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

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of isatuximab, carfilzomib, pomalidomide, and dexamethasone in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Isatuximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Carfilzomib may stop the growth of cancer cells by blocking some of the proteins needed for cell growth. Pomalidomide may help shrink or slow the growth of mutliple myeloma. Anti-inflammatory drugs, such as dexamethasone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving isatuximab, carfilzomib, pomalidomide, and dexamethasone may kill more cancer cells.

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.

What data supports the effectiveness of the drug combination used in the Quadruple Therapy for Multiple Myeloma?

Research shows that adding isatuximab to combinations with carfilzomib and dexamethasone or pomalidomide and dexamethasone significantly improves progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in patients with relapsed or refractory multiple myeloma. These combinations are generally well tolerated and offer important treatment options for these patients. ^{1 2 3 4 5}

Is the quadruple therapy for multiple myeloma safe for humans?

The combination of isatuximab with carfilzomib, dexamethasone, and pomalidomide has been generally well tolerated in studies for multiple myeloma, with a manageable safety profile. Common side effects include neutropenia (low white blood cell count), infections, and thrombocytopenia (low platelet count), but no new safety concerns have been identified. ^{1 3 5 6 7}

What makes the quadruple drug therapy for multiple myeloma unique?

This quadruple drug therapy combines four different types of drugs, including a monoclonal antibody (a protein that helps the immune system attack cancer cells), a proteasome inhibitor (which blocks the breakdown of proteins in cancer cells), an immunomodulatory drug (which boosts the immune system), and a corticosteroid (which reduces inflammation). This combination aims to improve treatment effectiveness for relapsed or refractory multiple myeloma compared to using fewer drugs. ^{1 3 4 5 8}

Research Team

Andrew Cowan, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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]

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 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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. [2022]

4. United States 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. [2023]

5. England 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. [2023]

6. England 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. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. [2022]