Carfilzomib + Lenalidomide + Vorinostat + Dexamethasone for Multiple Myeloma

(QUAD Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hackensack Meridian Health

Must be taking: Aspirin, Warfarin, Heparin

Must not be taking: Corticosteroids, HDAC inhibitors

Disqualifiers: Pregnancy, Heart failure, HIV, others

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

Compensation: Varies

Number of Visits: 42

Duration: 48 weeks

17 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the feasibility of combining four of the most active agents available for the treatment of multiple myeloma. Further the investigators will attempt to assess the activity of this combination.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for patients who have used HDAC inhibitors, including valproic acid, before starting vorinostat. Other specific medication requirements are not detailed, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone for treating multiple myeloma?

Carfilzomib combined with lenalidomide and dexamethasone has shown effectiveness in improving survival in patients with relapsed and refractory multiple myeloma, with a high overall response rate in real-world studies. However, the addition of vorinostat to this combination has not been specifically studied in the provided research. ^{1 2 3 4 5}

Is the combination of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone safe for humans?

The combination of Carfilzomib, Lenalidomide, and Dexamethasone has been studied for safety in multiple myeloma patients, showing a safety profile consistent with previous studies. Some patients experienced treatment-related side effects, including cardiovascular issues, but these were generally manageable. ^{1 2 4 5 6}

What makes the drug combination of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone unique for treating multiple myeloma?

This drug combination is unique because it combines multiple agents that target different pathways in cancer cells, potentially enhancing the treatment's effectiveness. Carfilzomib is a proteasome inhibitor, Lenalidomide modulates the immune system, Vorinostat is a histone deacetylase inhibitor, and Dexamethasone is a steroid that reduces inflammation, making this combination a comprehensive approach to treating multiple myeloma. ^{7 8 9 10 11}

Research Team

David S Siegel

Principal Investigator

Hackensack Meridian Health

Eligibility Criteria

Adults with symptomatic multiple myeloma who have relapsed or are refractory after at least one treatment can join. They must have measurable disease, adequate organ function, and a life expectancy over three months. Women of childbearing age must test negative for pregnancy and use two forms of birth control; men must use condoms.

Inclusion Criteria

I can follow the study's schedule and visit the institute for treatment and tests.

My liver is functioning well, with normal bilirubin levels.

Alanine aminotransferase (ALT) < 3 times ULN

Exclusion Criteria

I am currently taking a medication like Valproic acid.

I haven't used any experimental drugs or therapies in the last 28 days.

I do not have any mental health or medical conditions that could affect my treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carfilzomib, lenalidomide, vorinostat, and dexamethasone in 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity develops

48 weeks

12 cycles with 3 weeks of treatment and 1 week of rest per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Within 30 days of the last administration of study treatment

Treatment Details

Interventions

• Carfilzomib
• Dexamethasone
• Lenalidomide
• Vorinostat

Trial Overview The trial is testing the combination of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone in patients with multiple myeloma that has come back or hasn't responded to treatment. It aims to see if these four drugs work better together.

Participant Groups

Group I: carfilzomib for MML Experimental Treatment 1 Intervention

Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone - This study will be conducted as an open-label Phase I/II, single-center study in which subjects will receive carfilzomib, lenalidomide, vorinostat and dexamethasone, for relapsed and/or refractory multiple myeloma. Study treatment will be administered in sequential cohorts, with 3-6 subjects in each cohort. Treatment will be administered in 28-day cycles, with the fourth week as a rest week, for 12 cycles or until disease progression or unacceptable toxicity develops.

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?

Hackensack Meridian Health

Lead Sponsor

Trials

141

Recruited

42,900+

Findings from Research

In the ENDURANCE trial involving patients with newly diagnosed multiple myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve progression-free survival compared to the standard treatment of bortezomib, lenalidomide, and dexamethasone (VRd).

These findings suggest that KRd may not be a more effective treatment option than the current standard of care for patients with NDMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. Skarzynski, J.[2021]

In a study involving 792 patients with relapsed multiple myeloma, the combination of carfilzomib with lenalidomide and dexamethasone significantly improved progression-free survival, with a median of 26.3 months compared to 17.6 months for the control group.

The carfilzomib group also showed a higher overall response rate (87.1% vs. 66.7%) and better health-related quality of life, indicating a favorable risk-benefit profile despite similar rates of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Stewart, AK., Rajkumar, SV., Dimopoulos, MA., et al.[2022]

In a real-world study of 152 patients with relapsed and/or refractory multiple myeloma treated with carfilzomib plus dexamethasone, the overall response rate was 71.1%, indicating that this treatment is effective in a clinical setting.

Patients classified as trial-unfit had significantly shorter progression-free survival (3.6 months) and overall survival (15.0 months) compared to trial-fit patients (7.3 months and 36.8 months, respectively), highlighting the importance of patient fitness in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment outcomes of carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma, focusing on the impact of trial-fitness: CAtholic REsearch network for Multiple Myeloma study (CAREMM-2203). Park, SS., Goo, SY., Jeon, YW., et al.[2023]

In a phase 2 study involving 72 patients with newly diagnosed multiple myeloma, the combination of carfilzomib and dexamethasone (Kd) achieved a remarkable overall response rate of 90%, with 7% of patients reaching a complete response and 58% achieving a very good partial response.

The treatment was generally well-tolerated, with most adverse events being low grade; however, there was an 11.1% incidence of grade 3 or higher cardiovascular events, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. Forsberg, PA., Rossi, AC., Boyer, A., et al.[2020]

FK-037, a new cephalosporin antibiotic, demonstrated superior in vitro activity compared to ceftazidime, aztreonam, and piperacillin against various bacterial isolates from cancer patients, being 2 to 16 times more effective against Enterobacteriaceae.

FK-037 showed significant effectiveness against many gram-positive bacteria, including some methicillin-resistant staphylococci, indicating its potential as a broad-spectrum antimicrobial agent, although some organisms like Enterococcus spp. were resistant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of FK-037, a novel parenteral cephalosporin, against bacterial isolates from neutropenic cancer patients. Dholakia, N., Rolston, KV., Ho, DH., et al.[2019]

References

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

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Carfilzomib in addition to lenalidomide and dexamethasone in Asian patients with RRMM outside of a clinical trial. [2021]

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

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Use and Effectiveness of Carfilzomib Plus Dexamethasone in Relapsed/Refractory Multiple Myeloma in Europe. [2022]

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

Real-world treatment outcomes of carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma, focusing on the impact of trial-fitness: CAtholic REsearch network for Multiple Myeloma study (CAREMM-2203). [2023]

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

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. [2020]

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

Comparison of activities of broad-spectrum beta-lactam compounds against 1,128 gram-positive cocci recently isolated in cancer treatment centers. [2020]

8. France pubmed.ncbi.nlm.nih.gov

[Antibacterial activity of carumonam and cefpirome on hospital strains resistant to gentamicin and cephalothin: comparison with other beta-lactam antibiotics, new fluoroquinolones, aminoglycosides and other antibiotics]. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Subchronic and chronic toxicity of the new antibiotic cefpirome in rats. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

In vitro activity of FK-037, a novel parenteral cephalosporin, against bacterial isolates from neutropenic cancer patients. [2019]

11. Greece pubmed.ncbi.nlm.nih.gov

Cytotoxic effects of a new antitumor antibiotic, FK973, in malignant glioma. [2013]