Combination Therapy for Multiple Myeloma

(MagnetisMM-20 Trial)

Recruiting at 35 trial locations

Overseen By Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Pfizer

Must not be taking: BCMA-directed, CD47-SIRP alpha

Disqualifiers: Plasma cell leukemia, Cardiovascular diseases, others

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

Compensation: Varies

Number of Visits: Unknown

90 Participants Needed

Trial Summary

What is the purpose of this trial?

The main purpose of the study is to evaluate the safety and tolerability of the combination of elranatamab and carfilzomib and dexamethasone or elranatamab and maplirpacept. There are 2 parts to this study. Part 1 will evaluate the safety and tolerability of elranatamab when given in combination with carfilzomib plus dexamethasone. Part 2 has 2 arms. The first will evaluate the safety and tolerability of elranatamab when given in combination with maplirpacept. The second will identify the optimal dose(s) of elranatamab plus maplirpacept. All study medicines are given over 4-week cycles. Everyone taking part in this study will receive elranatamab as a shot under the skin. Participants in Part 1 will also receive weekly carfilzomib as an IV infusion (given directly into a vein) and dexamethasone either by mouth (as a pill) or by IV infusion. Participants in Part 2 will receive elranatamab in combination with maplirpacept as an IV infusion (given directly into a vein) The investigators will examine the experiences of people receiving the study medicines. This will help determine if the study medicines are safe and can be used for multiple myeloma treatment. Participants will take part in this study for about 2 years after the first dose.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination therapy for multiple myeloma?

Carfilzomib, when used in combination with other drugs like lenalidomide and dexamethasone, has shown to significantly prolong the time patients live without their disease getting worse in relapsed multiple myeloma, according to a large study. This suggests that carfilzomib can be an effective part of combination treatments for multiple myeloma. ^{1 2 3 4 5}

What safety data exists for Carfilzomib (Kyprolis) in humans?

Carfilzomib has been associated with some safety concerns, including cardiovascular issues (heart-related problems), nephrotoxicity (kidney damage), and serious infections. There have also been reports of fatal lung toxicity in some cases. ^{1 5 6 7 8}

What makes the combination therapy of Carfilzomib and Elranatamab unique for treating multiple myeloma?

This combination therapy is unique because it involves Carfilzomib, a proteasome inhibitor that selectively and irreversibly targets cancer cells, and Elranatamab, which is being explored for its potential to enhance immune response against multiple myeloma. This novel approach aims to improve treatment outcomes by combining different mechanisms of action. ^{1 2 4 5 9}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

This trial is for people with relapsed refractory multiple myeloma who've had prior treatments. Part 1 participants can have had 1-3 prior therapies and must not be pregnant, breastfeeding, or have used BCMA-directed therapy before. Part 2 requires at least 3 previous lines of treatment and no recent anti-BCMA or CD47-SIRP alpha-directed therapies (except CAR-T). All must meet specific disease measurement criteria and not have certain heart conditions or active infections.

Inclusion Criteria

I've had 1 to 3 treatments for my multiple myeloma, counting a stem cell transplant as one.

I previously responded well to carfilzomib, stopped it for reasons other than side effects, didn't relapse within 2 months after stopping, and it's been 6 months since my last dose.

Not pregnant or breastfeeding and willing to use contraception

Exclusion Criteria

I do not have any ongoing serious infections.

I had a stem cell transplant less than 3 months ago or I have ongoing graft versus host disease.

I have been treated with a BCMA-targeted therapy before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive elranatamab in combination with carfilzomib and dexamethasone over 4-week cycles

4 weeks per cycle, up to 2 years

Weekly visits for IV infusions

Treatment Part 2A

Participants receive elranatamab in combination with maplirpacept over 4-week cycles

4 weeks per cycle, up to 2 years

Weekly visits for IV infusions

Treatment Part 2B

Participants receive randomized doses of elranatamab plus maplirpacept over 4-week cycles

4 weeks per cycle, up to 2 years

Weekly visits for IV infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days after last dose

Treatment Details

Interventions

• Carfilzomib
• Elranatamab

Trial Overview The study tests the safety of combining elranatamab with carfilzomib plus dexamethasone (Part 1) or maplirpacept (Part 2). It's divided into two parts: first to assess safety/tolerability of the combination treatments, second to find the best dose. Treatments are given in cycles over approximately two years, involving shots under the skin and IV infusions.

