Isatuximab Combination Therapy for Multiple Myeloma

Recruiting at 80 trial locations

Overseen By Trial Transparency email recommended (Toll free number for US & Canada)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sanofi

Must not be taking: Anticoagulants, Antiplatelet, others

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 28 months

258 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining isatuximab (a monoclonal antibody therapy) with other new treatments, with or without dexamethasone, for individuals with multiple myeloma that has returned or stopped responding to treatment. Multiple myeloma is a cancer affecting plasma cells in the bone marrow. The trial includes different groups testing various drug combinations to identify the most effective one. Individuals who have undergone at least two prior treatments for multiple myeloma and still exhibit measurable signs of the disease might be suitable candidates. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering a chance to explore new treatment possibilities.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have taken any anti-multiple myeloma drugs, including dexamethasone, within 14 days before starting the study. There are also specific washout periods for certain therapies, like anti-CD38 drugs, depending on the substudy.

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

Research has shown that isatuximab, a treatment for multiple myeloma, is generally well-tolerated by patients. When combined with other drugs like pomalidomide or dexamethasone, isatuximab rarely causes severe side effects. However, some patients experienced infections, leading 2.8% to 4.9% to stop the treatment.

For the combination of isatuximab with SAR439459 and dexamethasone, detailed safety information for SAR439459 is not yet available, but isatuximab's safety remains consistent. Similarly, when combined with belumosudil or evorpacept, isatuximab relies on its known safety record.

Belantamab mafodotin, another drug in the study, has shown less favorable safety results in some reviews. Despite this, isatuximab's safety in combination therapies is supported by its FDA approval for certain multiple myeloma treatments.

Most of these treatments are in early trial stages, so long-term safety data is limited. Participants should know that while initial findings are promising, more research is needed to fully understand the safety of these combinations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these multiple myeloma treatments because they combine isatuximab with other innovative drugs to potentially improve patient outcomes. Isatuximab is an antibody that targets CD38, a protein found on multiple myeloma cells, and this trial explores its combination with drugs like pegenzileukin, SAR439459, and belantamab mafodotin, each adding a unique mechanism of action. For instance, belantamab mafodotin acts as an antibody-drug conjugate, delivering chemotherapy directly to cancer cells, while SAR439459 is designed to block a specific signaling pathway involved in tumor growth. These combinations aim to enhance the effectiveness of isatuximab, offering hope for better control of the disease compared to existing therapies.

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

In this trial, participants will receive different treatment combinations to evaluate their effectiveness in treating multiple myeloma. Isatuximab, which previous studies have shown to help patients live longer without disease progression, will be tested with various drugs. One arm will combine isatuximab with pomalidomide and dexamethasone, which past research has shown significantly extends the time patients live without disease progression. Another arm will explore isatuximab with belantamab mafodotin, which has reduced tumor size in patients whose multiple myeloma has returned or not responded to treatment. Additional arms will study isatuximab with pegenzileukin, which may boost the immune response against myeloma cells, and with belumosudil, which can cause myeloma cells to die and activate immune cells. Lastly, isatuximab will be tested with evorpacept, which researchers are studying for its potential to improve the effectiveness of isatuximab, aiming to provide better outcomes for patients. ^{1 2 3 6 7}

Who Is on the Research Team?

Clinical Sciences & Operations

Principal Investigator

Sanofi

Are You a Good Fit for This Trial?

Adults with relapsed or refractory multiple myeloma who've had at least 3 prior treatments, including proteasome inhibitors and immunomodulatory drugs, or 2 lines of multiagent regimens. They must have measurable disease levels and be able to use contraception. Those previously treated with anti-CD38 therapy can join if it's been over 6 months since the last dose.

Inclusion Criteria

My multiple myeloma is measurable by specific protein levels in my blood or urine.

I have been treated with anti-CD38 and anti-BCMA therapies.

I have had at least 3 treatments for my multiple myeloma, including specific types.

Exclusion Criteria

I haven't taken any medication for multiple myeloma, including dexamethasone, in the last 14 days.

Your platelet count is less than 50,000 per microliter.

I have a condition that affects how my body absorbs medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive isatuximab in combination with novel agents, with dose escalation and optimization phases, followed by dose expansion

Up to 28 months

Weekly visits initially, then every two weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Belantamab mafodotin
• Dexamethasone
• Isatuximab SAR650984
• Pomalidomide
• SAR439459
• SAR444245

Trial Overview The trial is testing isatuximab combined with new agents like Belumosudil and others, some in controlled experiments. It aims to see how well these combinations work for those whose myeloma has returned after treatment or hasn't responded to standard therapies.

How Is the Trial Designed?

