Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Phase III Comparing Conventional Dose RVD to High-Dose w PSCT in Initial Management of Myeloma

Protocol: OSU-14069

Full Title

A Randomized Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib and Dexamethasone (RVD) to High-Dose Treatment with Peripheral Stem Cell Transplant in the Initial Management of Myeloma in Patients up to 65 Years of Age.

Study Objective

PRIMARY OBJECTIVES:

I. To compare progression-free survival (PFS) between Arm I and Arm II.

SECONDARY OBJECTIVES:

I. To compare the response rates (RR) between the two arms.

II. To compare time to progression (TTP) between the two arms.

III. To compare the overall survival (OS) between the two arms.

IV. To compare the toxicity between the two arms.

V. To define genetic prognostic groups evaluated by gene expression profiling (GEP).

VI. To examine the best treatment in each Gene Expression Profile-defined prognostic group.

VII. To compare quality of life (QOL) between the two arms.

VIII. To collect medical resource utilization (MRU) information which may be used in economic evaluation models.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

INITIAL THERAPY: All patients receive lenalidomide orally (PO) once daily (QD) on days 1-14; bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11; and dexamethasone PO on days 1, 2, 4, 5, 8, 9, 11, and 12. Patients are then randomized to 1 of 2 treatment arms.

ARM I:

RVD THERAPY: Patients receive RVD as in initial therapy, with courses repeating every 21 days for 2 courses.

PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Patients undergo PBSC mobilization comprising cyclophosphamide IV over 1 hour 21 days after the last lenalidomide dose and filgrastim (G-CSF) subcutaneously (SC) beginning 24-48 hours after the cyclophosphamide dose and continuing until required PBSCs are collected.

CONSOLIDATION THERAPY: Patients receive RVD therapy as in initial therapy for 5 courses.

MAINTENANCE THERAPY: Within 3 weeks of completing RVD consolidation therapy, patients receive lenalidomide PO on days 1-28. Treatment continues every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

ARM II:

RVD THERAPY: Patients receive RVD therapy as in Arm I.

PBSC MOBILIZATION: Patients undergo PBSC mobilization as in Arm I.

PBSC TRANSPLANT: Patients receive melphalan IV over 30 minutes on either days -2 and -1 or on -2 or according to institutional practice then undergo PBSC transplant on day 0.

CONSOLIDATION THERAPY: Beginning 60-110 days after PBSC transplant, patients receive RVD consolidation therapy as in Arm I for 2 courses.

MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I.

After completion of study treatment, patients are followed up every 2 months for up to 3 years.

Are you eligible?

Inclusion Criteria:

Participants must have a diagnosis of MM, according to International Myeloma Foundation 2003 Diagnostic Criteria; according to these criteria, the following must be met:

Monoclonal plasma cells in the bone marrow; 10% (or proven plasmocytic infiltration in bone marrow biopsy) and/or presence of a biopsy-proven plasmacytoma within 35 days of initiation of protocol therapy

Monoclonal protein (M-protein) present in the serum and/or urine

Myeloma-related organ dysfunction (1 or more) of the following; a variety of other types of end-organ dysfunctions can occasionally occur and lead to a need for therapy; Note: laboratory assessments used to support the calcium, kidney (renal) failure, anemia, bone lesions (CRAB) criteria in the International Myeloma Foundation (IMF) 2003 Diagnostic Criteria of MM are performed at the time of diagnosis; these assessments are not required to be performed within the 21 days of initiation of protocol therapy

  • [C] Calcium elevation in the blood, defined as serum calcium > 10.5 mg/dl or upper limit of normal
  • [R] Renal insufficiency (defined as serum creatinine above normal)
  • [A] Anemia, defined as hemoglobin < 10 g/dl or 2 g < normal
  • [B] Lytic bone lesions or osteoporosis; if a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then; 30% plasma cells are required in the bone marrow or proven plasmocytic infiltration in bone/bone marrow biopsy

Note: these criteria identify stage IB (if the creatinine is > 2 mg/dl at presentation) and stages II and III A/B myeloma by Durie-Salmon stage; stage IA becomes smoldering or indolent myeloma

Participants must have documented symptomatic myeloma, with organ damage related to myeloma as defined above with laboratory assessments

