Isatuximab + Dexamethasone + Lenalidomide for Multiple Myeloma

(UltraFrailMM Trial)

Overseen By Rachel Kingsford

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Must be taking: Isatuximab, Dexamethasone

Disqualifiers: Investigational agents, Severe hypersensitivity, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 9 cycles (each cycle is 28 days)

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a gentle treatment plan for ultra-frail patients with multiple myeloma, a type of blood cancer. Researchers aim to determine if starting with two medications, Isatuximab (a monoclonal antibody) and dexamethasone, and later adding a third, lenalidomide, can help patients adhere to treatment and improve their daily lives. This approach suits those newly diagnosed with myeloma or Plasma Cell Leukemia who have received minimal prior treatment and have a high frailty score, indicating vulnerability. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that subjects currently taking prohibited medications are excluded. It's best to discuss your current medications with the trial team to see if they are allowed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of isatuximab, dexamethasone, and lenalidomide may help treat multiple myeloma. In earlier studies, most patients tolerated this combination well, with generally manageable side effects. However, some patients experienced more serious side effects, such as decreased blood cell counts.

Another study confirmed the safe dose of isatuximab when used with the other two drugs, ensuring safety. This testing found a balance between effectiveness and tolerability.

Overall, while some risks exist, this combination treatment demonstrated a reasonable safety profile in past trials. Participants considering this treatment should discuss potential side effects with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for multiple myeloma?

Researchers are excited about the combination of Isatuximab with dexamethasone and lenalidomide for multiple myeloma because Isatuximab offers a novel way to attack the cancer. Unlike most current treatments, which typically work by suppressing the immune system or directly killing cancer cells, Isatuximab is an antibody that targets a specific protein on the surface of myeloma cells called CD38. This targeted approach not only helps the immune system recognize and attack the cancer cells more effectively but also potentially reduces damage to healthy cells, leading to fewer side effects. This precise targeting might make it a game-changer for patients who have limited options with the existing standard therapies.

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

Research has shown that Isatuximab, when combined with other treatments, effectively treats multiple myeloma. In one study, 74% of patients maintained stable disease for over 20 months. Another study found that 63% of patients remained disease-free for five years with this treatment combination. On its own, Isatuximab benefited about a quarter of patients by shrinking their cancer or halting its growth, with a response rate of 26.3%. The treatment acts quickly, with patients experiencing improvements within one month, and these effects can last over 10 months. These findings suggest that Isatuximab can be a strong component of a multiple myeloma treatment plan. ^{6 7 8 9 10}

Who Is on the Research Team?

Ghulam Rehman Mohyuddin, MBBS

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

This trial is for ultra-frail patients with multiple myeloma who often have difficulty tolerating standard treatments. It's designed to test if starting treatment slowly improves their ability to stick with the therapy and enhances their quality of life.

Inclusion Criteria

IMWG defined frailty score ≥ 3. IMWG definition available here: http://www.myelomafrailtyscorecalculator.net

I agree to use a latex condom during sex throughout the study, even though I've had a vasectomy.

I agree to follow the birth control requirements and participate in the Lenalidomide REMS program.

Exclusion Criteria

Receiving other investigational agents

I am severely allergic to certain drugs or ingredients used in this study.

Any condition that would, in the Investigator's judgment, compromise the subject's ability to understand the subject information, give informed consent, and/or contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, subjects may not receive the drug through a feeding tube, social/ psychological issues, etc.)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Isatuximab and Dexamethasone initially, with Lenalidomide introduced from the third cycle onwards

9 cycles (each cycle is 28 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Isatuximab

Trial Overview The study tests a 'go-slow' approach using Isatuximab and Dexamethasone initially, then gradually introducing Lenalidomide from the third cycle onwards. The aim is to see if this method reduces early treatment mortality and increases adherence in frail patients.

How Is the Trial Designed?

Group I: Combination Treatment Experimental Treatment 1 Intervention

Isatuximab

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

Approved in European Union as Sarclisa for:

• Multiple myeloma

Approved in United States as Sarclisa for:

• Multiple myeloma in combination with pomalidomide and dexamethasone for adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
• Multiple myeloma in combination with carfilzomib and dexamethasone for adults with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
• Newly diagnosed multiple myeloma in combination with bortezomib, lenalidomide, and dexamethasone for adults who are not eligible for autologous stem cell transplant

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Sanofi

Industry 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

Isatuximab, an anti-CD38 monoclonal antibody, significantly improves progression-free survival and tumor response when combined with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma, based on phase III studies.

The combination therapies involving isatuximab were generally well tolerated, maintaining health-related quality of life and showing a manageable safety profile without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab: A Review of Its Use in Multiple Myeloma. Frampton, JE.[2022]

Isatuximab is an IgG1 monoclonal antibody that targets CD38 on cancer cells and has been approved in the USA for treating multiple myeloma in patients who have undergone at least two prior therapies.

The approval of isatuximab, in combination with pomalidomide and dexamethasone, marks a significant advancement in treatment options for adult patients with relapsed and refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab: First Approval. Dhillon, S.[2021]

In a phase 3 study involving 302 patients with relapsed multiple myeloma, the addition of isatuximab to carfilzomib-dexamethasone significantly improved progression-free survival compared to carfilzomib-dexamethasone alone, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of disease progression.

While the isatuximab group experienced a higher rate of treatment-emergent adverse events (77% vs. 67%), the overall safety profile was similar, with no significant difference in fatal adverse events, suggesting that isatuximab can be safely integrated into treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Moreau, P., Dimopoulos, MA., Mikhael, J., et al.[2022]

In a phase 2 study involving 164 patients with relapsed/refractory multiple myeloma, the combination of isatuximab and dexamethasone showed a significantly higher overall response rate (43.6%) compared to isatuximab alone (23.9%).

