Quadruple Therapy for Multiple Myeloma

(VICD Trial)

Recruiting at 2 trial locations

Overseen By Medical College of Wisconsin Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Medical College of Wisconsin

Disqualifiers: Other malignancies, CNS involvement, 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

Duration: 4 weeks

41 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm, open-label phase II study with a safety lead-in phase.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that no prior multiple myeloma-directed therapy is allowed except for specific medications like dexamethasone, bortezomib, and cyclophosphamide under certain conditions. It's best to discuss your current medications with the study team to get a clear answer.

What data supports the effectiveness of the drug combination Bortezomib, Velcade, Cyclophosphamide, Cytoxan, Neosar, Endoxan, Dexamethasone, Decadron, Dexone, Hexadrol, Isatuximab, Sarclisa, isatuximab-irfc, SAR-650984 for treating multiple myeloma?

Research shows that isatuximab, when combined with other drugs like dexamethasone, improves progression-free survival (the time during which the disease does not get worse) in multiple myeloma patients. Additionally, a similar four-drug regimen including bortezomib, cyclophosphamide, and dexamethasone has shown high response rates in patients with relapsed or refractory multiple myeloma. ^{1 2 3 4 5}

Is the quadruple therapy for multiple myeloma safe for humans?

The quadruple therapy, which includes drugs like isatuximab, bortezomib, cyclophosphamide, and dexamethasone, has been generally well tolerated in studies for multiple myeloma, showing a manageable safety profile with common side effects like fatigue, infections, and blood cell count changes. Serious side effects were less common, and the treatment was considered safe enough for further studies. ^{2 3 5 6 7}

What makes the quadruple drug therapy for multiple myeloma unique?

The quadruple drug therapy for multiple myeloma is unique because it combines four different drugs, including isatuximab, which is a monoclonal antibody that targets a specific protein on cancer cells, with bortezomib, cyclophosphamide, and dexamethasone. This combination aims to enhance treatment effectiveness by using multiple mechanisms to attack the cancer, potentially improving outcomes compared to traditional three-drug regimens. ^{2 3 4 8 9}

Research Team

Binod Dhakal, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

This trial is for adults with multiple myeloma who haven't had much prior treatment, can perform daily activities (ECOG 0-2), and have measurable disease. They must be able to give consent, agree to use contraception if necessary, and be eligible for stem cell transplantation. Exclusions include other cancers, central nervous system involvement by myeloma, significant heart issues or other conditions that could affect the study.

Inclusion Criteria

I am eligible for a high-dose therapy and stem cell transplant according to my hospital's rules.

I am a man and will use effective contraception or practice abstinence.

You have a disease that can be measured using certain criteria.

Exclusion Criteria

I haven't had major surgery within the last two weeks and don't plan any during the study.

I do not have any serious heart conditions.

You have HIV, hepatitis B, or untreated hepatitis C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Initial cohort of patients receive treatment to assess safety

4 weeks

4 visits (in-person)

Treatment

Participants receive Bortezomib, Isatuximab, Cyclophosphamide, and Dexamethasone

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

14 weeks

Treatment Details

Interventions

• Bortezomib
• Cyclophosphamide
• Dexamethasone
• Isatuximab

Trial Overview The trial tests a combination of drugs: Bortezomib, Isatuximab, Cyclophosphamide and Dexamethasone in patients eligible for stem cell transplant. It's an open-label phase II study which means everyone gets the same treatment and both doctors and patients know what's being given.

Participant Groups

Group I: Safety Lead-in Cohort A Experimental Treatment 4 Interventions

Six transplant-eligible multiple myeloma patients with renal impairment will be enrolled. Bortezomib (1.5 mg/m\^2) subcutaneous on days 1,8 and 15 Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22 Cyclophosphamide (250 mg/m\^2) IV on days 1, 8 and 15 Dexamethasone 20 mg PO or IV (10 mg if \>75 years) on days 1, 2, 8, 9,15,16, 22 and 23

Group II: Expansion Cohort A Experimental Treatment 4 Interventions

35 transplant-eligible multiple myeloma patients with renal impairment will be enrolled. Bortezomib (1.5 mg/m\^2)subcutaneous on days 1, 8 and 15 Isatuximab (10 mg/kg) IV on days 1, 8, 15 and 22 Cyclophosphamide (250 mg/m\^2) IV on days 1, 8 and 15 Dexamethasone 20 mg PO or IV (10 mg if \>75 years) on days 1, 2, 8, 9,15,16, 22 and 23

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?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Findings from Research

In a subgroup analysis of the CASTOR trial involving 498 patients, daratumumab combined with bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) in patients with high cytogenetic risk (12.6 months) compared to bortezomib and dexamethasone alone (6.2 months).

D-Vd also demonstrated a higher rate of minimal residual disease (MRD) negativity, indicating deeper responses in treatment effectiveness, while maintaining a safety profile consistent with the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. Weisel, K., Spencer, A., Lentzsch, S., et al.[2021]

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 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]

The treatment landscape for multiple myeloma has expanded significantly with the approval of 10 new therapies over the past decade, highlighting the effectiveness of 3-drug combinations over 2-drug therapies, as supported by current guidelines.

Recent studies, including the approval of daratumumab combined with bortezomib, melphalan, and prednisone, suggest that 4-drug combinations may offer benefits for newly diagnosed patients who are not pursuing autologous transplant, with ongoing research exploring their efficacy in various patient settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are 4-Drug Regimens Here to Stay? Role in Induction and Salvage Therapies. Richter, J., Jagannath, S.[2020]

In a study of 70 patients with relapsed or refractory multiple myeloma, a four-drug combination therapy (bortezomib, cyclophosphamide, thalidomide, and dexamethasone) achieved an impressive overall response rate of 88%, with 46% of patients experiencing a complete response.

The treatment demonstrated a median progression-free survival of 14.6 months and a median overall survival of 31.6 months, while showing manageable side effects, with serious adverse events occurring in a small percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. Kim, YK., Sohn, SK., Lee, JH., et al.[2022]

In a phase 1b study involving 45 patients with relapsed/refractory multiple myeloma, the combination of isatuximab, pomalidomide, and dexamethasone showed a 62% overall response rate and a median duration of response of 18.7 months, indicating significant efficacy in a heavily pretreated population.

The safety profile was manageable, with common adverse events including fatigue and infections, and the recommended dose for future studies was determined to be 10 mg/kg of isatuximab given weekly for the first four weeks and then every two weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Mikhael, J., Richardson, P., Usmani, SZ., et al.[2021]

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]

In the phase 3 ICARIA-MM trial, isatuximab combined with pomalidomide-dexamethasone significantly improved median progression-free survival (mPFS) in high-risk multiple myeloma patients, showing 7.5 months compared to 3.7 months with standard treatment.

Despite a higher incidence of grade ≥3 adverse events in high-risk patients receiving isatuximab (95.7% vs. 67.6% in the control group), the treatment did not lead to increased discontinuation or treatment-related mortality, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics. Harrison, SJ., Perrot, A., Alegre, A., et al.[2021]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. [2021]

2. France pubmed.ncbi.nlm.nih.gov

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

3. 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]

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

Are 4-Drug Regimens Here to Stay? Role in Induction and Salvage Therapies. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. [2022]

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

A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. [2021]

7. England 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. [2023]

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

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics. [2021]

9. 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]