Quadruple Therapy for Multiple Myeloma

Overseen By Andrew J. Cowan

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: Anti-CD38 antibodies

Disqualifiers: Cardiovascular disease, Hypertension, Plasma cell leukemia, 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: 7

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of four drugs to treat multiple myeloma, a type of blood cancer, in individuals whose disease has returned or stopped responding to treatment. The drugs under study include isatuximab, an antibody therapy that helps stop cancer cell growth, along with carfilzomib, pomalidomide, and dexamethasone, which work together to kill cancer cells. This trial suits those whose multiple myeloma has returned after previous treatments, especially if they have already tried lenalidomide. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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 use other anticancer agents or experimental treatments while participating.

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

Research has shown that the combination of isatuximab, carfilzomib, pomalidomide, and dexamethasone is generally well-tolerated by patients with multiple myeloma, a type of cancer that has returned or not responded to treatment. One study found that patients taking isatuximab with carfilzomib and dexamethasone lived without disease progression for an average of 41.7 months, compared to 20.8 months for those taking only carfilzomib and dexamethasone.

This finding suggests that adding isatuximab could be a safe and effective option. The treatment is part of a phase II trial, indicating some safety in earlier studies. Side effects can occur, and individual reactions may vary. It is important to consult healthcare providers to understand what to expect. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this quadruple therapy for multiple myeloma because it combines four powerful drugs: carfilzomib, dexamethasone, isatuximab, and pomalidomide. Unlike standard treatments that often involve combinations of two or three drugs, this approach harnesses the benefits of four distinct mechanisms of action. Isatuximab is particularly noteworthy as it targets the CD38 protein on myeloma cells, enhancing the immune response. This comprehensive strategy aims to improve treatment effectiveness and potentially prolong remission periods compared to current options.

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

This trial will evaluate the effectiveness of combining isatuximab, carfilzomib, pomalidomide, and dexamethasone for treating relapsed or refractory multiple myeloma. Research has shown that in earlier studies, patients who took isatuximab with carfilzomib and dexamethasone lived without disease progression for an average of 41.7 months, compared to 20.8 months for those who only took carfilzomib and dexamethasone. Pomalidomide is believed to help reduce or slow the growth of multiple myeloma. Together, these drugs may more effectively kill cancer cells and manage the disease. ^{1 2 3 4 6}

Who Is on the Research Team?

Rahul Banerjee, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for adults with multiple myeloma that has returned or isn't responding to treatment. Participants must have had prior therapy including lenalidomide, measurable disease by specific criteria, and adequate organ function. They should not have uncontrolled infections, certain heart conditions, other primary malignancies not in remission for at least a year (with some exceptions), or recent anti-CD38 monoclonal antibody therapy.

Inclusion Criteria

You have a high amount of plasma cells in your bone marrow.

Your kidney function, as measured by eGFR, needs to be at least 20 ml/min or higher.

Your total bilirubin level is within the normal range.

Exclusion Criteria

You are currently taking other cancer medications or experimental treatments.

I have serious heart problems, including recent heart attack or heart failure.

I had Hepatitis C but have been treated and cured, or I am currently being treated with an undetectable viral load.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Patients receive isatuximab, carfilzomib, pomalidomide, and dexamethasone. Treatment repeats every 28 days for 6 cycles.

24 weeks

4 visits per cycle (in-person)

Maintenance

Patients continue receiving isatuximab, carfilzomib, pomalidomide, and dexamethasone. Cycles repeat every 28 days for up to 24 months.

24 months

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Dexamethasone
• Isatuximab
• Pomalidomide

Trial Overview The study examines the combination of isatuximab (a cancer cell growth inhibitor), carfilzomib (blocks proteins needed for cancer cell growth), pomalidomide (may shrink/slow tumor growth), and dexamethasone (an anti-inflammatory) in treating relapsed/refractory multiple myeloma. It's a phase II trial aiming to see if this drug combo can effectively kill more cancer cells.

How Is the Trial Designed?

Group I: Treatment (isatuximab, carfilzomib, pomalidomide, steroid) Experimental Treatment 10 Interventions

INDUCTION: Patients receive isatuximab IV on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1,8, 15, and 22. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive isatuximab IV days 1 and 15, carfilzomib IV over 30 minutes on days 1 and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. All patients undergo bone marrow aspirate and biopsy during screening, skeletal x-ray, CT, PET-CT, or MRI, bone marrow and blood sample collection throughout the study.

