory multiple myeloma patients exhibiting only biochemical progression-A single center retrospective study. Regidor, BS., Jew, S., Goldwater, MS., et al.[2023]

In a study of 22 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and dexamethasone (BD therapy) resulted in a high response rate, with 77.3% achieving at least a partial response, indicating its efficacy.

Switching to a once-weekly administration of bortezomib after initial twice-weekly treatment significantly reduced severe gastrointestinal side effects while maintaining the therapy's effectiveness, suggesting a safer dosing strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Fukushima, T., Nakamura, T., Iwao, H., et al.[2015]

In a study of 16 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and dexamethasone resulted in a high clinical response rate of 87.5%, with 6 patients achieving near complete response.

The treatment was associated with manageable side effects, primarily gastrointestinal issues and thrombocytopenia, which were alleviated with supportive care, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma]. Yuan, ZG., Hou, J., Zhou, F., et al.[2015]

In a study of 23 patients with relapsed or refractory multiple myeloma, both low (1.0 mg/m2) and standard (1.3 mg/m2) doses of bortezomib combined with dexamethasone showed similar response rates, with 70% for the low dose and 61.5% for the standard dose, indicating that lower doses can be just as effective.

However, the standard dose of 1.3 mg/m2 was associated with more adverse effects, including serious infections and treatment-related deaths, suggesting that while it may be more effective, it also carries a higher risk of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of bortezomib at different doses in combination with dexamethasone in treatment of relapsed or refractory multiple myeloma: a comparative study]. Bao, L., Lu, XJ., Zhang, XH., et al.[2015]

In a study of 85 patients with relapsed/refractory multiple myeloma, the combination of bortezomib and dexamethasone resulted in a 55% overall response rate, with 19% achieving complete response and 35% achieving very good partial response after a median of 6 treatment cycles.

While bortezomib-dexamethasone was effective, with a median overall survival of 22 months, 78% of patients experienced peripheral neuropathy, highlighting the need for monitoring and management of this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. Pantani, L., Zamagni, E., Zannetti, BA., et al.[2015]

Iberdomide combined with dexamethasone demonstrated meaningful clinical activity in heavily pretreated patients with relapsed or refractory multiple myeloma, achieving an overall response rate of 32% in the dose-escalation cohort and 26% in the dose-expansion cohort, indicating its potential effectiveness even in difficult-to-treat cases.

The treatment was generally safe, with a recommended phase 2 dose established at 1.6 mg, although some patients experienced serious adverse events, including neutropenia and infections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lonial, S., Popat, R., Hulin, C., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1936263/

Bortezomib (Velcade™) in the Treatment of Multiple Myeloma At one year, overall survival was 80% in those who had received bortezomib compared with 67% in the dexamethasone arm, with a six month survival advantage for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4117625/

Bortezomib in multiple myeloma: systematic review and ... In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.

3. myeloma.org myeloma.org/velcade-bortezomib

Velcade (Bortezomib) & Multiple Myeloma Treatment | IMF Velcade has demonstrated the ability to produce a beneficial effect even in patients who were already treated with Velcade in a prior line of therapy. Velcade ...

4. bloodcancerstoday.com bloodcancerstoday.com/post/out-with-the-old-in-with-the-new-shifting-the-standard-of-care-in-myeloma

Shifting the Standard of Care in Myeloma The overall response rate was 73% with once-weekly administration versus 66% with twice-weekly, while the progression-free survival (PFS) was ...

5. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(19)32010-5/fulltext

Three-year Follow-up of CASTOR After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5529203/

Efficacy and safety of bortezomib maintenance in patients ... Bortezomib maintenance statistically significantly improved both progression-free survival (PFS) (hazard ratio (HR) 0.67, 95% confidence interval (CI) = 0.51 to ...

7. consultqd.clevelandclinic.org consultqd.clevelandclinic.org/study-identifies-safety-concern-about-bortezomib-as-post-transplant-gvhd-prophylaxis-in-high-risk-multiple-myeloma

Study Identifies Safety Concern about Bortezomib as Post ... Study Identifies Safety Concern about Bortezomib as Post-Transplant GVHD Prophylaxis in High-Risk Multiple Myeloma. Surprising outcome differs ...