The addition of dexamethasone did not increase safety concerns, as the incidence of serious adverse events, including infections, was similar between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab as monotherapy and combined with dexamethasone in patients with relapsed/refractory multiple myeloma. Dimopoulos, M., Bringhen, S., Anttila, P., et al.[2023]

In a phase 1b study involving 57 patients with relapsed/refractory multiple myeloma, the combination of isatuximab, lenalidomide, and dexamethasone was found to be generally well tolerated, with only one dose-limiting toxicity reported, indicating a favorable safety profile.

The treatment demonstrated an overall response rate of 56% and a median progression-free survival of 8.5 months, suggesting that isatuximab is an effective option for patients who have previously undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Martin, T., Baz, R., Benson, DM., et al.[2021]

In a Phase 3 trial with 302 patients suffering from relapsed/refractory multiple myeloma, the combination of isatuximab with carfilzomib-dexamethasone significantly prolonged progression-free survival (PFS) to a median of 35.7 months compared to 19.2 months for carfilzomib-dexamethasone alone.

The addition of isatuximab also resulted in higher rates of complete response (44.1% vs 28.5%) and minimal residual disease negativity (33.5% vs 15.4%), indicating improved efficacy without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Martin, T., Dimopoulos, MA., Mikhael, J., et al.[2023]

In a subgroup analysis of 36 East Asian patients with relapsed/refractory multiple myeloma, the combination of isatuximab, pomalidomide, and dexamethasone (Isa-Pd) showed improved progression-free survival compared to pomalidomide and dexamethasone alone, with a median progression-free survival not reached in the Isa-Pd group versus 7.9 months in the Pd group.

The safety profile of Isa-Pd in East Asian patients was consistent with the overall population, although a higher incidence of Grade ≥ 3 neutropenia was observed, indicating that while the treatment is effective, monitoring for this side effect is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis. Sunami, K., Ikeda, T., Huang, SY., 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 Phase 1b study involving 73 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation, the combination of isatuximab with bortezomib-lenalidomide-dexamethasone (Isa-VRd) showed a remarkable overall response rate of 98.6%, with over half of the patients achieving a complete response.

While 79.5% of patients experienced grade ≥3 treatment-emergent adverse events, the pharmacokinetics of isatuximab remained consistent, indicating that the combination treatment does not affect its metabolism, supporting further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation. Ocio, EM., Perrot, A., Bories, P., et al.[2023]

Isatuximab, a monoclonal antibody targeting CD38, was shown to significantly improve progression-free survival in adult patients with relapsed and refractory multiple myeloma when used in combination with pomalidomide and dexamethasone, compared to pomalidomide plus dexamethasone alone.

While treatment with isatuximab was associated with a higher incidence of treatment-related adverse events, including serious complications, the overall safety profile was deemed acceptable, leading to a positive benefit-risk ratio for its use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Isatuximab in Combination with Pomalidomide and Dexamethasone for the Treatment of Adult Patients with Relapsed and Refractory Multiple Myeloma. Delgado, J., Zienowicz, M., van Hennik, PB., et al.[2021]

Citations

1. sarclisa.com sarclisa.com/previously-treated-trial-results

for adults with previously treated multiple myeloma In an earlier analysis, at a median follow-up of 20.7 months, 74% (133 of 179 patients) lived progression free with SARCLISA + Kd vs 59% (73 of 123 patients) ...

2. myeloma.org myeloma.org/sarclisa-isatuximab-irfc

Sarclisa (isatuximab-irfc) The study included 307 patients from 96 centers across 24 countries. The main efficacy outcome measure was progression-free survival (PFS) using IMWG criteria.

3. sarclisahcp.com sarclisahcp.com/imroz-efficacy

IMROZ Efficacy - SARCLISA® (isatuximab-irfc) Higher 5-year PFS rate with SARCLISA + VRd vs VRd alone: 63% of patients remained alive and progression free at a median follow-up of 60 months. PFS results ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40257476/

Efficacy and safety of isatuximab monotherapy to treat ... Isatuximab 20 mg/kg monotherapy was effective in the treatment of individuals with RRMM, with an overall response rate (ORR) of 26.3%, a median progression- ...

5. cancernetwork.com cancernetwork.com/view/isatuximab-shows-efficacy-acceptable-safety-across-multiple-myeloma-trials

Isatuximab Shows Efficacy, Acceptable Safety Across ... At a median time to response of 1 month, isatuximab elicited a median duration of response of 10.3 months in patients with multiple myeloma.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01749969

NCT01749969 | SAR650984 (Isatuximab), Lenalidomide, ... To evaluate the safety, including immunogenicity, of SAR650984 (isatuximab) in combination with LD in relapsed or refractory multiple myeloma. The severity ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5482100/

A phase 1b study of isatuximab plus lenalidomide and ... Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide ...

8. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/7317/490110

Updated Safety Run-in Results from the Randomized Phase 3 ... Isatuximab in combination with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma: updated safety run-in results.

9. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2020-1229.html

A Phase 3 randomized, open label, multicenter study of ... Primary Objectives: * Safety run-in Part: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants ...

10. sarclisa.com sarclisa.com/newly-diagnosed-trial-results

Newly Diagnosed Trial Results At a median follow-up of 60 months, 63% (167 out of 265 patients) lived progression free with SARCLISA + Velcade (bortezomib), Revlimid (lenalidomide), and ...