Carfilzomib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Kyprolis for:

• Multiple myeloma

Approved in European Union as Kyprolis for:

• Multiple myeloma

Approved in Canada as Kyprolis for:

• Multiple myeloma

Approved in Japan as Kyprolis for:

• Multiple myeloma

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

Genzyme, a Sanofi Company

Industry Sponsor

Trials

528

Recruited

186,000+

David Meeker

Genzyme, a Sanofi Company

Chief Executive Officer since 2011

MD from the University of Vermont Medical School, Advanced Management Program at Harvard Business School

Jean-Paul Kress

Genzyme, a Sanofi Company

Chief Medical Officer since 2015

MD from Faculte Necker-Enfants Malades, Paris

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]

In a phase 2 study involving 46 patients with newly diagnosed multiple myeloma, the quadruplet regimen of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) achieved a stringent complete response (sCR) and/or measurable residual disease (MRD)-negativity rate of 58% after 8 cycles, indicating significant efficacy without the need for autologous stem cell transplant (ASCT).

The study demonstrated a 3-year progression-free survival (PFS) rate of 72% overall, and an impressive 92% for patients who achieved MRD-negativity, suggesting that MRD-guided therapy could allow for reduced treatment exposure while maintaining effective outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study. Derman, BA., Kansagra, A., Zonder, J., et al.[2023]

The introduction of carfilzomib, a new proteasome inhibitor, and pomalidomide, an immunomodulatory drug, has significantly improved the effectiveness of multiple myeloma treatment.

Updated NCCN Clinical Practice Guidelines now recommend the use of these drugs, indicating a positive shift in treatment options as new therapies, including monoclonal antibodies, continue to emerge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple myeloma: new uses for available agents, excitement for the future. Anderson, KC.[2019]

The QUAD regimen, combining carfilzomib, lenalidomide, vorinostat, and dexamethasone, was found to be feasible and showed promising anti-multiple myeloma activity in a phase I study with 17 patients, achieving an overall response rate of 53%.

No dose-limiting toxicities were observed, indicating a favorable safety profile, although common grade ≥3 adverse events included neutropenia and thrombocytopenia, suggesting careful monitoring is needed during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Vesole, DH., Bilotti, E., Richter, JR., 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 107 relapsed/refractory myeloma patients treated with isatuximab, pomalidomide, and dexamethasone (IsaPomDex), the overall response rate was 66.4%, indicating significant efficacy in a real-world setting.

The treatment was associated with a median progression-free survival of 10.9 months and a median overall survival of 18.8 months, although adverse events were common, with 87.9% of patients experiencing any grade adverse effects, primarily neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset. Djebbari, F., Rampotas, A., Vallance, G., et al.[2022]

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]

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]

Citations

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

for adults with previously treated multiple myeloma Patients lived progression free for a median of 41.7 months with SARCLISA + Kyprolis (carfilzomib) and dexamethasone (Kd) vs 20.8 months with Kd alone.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04883242

Study Details | NCT04883242 | Isatuximab, Carfilzomib, ... Pomalidomide may help shrink or slow the growth of multiple myeloma. Anti-inflammatory drugs, such as dexamethasone lower the body's immune response and are ...

3. sarclisahcp.com sarclisahcp.com/ikema-efficacy

IKEMA Efficacy - SARCLISA® (isatuximab-irfc) Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized phase 3 study.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12030129/

Efficacy and Safety of Isatuximab, Carfilzomib, ... Conclusions: These real-world data support the use of IsaKd as a valuable option for len-R MM patients relapsing after the first-line therapy, ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S235230262400070X

Isatuximab, carfilzomib, lenalidomide, and dexamethasone ... Results from this study show the safety and efficacy of this four-drug regimen in newly diagnosed multiple myeloma, including standard-risk and high-risk ...

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa2400712

Isatuximab, Bortezomib, Lenalidomide, and ... Isatuximab-VRd was more effective than VRd as initial therapy in patients 18 to 80 years of age with newly diagnosed multiple myeloma who were ...