Melphalan Hydrochloride in Treating Participants With Newly-Diagnosed Multiple Myeloma Undergoing Donor Stem Cell Transplantation

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of melphalan hydrochloride in treating participants with newly-diagnosed multiple myeloma who are undergoing a donor stem cell transplantation. Giving chemotherapy before a donor stem cell transplantation helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant, they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving melphalan hydrochloride before a donor stem cell transplantation may work better than standard chemotherapy in helping to prevent multiple myeloma from coming back.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the optimal dose and schedule of melphalan for injection (melphalan hydrochloride [Evomela]) prior to autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma (MM). II. To collect the pharmacokinetic data and compare the exposure-response evaluations between the 2 infusion schedules. SECONDARY OBJECTIVES: I. To determine the incidence of treatment related mortality (TRM) at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. II. To determine the rate of minimal residual disease (MRD) negative complete response (CR) rate at day 90 after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. III. To determine the progression-free survival (PFS) after auto-HCT in newly diagnosed myeloma patients treated on different schedules and doses of Evomela. OUTLINE: This is a phase I, dose escalation study of melphalan hydrochloride followed by a phase II study. PREPARATIVE REGIMEN: Participants are randomized to 1 of 2 groups. GROUP 1: Participants receive melphalan hydrochloride intravenously (IV) over 30-60 minutes on day -2. GROUP 2: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz subcutaneously (SC) once daily (QD) starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an absolute neutrophil count (ANC) of 0.5 x 10^9/L. After completion of study treatment, participants are followed up at 3 months, every 3 months for 1 year, and then annually for 1 year.

Official Title
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Prospective Phase I/II Trial to Jointly Optimize the Administration Schedule(s) and Dose(s) of Melphalan for Injection (Evomela) as a Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Plasma Cell Myeloma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Biological: Filgrastim-sndz
* Drug: Melphalan Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with non-relapsed multiple myeloma in complete response (CR), partial remission (PR), very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain multiple myeloma (MM) detected in the serum by free light chain assay OR Patients with non-secretory multiple myeloma (absence of a monoclonal protein [M protein] in serum as measured by electrophoresis [serum protein electrophoresis (SPEP)] and immunofixation (serum immunofixation electrophoresis [SIFE]) and the absence of Bence Jones protein in the urine [urine protein electrophoresis (UPEP)] defined by use of conventional electrophoresis and immunofixation [urine immunofixation electrophoresis (UIFE) techniques]) but with measurable disease on imaging studies like magnetic resonance imaging (MRI), computed tomography (CT) scan or positron emission tomography (PET) scan. Patients who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy. Karnofsky performance score 70% or higher. Left ventricular ejection fraction at rest > 40% within 3 months of registration. Bilirubin < 2 x the upper limit of normal (except patients with Gilbert syndrome in whom bilirubin level of > 2 x upper normal limit will be allowed) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of normal. Creatinine clearance of >= 40 mL/min, estimated or calculated using the Cockcroft-Gault equation. Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC) > 50% of predicted value (corrected for hemoglobin) within 3 months of registration. All female and male subjects of reproductive potential must consent to the use of effective contraceptive methods as advised by the study doctor during treatment. Signed informed consent form. Exclusion Criteria: Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients seropositive for the human immunodeficiency virus (HIV). Patients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients participating in an investigational new drug protocol within 14 days before enrollment. Female patients who are pregnant (positive beta-human chorionic gonadotropin [b-HCG]) or breast feeding. Prior hematopoietic cell transplantation allogeneic or autologous (A prior autologous HCT will be allowed as long as it was part of tandem transplantation). Prior organ transplant requiring immunosuppressive therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (melphalan hydrochloride, HSCT, filgrastim)<br>PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 30-60 minutes on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Biological: Filgrastim-sndz<br>* Given SC<br>* Other names: Zarxio;Drug: Melphalan Hydrochloride<br>* Given IV<br>* Other names: Evomela;|
| Experimental: Group 2 (melphalan hydrochloride, HSCT, filgrastim)<br>PREPARATIVE REGIMEN: Participants receive melphalan hydrochloride IV over 8-9 hours on day -2. TRANSPLANT: Participants in both groups undergo donor stem cell transplantation IV on day 0 over 30-60 minutes. POST-TRANSPLANT: Participants in both groups receive filgrastim-sndz SC QD starting on day 5 and continuing in the absence of disease progression, unacceptable toxicity, or until evidence of an ANC of 0.5 x 10^9/L. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo HSCT<br>* Other names: Stem Cell Transplantation, Autologous;Biological: Filgrastim-sndz<br>* Given SC<br>* Other names: Zarxio;Drug: Melphalan Hydrochloride<br>* Given IV<br>* Other names: Evomela;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity of melphalan hydrochloride | Toxicity will be defined as grade 4 mucositis or any grade 4 or 5 non-hematologic or non-infectious toxicity occurring within 30 days from the start of infusion. | Within 30 days after the start of infusion | 
| The Pharmacokinetics of melphalan hydrochloride parameters will assessed. | The investigators will determine pharmacokinetic parameters such as Cmax for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis). | Up to 1 year | 
| The Pharmacokinetics of melphalan hydrochloride parameters will assessed. | The investigators will determine pharmacokinetic parameters such as, Clearance for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis). | Up to 1 year | 
| The Pharmacokinetics of melphalan hydrochloride parameters will assessed. | The investigators will determine pharmacokinetic parameters such as Half-life for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis). | Up to 1 year | 
| The Pharmacokinetics of melphalan hydrochloride parameters will assessed. | The investigators will determine pharmacokinetic parameters such as AUC (area under the curve) for each patient using the melphalan plasma concentrations at various time points described above.The investigators will also examine the correlation of theses PK parameters such as (AUC, Clearance, Cmax) with efficacy outcomes (such as OS, PFS) and toxicities (such as mucositis). | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | PFS will be computed from the date of Evomela injection to the last time of follow-up or the event of interest (progression or death). Unadjusted PFS distributions will be estimated by the Kaplan and Meier method. | From the date of Evomela injection up to 1 year | 
| Incidence of treatment related mortality (TRM) | TRM will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of TRM from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the Bayesian Model Averaging continual reassessment method (BMA-CRM). | At day 90 post-transplant | 
| Rate of minimal residual disease (MRD) | MRD negative is defined as absence of phenotypically aberrant clonal plasma cells by nerve growth factor (NGF) on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10^5 nucleated cells or higher. MRD will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of MRD from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM. | At day 90 post-transplant | 
| Complete response rate (CR) | CR will be estimated along with 95% posterior credible intervals, assuming beta (.50, .50) priors. The probabilities of CR from the two infusion schedules will also be compared using posterior probabilities of the form Pr(p1 < p2 | data), where pj denotes the probability of the event with schedule j=1,2, based on the data for patients treated at the optimal within-schedule dose chosen by the BMA-CRM. | At 90 days post-transplant |