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Melphalan with or without Siltuximab for the Treatment of Patients with Multiple Myeloma Undergoing an Autologous Stem Cell Transplant
Trial Status: active
This phase II trial compares the effect of population (Pop) pharmacokinetics (PK) dosed melphalan with siltuximab to body surface area (BSA) dosed melphalan alone in treating patients with multiple myeloma (MM) undergoing an autologous hematopoietic stem cell transplant (AHCT). Melphalan is in a class of medications called alkylating agents. It may kill tumor cells by damaging their deoxyribonucleic acid (DNA) and stopping them from dividing. PK is the way the body absorbs, distributes, and gets rid of a drug. BSA dosing is calculated by using height and weight, while Pop PK dosing uses information based on people who have previously received the drug. Siltuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Siltuximab blocks a protein in the body called IL-6, which is involved in inflammation. High levels of IL-6 can affect inflammation levels and increase symptoms in people receiving an AHCT and higher doses of melphalan can be associated with higher levels of IL-6. Giving Pop PK dosed melphalan with siltuximab may be as effective as BSA dosed melphalan alone in treating patients with MM undergoing an AHCT. In addition, melphalan in combination with siltuximab may help decrease symptoms after AHCT compared to melphalan alone.
Inclusion Criteria
Histologically-confirmed symptomatic multiple myeloma undergoing autologous hematopoietic cell transplantation (HCT) with plan off study for melphalan 140 or 200 mg/m^2 undergoing HCT within 12 months of diagnosis
At least 60 years of age
Have at least 3 million x 10^6 CD34+ cells/kg to be infused
Karnofsky performance status (KPS) performance status > 60% or Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2
Diffusion capacity > 45% (adjusted for hemoglobin) as predicted by pulmonary function testing (within 6 weeks prior to enrollment)
Left ventricular ejection fraction (LVEF) > 45% by MUGA or rest ECHO (within 6 weeks prior to enrollment)
Platelet count ≥ 20 x 10^9/L (within 6 weeks prior to enrollment)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (within 6 weeks prior to enrollment)
Total bilirubin ≤ 2.5 x ULN; except if the elevation is due to Gilbert's syndrome (within 6 weeks prior to enrollment)
Before enrollment, all women are expected to be not of childbearing potential as they will be age 60+
A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream suppository, and all men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug
Exclusion Criteria
Prior exposure to agents targeting IL-6 or the IL-6 receptor
Other malignancy within the past 2 years, except for the following if treated and not active: basal cell or non-metastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or International Federation of Gynecology and Obstetrics (FIGO) stage 1 carcinoma of the cervix. Prostate cancer under observation may be enrolled after discussion with the Memorial Sloan Kettering (MSK) principal investigator
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
Ischemic heart disease requiring intervention in the prior 3 months or uncontrolled heart failure or an uncontrolled arrhythmia corrected QT interval (QTc) is > 460ms by Fridericia. If they have a right or left bundle branch block or intraventricular conduction delay then exclusion will be for > 500ms by Friderica
Vaccination with live attenuated vaccines within 4 weeks of first study agent administration
Clinically significant infection, including known HIV or hepatitis C infection, or known hepatitis B (Hep B) surface antigen positivity. Patients with Hep B Core positivity can be enrolled if the Hep B polymerase chain reaction (PCR) is negative, and they are on antiviral suppression. Patients with hepatitis C antibody (Ab) positive who are PCR negative and have completed hepatitis C treatment can be enrolled. HIV with negative viral load on highly active antiretroviral therapy (HAART) can be enrolled
Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 14 days or 5 half lives before enrollment or is currently enrolled in the treatment stage of an investigational study
Had hospitalization for infection or major surgery (eg, requiring general anesthesia) within 2 weeks before enrollment or have not fully recovered from surgery. Note: subjects with surgical procedures conducted under local anesthesia may participate
A man who plans to father a child while enrolled in this study or within 3 months after the last dose of study agent
Additional locations may be listed on ClinicalTrials.gov for NCT06679829.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
New York
Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Gunjan L. Shah
Phone: 646-608-3734
PRIMARY OBJECTIVES:
I. To evaluate the feasibility of achieving the area under the curve (AUC) target using the population pharmacokinetics (Pop PK) melphan dosing. (Run-In Phase)
II. To evaluate whether Pop PK melphalan dosing improves the rate of stringent complete response (sCR) compared to patients who receive standard melphalan dosing (mg/m^2).
III. To evaluate if IL-6 blockade with siltuximab reduces post-autologous hematopoietic stem cell transplantation (AHCT) toxicity, as assessed by the MD Anderson Symptom Inventory Multiple Myeloma Module (MDASI-MM), in patients at high risk for developing severe symptom burden post-AHCT (age 60-75 with MM) through day 30 compared to patients who do not receive siltuximab and achieve versus (vs) do not achieve the target AUC goal.
SECONDARY OBJECTIVES:
I. To evaluate and define the safety profile of pre- and post-transplant siltuximab administration in patients with MM undergoing AHCT.
II. To understand the impact of reducing symptom burden on length of stay in those who receive siltuximab/AHCT in the inpatient setting, as well as readmission rates when siltuximab/AHCT occurs in the outpatient setting.
III. To quantify the rates of neutropenic fever and culture positive blood stream infections with the use of siltuximab pre and post AHCT.
IV. To evaluate post-transplant disease status including minimal residual disease (MRD), and overall survival (OS), and progression-free survival (PFS) at day 100 and day 365, as per institutional guidelines.
V. To evaluate the impact of melphalan pharmacokinetics (PK) on symptom burden and disease response and compare outcomes of patients in both arms who achieved the AUC target vs those who did not.
EXPLORATORY OBJECTIVES:
I. To evaluate and correlate levels of IL-6 and C-reactive protein (CRP) in the acute phase of transplant to a patient-reported symptom inventory (MDASI-MM).
II. To explore DNA adduct formation and repair in relation to symptom burden and Pop PK AUC.
III. To compare the rates of grade 3+ atrial fibrillation between the two arms.
OUTLINE: Patients are randomized to 1 of 2 arms. Patients in the run-in portion of the study receive treatment according to Arm A.
ARM A: Patients receive siltuximab intravenously (IV) over 1 hour on days -7 and 14. Patients also receive the minimum equivalent dose of melphalan IV over 30 minutes on day -2 and then Pop PK dosed melphalan IV over 30 minutes on day -1. Additionally, patients undergo positron emission tomography (PET)/computed tomography (CT), CT or magnetic resonance imaging (MRI), bone marrow biopsy and aspiration, and echocardiography (ECHO) or multigated acquisition scan (MUGA) at enrollment and undergo blood sample collection throughout the study.
ARM B: Patients receive body surface area (BSA) based melphalan IV over 30 minutes on day -2. Additionally, patients undergo PET/CT, CT or MRI, bone marrow biopsy and aspiration, and ECHO or MUGA at enrollment and undergo blood sample collection throughout the study.
After completion of study treatment, patients are follow up at days 100 and 365.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
