Melphalan + Siltuximab for Multiple Myeloma

Recruiting at 6 trial locations

Overseen By Heather Landau, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: IL-6 inhibitors

Disqualifiers: Other malignancy, Autoimmune disease, 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: Unknown

Duration: 2 days

215 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to see if siltuximab plus population pharmacokinetic (PK)-dosed melphalan works as well as the usual approach (body surface area \[BSA\]-dosed melphalan) in people with multiple myeloma (MM) who are receiving an autologous stem cell transplant (ASCT) as part of their standard treatment. The researchers will also see if siltuximab in combination with population PK-dosed melphalan works to decrease symptoms after an ASCT, and will study the safety of siltuximab. For the run-in, 15 patients will receive siltuximab, 11 mg/kg, seven days before and 14 days after autologous hematopoietic stem cell infusion (+/-2 day).

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the drug combination Melphalan and Siltuximab for treating multiple myeloma?

Research shows that Siltuximab, when combined with Melphalan, increases the effectiveness of Melphalan in killing multiple myeloma cells. This combination enhances the process of cell death and reduces drug resistance, making it a promising approach for treating multiple myeloma. ^{1 2 3 4 5}

Is the combination of Melphalan and Siltuximab safe for humans?

Melphalan, especially in its propylene glycol-free form (Evomela), has been shown to have an acceptable safety profile in patients with multiple myeloma, with low rates of severe side effects like mucositis (mouth sores). Siltuximab, when combined with melphalan, has shown enhanced effects in preclinical studies, but specific safety data for this combination in humans is not detailed in the available research. ^{1 2 6 7 8}

How does the drug combination of Melphalan and Siltuximab differ from other treatments for multiple myeloma?

The combination of Melphalan and Siltuximab is unique because Siltuximab, an antibody that blocks interleukin-6 (a protein that helps myeloma cells grow), enhances the effectiveness of Melphalan by making cancer cells more sensitive to it, potentially overcoming drug resistance and improving treatment outcomes. ^{1 2 3 6 7}

Research Team

Gunjan Shah, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for people with multiple myeloma who are undergoing an autologous stem cell transplant as part of their treatment. Specific eligibility criteria details were not provided, so interested individuals should contact the study organizers for more information.

Inclusion Criteria

LVEF >45% by MUGA or rest ECHO

Have at least 3 million x 10^6 CD34+ cells/kg to be infused

I am mostly self-sufficient and can carry out daily activities.

Exclusion Criteria

I have been treated with drugs targeting IL-6 or its receptor.

Concurrent medical condition or disease (eg, autoimmune disease, active systemic Infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in the study

I haven't had major surgery or been hospitalized for an infection in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

15 patients receive siltuximab, 11 mg/kg, seven days before and 14 days after autologous hematopoietic stem cell infusion

3 weeks

Multiple visits for infusion and monitoring

Treatment

Patients receive melphalan dosing and PK testing; siltuximab is administered in Arm A

2 days

In-patient for infusion and PK sampling

Follow-up

Participants are monitored for safety and effectiveness after treatment

100 days

Regular follow-up visits for disease evaluation

Treatment Details

Interventions

• Melphalan
• Siltuximab

Trial Overview The study is testing if adding siltuximab to a tailored dose of melphalan (based on population pharmacokinetics) improves outcomes compared to the usual dosing method (based on body surface area) in multiple myeloma patients receiving stem cell transplants.

Participant Groups

Group I: Siltuximab plus population PK-dosed melphalan Experimental Treatment 2 Interventions

For patients randomized to Arm A, the siltuximab, 11 mg/kg, will be administered seven days before and 14 days after autologous hematopoietic stem cell infusion (+/-2 day). Patients will then receive 70mg/m2 of melphalan on Day -2. The melphalan will be infused over 30 minutes. Six peripheral blood samples of 5 ml in lithium heparin tubes will be collected at 5, 15, 30, 40, 75, and 150 minutes after the end of the melphalan infusion for PK testing. The first four time points are +/- 2 min and the last two time points are +/- 5 minutes. The population PK formula in the Insight Rx software will be used to calculate the melphalan dose for Day -1 to achieve a total target area under the curve (AUC) of 13 mg\*h/L (+/-1.5). The six PK samples will be collected again after the dose on Day -1 to confirm the total AUC. Patients will receive a minimum of the equivalent of 70mg/m2 and a maximum of the equivalent of 260mg/m2.

Group II: Standard BSA-dosed melphalan Active Control 1 Intervention

Patients randomized to Arm B with received Standard of care (SOC) BSA based melphalan dosing at 140 or 200mg/m2 per treating physician on Day -2 and will not receive the siltuximab. The melphalan will be infused over 30 minutes. Six peripheral blood samples of 5 ml in lithium heparin tubes will be collected at 5, 15, 30, 40, 75, and 150 minutes after the end of the melphalan infusion for PK testing. The first four time points are +/- 2 min and the last two time points are +/- 5 minutes.