Group I: isatuximab + dexamethasone + belantamab mafodotin (Substudy 03) Experimental Treatment 3 Interventions

Belantamab mafodotin in combination with isatuximab and dexamethasone Part 1: 1 DL of IV belantamab mafodotin in Part 1 and de-escalation dose DL-1: * DL1 belantamab mafodotin IV dose QW4 or de-escalation dose DL-1 QW8 * Isatuximab dose, IV QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. Part 2: * Isatuximab IV dose QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Belantamab mafodotin IV dose Q4W or Q8W * Dexamethasone fixed dose and schedule: QW by mouth.

Group II: isatuximab + SAR439459 + dexamethasone (Substudy 02) Experimental Treatment 3 Interventions

SAR439459 in combination with isatuximab and dexamethasone Part 1: 2 dose levels (DLs) of IV SAR439459: * DL1 SAR439459 dose Q2W. * DL2 SAR439459 dose Q2W. * Isatuximab dose IV QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8). Part 2: * SAR439459 IV dose Q2W. * Isatuximab IV dose QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8).

Group III: Isatuximab + pegenzileukin (Substudy 04) Experimental Treatment 2 Interventions

Pegenzileukin in combination with isatuximab Part 1- dose escalation: * Up to 3 DLs of IV pegenzileukin are planned to be evaluated: * DL1 will explore pegenzileukin at Q2W. * DL2 will explore pegenzileukin at Q2W. * DL3 will explore pegenzileukin at Q2W. * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). Part 1 - dose optimization: * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin at potential doses (DL A and DL B) Q2W. Part 2 (dose expansion): * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin IV dose Q2W.

Group IV: Isatuximab + evorpacept + dexamethasone (Substudy 06) Experimental Treatment 3 Interventions

Isatuximab in combination with evorpacept and dexamethasone Part 1- dose escalation: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization * Evorpacept IV at potential doses (DL A and DL B), Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth

Group V: Experimental: Isatuximab + Dexamethasone + Belumosudil (Substudy 05) Experimental Treatment 3 Interventions

Isatuximab in combination with belumosudil and dexamethasone Part 1- dose escalation: During the first cycle, belumosudil will be evaluated in monotherapy during 2 to 4 weeks, then isatuximab and dexamethasone will be added, and continued for the subsequent cycles. * Belumosudil by mouth at Dose Level (DL) 1, DL2, DL3, and DL4 * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization: * Belumosudil at potential doses (DL A and DL B), daily by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Belumosudil dose daily, by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth

Group VI: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 01) Active Control 3 Interventions

* Isatuximab, intravenous (IV) doseweekly (QW) × 4 weeks (Cycle 1), followed by every two weeks (Q2W) (subsequent cycles). * Pomalidomide dose by mouth daily Day 1 to Day 21. * Dexamethasone dose by mouth QW.

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

Approved in United States as Blenrep for:

• Relapsed or refractory multiple myeloma (approval withdrawn)

Approved in European Union as Blenrep for:

• Relapsed or refractory multiple myeloma

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Published Research Related to This Trial

In a real-world study of 106 patients with relapsed or refractory multiple myeloma, belantamab mafodotin (BM) demonstrated an overall response rate of 38.1% and a median overall survival of 9.3 months, indicating its efficacy as a treatment option for heavily pre-treated patients.

The treatment was associated with significant safety concerns, particularly ophthalmic adverse events, with 48% of patients experiencing eye-related issues, including keratopathy in 37.5% of cases, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study. Talbot, A., Bobin, A., Tabone, L., et al.[2023]

In a study of 27 triple-class refractory multiple myeloma patients, the anti-BCMA monoclonal antibody belantamab mafodotin demonstrated an overall response rate of 52% and a disease control rate of 70%, indicating its effectiveness in a challenging patient population.

The most common side effect was eye toxicity, affecting 44% of patients, with 33.3% experiencing moderate to severe keratopathy, highlighting the need for monitoring eye health during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma. Ntanasis-Stathopoulos, I., Malandrakis, P., Fotiou, D., et al.[2023]

In the DREAMM-2 study involving 196 patients with relapsed or refractory multiple myeloma, belantamab mafodotin demonstrated anti-myeloma activity, with overall response rates of 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort.

The treatment had a manageable safety profile, with common grade 3-4 adverse events including keratopathy and thrombocytopenia, and only two treatment-related deaths, indicating that while there are risks, the benefits may outweigh them for patients with limited options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lonial, S., Lee, HC., Badros, A., et al.[2020]

Belantamab mafodotin (BLENREP) received accelerated FDA approval for treating relapsed or refractory multiple myeloma in adults who have undergone at least four prior therapies, showing an overall response rate of 31% to 34% in the DREAMM-2 trial with 2.5 or 3.4 mg/kg doses.