Participant Groups

Group I: Part 2B Dose Randomization Experimental Treatment 2 Interventions

Randomized dose level Elranatamab plus Maplirpacept

Group II: Part 2A Dose Escalation Experimental Treatment 2 Interventions

Non randomized Elranatamab plus Maplirpacept

Group III: Part 1 Dose Escalation Experimental Treatment 2 Interventions

Non randomized Elranatamab plus Carfilzomib and Dexamethasone

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?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

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 multicenter study of 85 patients with relapsed/refractory multiple myeloma, the KRd combination (Carfilzomib, lenalidomide, and dexamethasone) showed a high overall response rate of 95% and a median progression-free survival of 36 months after a median follow-up of 40 months.

The KRd regimen was found to be safe, with a low discontinuation rate of 6% due to toxicities, and most adverse events were mild, confirming its feasibility in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone in relapsed refractory multiple myeloma: a prospective real-life experience of the Regional Tuscan Myeloma Network. Antonioli, E., Pilerci, S., Attucci, I., et al.[2023]

Carfilzomib-containing combinations as frontline therapy for multiple myeloma showed a high overall response rate of 94% and a complete response rate of 21% across 13 trials involving 704 subjects.

The combination of carfilzomib with lenalidomide and dexamethasone (CFZ-LEN-DEX) resulted in a significantly higher complete response rate of 49% compared to other combinations, indicating it may be the most effective regimen for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. Sheng, Z., Li, G., Li, B., et al.[2018]

Carfilzomib, when used in combination with lenalidomide and dexamethasone, significantly prolongs progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma, based on results from the phase III ASPIRE study involving a multinational patient population.

The combination therapy has a manageable safety profile, with low incidences of severe adverse events, suggesting it is a viable treatment option for patients who have received prior therapies, although overall survival data is still pending.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. Hoy, SM.[2018]

In a phase 1b study involving patients with newly diagnosed multiple myeloma, the combination of carfilzomib, cyclophosphamide, and dexamethasone showed an impressive overall response rate of 87.5% at the highest carfilzomib dose of 56 mg/m2.

The treatment was generally well-tolerated, with manageable adverse effects; however, some patients experienced grade 3 or higher toxicities, including anemia and neutropenia, indicating that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2). Boccia, RV., Bessudo, A., Agajanian, R., et al.[2018]

Carfilzomib significantly improves progression-free survival, overall survival, and overall response rate in patients with relapsed/refractory multiple myeloma, based on evidence from 14 systematic reviews involving moderate quality data.

However, treatment with carfilzomib is associated with increased risks of cardiovascular events, nephrotoxicity, and serious infections, highlighting the need for careful monitoring and further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of carfilzomib for the treatment of multiple myeloma: An overview of systematic reviews. Georgoulis, V., Haidich, AB., Bougioukas, KI., et al.[2022]

Carfilzomib, a proteasome inhibitor approved for relapsing multiple myeloma, was associated with a case of fatal pulmonary toxicity in a 61-year-old male patient, highlighting a potential serious side effect of the drug.

The patient developed acute respiratory distress syndrome and diffuse alveolar hemorrhage shortly after starting carfilzomib, suggesting a direct link between the medication and the severe lung complications, which had not been previously reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). Lataifeh, AR., Nusair, A.[2020]

In patients with mild to moderate hepatic impairment, carfilzomib showed approximately 20-50% higher drug exposure compared to those with normal liver function, but this increase is not expected to be clinically significant due to the drug's pharmacokinetic variability.

The safety profile of carfilzomib in patients with advanced solid tumors was consistent with previous findings, although there was a noted increase in adverse events related to liver function abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study. Brown, J., Plummer, R., Bauer, TM., et al.[2020]

Carfilzomib is a highly effective proteasome inhibitor that has shown strong and lasting responses in patients with relapsed and refractory multiple myeloma, leading to its approval in the US.

Its favorable safety profile makes carfilzomib a promising candidate for combination therapies with other treatments, and ongoing Phase III studies are evaluating its efficacy and safety in various patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of carfilzomib combination therapy in the management of multiple myeloma. Moreau, P.[2014]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone in relapsed refractory multiple myeloma: a prospective real-life experience of the Regional Tuscan Myeloma Network. [2023]

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

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. [2018]

4. France pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. [2018]

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

A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2). [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of carfilzomib for the treatment of multiple myeloma: An overview of systematic reviews. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). [2020]

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

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study. [2020]

9. England pubmed.ncbi.nlm.nih.gov

The emerging role of carfilzomib combination therapy in the management of multiple myeloma. [2014]