Melphalan is already approved in European Union, United States for the following indications:

Approved in European Union as Alkeran for:

• Multiple myeloma
• Malignant lymphoma
• Acute lymphoblastic leukemia
• Acute myeloblastic leukemia
• Childhood neuroblastoma
• Ovarian cancer
• Mammary adenocarcinoma

Approved in United States as Alkeran for:

• Multiple myeloma
• High-dose conditioning before hematopoietic stem cell transplant
• Uveal melanoma with unresectable hepatic metastases

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Recordati Pharmaceutical company

Collaborator

Trials

2

Recruited

230+

RECORDATI GROUP

Industry Sponsor

Trials

13

Recruited

4,500+

Findings from Research

The IL-6-neutralizing monoclonal antibody siltuximab enhances the effectiveness of melphalan, a chemotherapy drug, against multiple myeloma cells, showing additive to synergistic effects in various human myeloma cell lines.

Siltuximab not only increases the cytotoxicity of melphalan but also promotes apoptosis through the activation of key caspases and suppression of the IL-6 signaling pathway, suggesting a promising combination therapy for patients with myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Hunsucker, SA., Magarotto, V., Kuhn, DJ., et al.[2021]

Melphalan is a key treatment for multiple myeloma and ovarian cancer, with oral melphalan combined with prednisone being the standard therapy for elderly patients since the 1960s.

Recent advancements in understanding drug resistance have led to the development of novel therapies like thalidomide, lenalidomide, and bortezomib, which can enhance the effectiveness of melphalan and change treatment approaches for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan and its role in the management of patients with multiple myeloma. Falco, P., Bringhen, S., Avonto, I., et al.[2020]

Melflufen, a derivative of melphalan, demonstrated significantly higher potency against lymphoma cells compared to melphalan, with IC50 values showing up to 49-fold superiority in cell lines and an average of 108-fold in primary cultures.

In preclinical studies, melflufen showed effective cytotoxicity with minimal side effects in a xenograft model, indicating its potential as a safer and more effective treatment option for relapsed or refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo activity of melflufen (J1)in lymphoma. Delforoush, M., Strese, S., Wickström, M., et al.[2019]

In the OCEAN study, melphalan flufenamide (melflufen) showed similar progression-free survival (PFS) and overall survival (OS) compared to pomalidomide in 153 patients with relapsed/refractory multiple myeloma who were refractory to prior alkylators.

Among patients with a longer time to progression (TTP ≥ 36 months) after prior autologous stem cell transplantation, melflufen demonstrated longer median PFS and OS compared to pomalidomide, indicating its potential effectiveness in a specific subgroup of alkylator-refractory patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study. Schjesvold, FH., Ludwig, H., Mateos, MV., et al.[2023]

Melflufen is a first-in-class peptide-drug conjugate that effectively targets and delivers alkylating agents directly into tumor cells, showing anti-myeloma activity even in cells resistant to standard treatments like bortezomib and melphalan.

In early phase studies, melflufen combined with dexamethasone demonstrated promising clinical activity and a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, indicating its potential as a valuable treatment option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melflufen: A Peptide-Drug Conjugate for the Treatment of Multiple Myeloma. Mateos, MV., Bladé, J., Bringhen, S., et al.[2023]

EVOMELA, a new formulation of melphalan that is free from propylene glycol, has been shown to be safe and effective for high-dose conditioning in autologous stem cell transplantation for multiple myeloma, with a 100% overall response rate in a study of 61 patients.

The study reported low incidences of severe side effects, such as grade 3 mucositis (10%) and stomatitis (5%), indicating that EVOMELA has an acceptable safety profile compared to traditional formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. Hari, P., Aljitawi, OS., Arce-Lara, C., et al.[2017]

In a study of 514 multiple myeloma patients, the propylene glycol-free formulation of melphalan (PGF-mel) showed similar efficacy to the conventional propylene glycol-based formulation (PG-mel) in terms of relapse rates after high-dose melphalan with autologous hematopoietic cell transplantation.

However, PGF-mel was associated with fewer severe adverse events like mucositis and febrile neutropenia, leading to a preference for PG-mel despite the potential benefits of PGF-mel, due to cost considerations and other factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Khan, AM., Yucebay, F., Zhao, Q., et al.[2023]

The combination treatment of melphalan, prednisone, and lenalidomide (MPR) shows significant antimyeloma activity in newly diagnosed multiple myeloma patients, with a median progression-free survival of 28.5 months and a 2-year overall survival rate of 91%.

While MPR treatment resulted in manageable hematologic side effects, including grade 3/4 neutropenia in 52% of patients and grade 3/4 thrombocytopenia in 24%, no serious bleeding complications were reported, indicating that the regimen is relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melphalan, prednisone, and lenalidomide for newly diagnosed myeloma: kinetics of neutropenia and thrombocytopenia and time-to-event results. Palumbo, A., Falco, P., Falcone, A., et al.[2018]

References

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

Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Melphalan and its role in the management of patients with multiple myeloma. [2020]

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

In vitro and in vivo activity of melflufen (J1)in lymphoma. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Melflufen in relapsed/refractory multiple myeloma refractory to prior alkylators: A subgroup analysis from the OCEAN study. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Melflufen: A Peptide-Drug Conjugate for the Treatment of Multiple Myeloma. [2023]

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

A Phase IIb, Multicenter, Open-Label, Safety, and Efficacy Study of High-Dose, Propylene Glycol-Free Melphalan Hydrochloride for Injection (EVOMELA) for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation. [2017]

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

Comparison of Patient Outcomes With Two Different Formulations of Melphalan as Conditioning Chemotherapy for Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. [2023]

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

Melphalan, prednisone, and lenalidomide for newly diagnosed myeloma: kinetics of neutropenia and thrombocytopenia and time-to-event results. [2018]