Participants must have myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains; measurable disease is defined as one or more of the following: serum M-protein >= 1 g/dl (except patients with immunoglobulin [Ig] D or IgA myeloma), urine M-protein >= 200 mg/24 hour (h), and/or serum free light chain (FLC) assay: involved FLC level >= 10 mg/dl with abnormal serum FLC ratio; for patients with IgD or IgA myeloma, a serum M-protein of greater than or equal to 0.5 g/dl will suffice; free light chain patients not measurable by urine or serum evaluation may be considered for inclusion

Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

Negative human immunodeficiency virus (HIV) blood test within 21 days of study entry; HIV-positive individuals on combination antiretroviral therapy are ineligible

All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS®) program, and be willing and able to comply with the requirements of Revlimid REMS®

Females of childbearing potential* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMS®) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide

A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)

Females of childbearing potential must also agree to ongoing pregnancy testing

Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy

Ability to understand and the willingness to sign a written informed consent document; voluntary written informed consent must be obtained before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care

Exclusion Criteria:

Participant treated with any prior systemic therapy for myeloma; treatment by localized radiotherapy is not an exclusion criterion if an interval of at least 7 days between the end of radiotherapy and initiation of protocol therapy is observed; intervals of less than 7 days between radiotherapy and initiation of protocol therapy will be considered on a case by case basis with the lead principal investigator (PI), provided toxicity is not a concern; similarly, the dose of corticosteroids received by the participant as part of initial therapy for myeloma should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol therapy

Primary amyloidosis (AL) or myeloma complicated by amyloidosis

Participants receiving any other investigational agents

Participants with known brain metastases should be excluded from this clinical trial

Poor tolerability or known allergy to any of the study drugs or compounds of similar chemical or biologic composition to lenalidomide, bortezomib and/or dexamethasone

Participants with platelet level < 50,000/mm^3, within 21 days of initiation of protocol therapy for patients in whom < 50% of bone marrow nucleated cells are plasma cells; or platelet count < 30,000/mm^3 for patients in whom >= 50% of bone marrow nucleated cells are plasma cells; transfusion within 7 days of screening is not allowed to meet platelet eligibility criteria

Participants with an absolute neutrophil count (ANC) < 1000/mm^3, within 21 days of initiation of protocol therapy; growth factor within 7 days of screening is not allowed to meet ANC eligibility criteria

Participants with hemoglobin level < 8 g/dL, within 21 days of initiation of protocol therapy; transfusion may be used to meet hemoglobin eligibility criteria

Total bilirubin > 1.5 x institutional upper limit of normal (ULN) (patients with benign hyperbilirubinemia [e.g., Gilbert’s syndrome] are eligible), within 21 days of initiation of protocol therapy

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) >= 2 x institutional ULN, within 21 days of initiation of protocol therapy

Alkaline phosphatase >= 2 x institutional ULN, within 21 days of initiation of protocol therapy

Renal insufficiency at the time of screening, defined as serum creatinine > 2.0 mg/dL or creatinine clearance < 50 mL/min (either actual or calculated value may be used), within 21 days of initiation of protocol therapy; creatinine clearance will be the primary eligibility criteria in determining renal insufficiency; the Cockcroft-Gault formula should be used for calculating creatinine clearance values

Respiratory compromise, defined as ventilation tests with diffusion capacity of the lung for carbon monoxide (DLCO) < 50%

Participant with clinical signs of heart or coronary failure, or evidence of left ventricular ejection fraction (LVEF) < 40%; participant with myocardial infarction within 6 months prior to enrollment or have 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 conductive system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant

Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements; for patients with a positive hepatitis B antibody result, but no signs of active infection, participating sites must contact the study PI for approval

Participants with previous history of another malignant condition are excluded, except for localized cancers that have been adequately treated; this includes completely resected basal cell carcinoma or squamous cell carcinoma of the skin, in situ malignancy (e.g. ductal carcinoma in situ [DCIS] of the breast), good risk prostate cancer after curative therapy and/or considered appropriate for watchful waiting (e.g. Gleason 6 or less, T2 or less and prostate-specific antigen [PSA] < 10) , and stage I cervical cancer; if invasive malignancy was experienced 2 or more years ago and confirmed as cured, these participants may be considered for the study on case by case basis with PI discussion and approval

Female participants pregnant or breast-feeding; pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with lenalidomide; these potential risks may also apply to other agents used in this study; lactating females must agree not to breast feed while taking lenalidomide

Inability to comply with an anti-thrombotic treatment regimen (e.g., administration of aspirin, enoxaparin, or low molecular weight heparin administration [type Innohep or equivalent])

Peripheral neuropathy >= grade 2 on clinical examination, within 21 days of initiation of protocol therapy

Multiple Myeloma