The most common side effect was keratopathy, affecting 71% to 77% of patients, leading to a boxed warning for ocular toxicity, indicating the need for careful monitoring and a restricted distribution program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma. Baines, AC., Ershler, R., Kanapuru, B., et al.[2023]

Belantamab mafodotin (belamaf) is an effective treatment for relapsed or refractory multiple myeloma, showing a 32% overall response rate in the phase II DREAMM-2 study with 95 patients.

While most patients experienced microcyst-like epithelial changes (MECs) as a side effect, these were generally manageable, with a high resolution rate and no permanent vision loss reported, indicating a need for careful monitoring and collaboration between eye care and oncology professionals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody-Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Farooq, AV., Degli Esposti, S., Popat, R., et al.[2020]

Belantamab mafodotin (belamaf) is an approved treatment for adults with relapsed/refractory multiple myeloma, showing effectiveness by targeting BCMA and eliminating myeloma cells through multiple mechanisms.

The ongoing DREAMM-5 study is exploring the safety and efficacy of belamaf in combination with other novel therapies, which may enhance its anticancer effects compared to belamaf alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design. Nooka, AK., Weisel, K., van de Donk, NW., et al.[2021]

Belantamab mafodotin (belamaf) significantly improves overall survival (OS) and duration of response (DoR) in patients with relapsed/refractory multiple myeloma compared to selinexor plus low-dose dexamethasone, with a hazard ratio of 0.53 for OS and 0.41 for DoR, indicating its efficacy as a treatment option.

Belamaf also shows a favorable safety profile, with fewer severe adverse events compared to selinexor plus dexamethasone, making it a promising single-agent therapy for patients who have already undergone multiple lines of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma. Prawitz, T., Popat, R., Suvannasankha, A., et al.[2022]

Belantamab mafodotin is a first-in-class monoclonal antibody-drug conjugate designed to treat relapsed or refractory multiple myeloma by targeting B-cell maturation antigen (BCMA) and delivering a cytotoxic agent directly to cancer cells.

It received regulatory approval in the USA and EU in August 2020 based on promising results from the DREAMM-2 trial, specifically for patients who have undergone at least four prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belantamab Mafodotin: First Approval. Markham, A.[2021]

In a study of 156 patients with relapsed and refractory multiple myeloma, belantamab-mafodotin (belamaf) demonstrated an overall response rate of 41.8%, with significant improvements in progression-free survival for those achieving at least minimal response (MR).

The safety profile of belamaf was manageable, with corneal events being the most common adverse effects, affecting 87.9% of patients, though only 1.3% discontinued treatment due to ocular toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belantamab Mafodotin in Patients with Relapsed/Refractory Multiple Myeloma: Results of the Compassionate Use or the Expanded Access Program in Spain. de la Rubia, J., Alonso, R., Clavero, ME., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04643002

Study Details | NCT04643002 | Isatuximab in Combination ... The purpose of this umbrella study is to evaluate isatuximab when combined with novel agents with or without dexamethasone in participants with relapsed or ...

2. bloodcancerstoday.com bloodcancerstoday.com/post/fdas-odac-votes-belantamab-mafodotin-at-proposed-dosing-unfavorable-in-multiple-myeloma

FDA's ODAC Votes Belantamab Mafodotin at Proposed ... In DREAMM-8, the rates were 89% with BPd versus 30% with pomalidomide, bortezomib, and dexamethasone (PVd). In both trials, ocular events were ...

3. myeloma.org myeloma.org/news-events/multiple-myeloma-news/eu-approves-sarclisar-isatuximab-irfc-treatment-transplant-eligible-newly-diagnosed-multiple

EU Approves SARCLISA® for Treatment of Myeloma Sarclisa-VRd demonstrated a deep and rapid response in transplant-eligible (TE) NDMM patients compared to VRd alone, reflected by a ...

4. hematologyadvisor.com hematologyadvisor.com/news/blenrep-returns-with-new-fda-approval-in-r-r-multiple-myeloma/

Blenrep Returns With New FDA Approval in R/R Multiple ... The drug had initially received accelerated approval in 2020 for R/R multiple myeloma based on data from the DREAMM-2 study (ClinicalTrials.gov ...

5. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple

FDA approves isatuximab-irfc with bortezomib ... A total of 446 patients were randomized (3:2) to receive either isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) or ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04643002

Study Details | NCT04643002 | Isatuximab in Combination ... The purpose of this umbrella study is to evaluate isatuximab when combined with novel agents with or without dexamethasone in participants with relapsed or ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12042999/

Belantamab Mafodotin Monotherapy for Multiply‐Relapsed ... Belantamab mafodotin (belamaf) was the first BCMA‐targeting immunotherapy licensed in myeloma and was available as monotherapy for a fifth or greater line of ...