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.

Summary

This is a Phase iii, multicenter, randomized, open-label study designed to evaluate the clinical benefit from the drug combination lenalidomide, bortezomib and dexamethasone (RVD) without immediate high-dose therapy (HDT) and autologous peripheral blood stem cell transplant (PBSCT), followed by lenalidomide maintenance (arm a) versus RVD plus HDT and PBSCT, followed by lenalidomide maintenance (arm B). The aim of the protocol is to determine if, in the era of novel drugs, HDT is still necessary in the initial management of multiple myeloma (MM) in younger patients. [Quote]High-dose[Quote] chemotherapy (arm B) will be considered superior if it significantly prolongs progression-free survival as compared to [Quote]conventional-dose[Quote] treatment (arm a).


arm a:
arm a:
* RVD q 21 days (2 cycles)
* Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and filgrastim or G-CSF type Granocyte[RegisteredTM] or equivalent
* RVD q 21 days (5 cycles)
* Maintenance Lenalidomide q28 days (until disesase progression)


arm B:
* RVD q 21 days (2 cycles)
* Collection of peripheral blood stem cells (PBSCs) using cyclophosphamide and filgrastim or G-CSF type Granocyte[RegisteredTM] or equivalent
* autologous stem cell transplant:
o Melphalan: infused over two days (day minus 2 and minus 1) or as a single infusion (day minus 2), according to institutional practice
o Re-infusion of PBSCs
* RVD q 21 days (2 cycles)
* Maintenance Lenalidomide q28 days (until disease progression)

RanDoMiZaTion
Stratify according to:
* iSS stage (stage i, ii, or iii)
* Cytogenetics: standard vs. high-risk vs. FiSH failures. High-risk is defined as presence of del(17p), or t(4:14), or t(14;16) using FiSH.

Participant Eligibility

Inclusion Criteria for Registration
All laboratory assessments must be performed within 21 days of initiation of protocol therapy. Bone marrow biopsy, skeletal survey, MRI, CT scans, and chest X-ray must be performed within 35 days of initiation of protocol therapy.

1. 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 plasmacytomam (within 35 days)

* Monoclonal protein (M-protein) present in the serum and/or urine. (within 21 days)

* 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:

[C] Calcium elevation in the blood, defined as serum calcium > 10.5 mg/dl or upper limit of normal (within 21 days)

[R] Renal insufficiency (defined as serum creatinine above normal) (within 21 days)

[A] Anemia, defined as hemoglobin <10 g/dl or 2 g < normal (within 21 days)

[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. (within 21 days)

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.

2. Participants must have documented symptomatic myeloma, with organ damage related to myeloma as defined in section 3.1.1 of the protocol with laboratory assessments performed within 21 days of initiation of protocol therapy.

3. 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, urine M-protein >= 200 mg/24 h, and/or serum FLC assay: involved FLC level >= 10 mg/dl with abnormal serum FLC ratio.
Free light chain patients not measurable by urine or serum evaluation may be considered for inclusion.

4. Age between 18 and 65 years at the time of signing the informed consent form.

5. ECOG performance status <=2 (Karnofsky >=60%, see Appendix III of the protocol).

6. Negative HIV blood test within 21 days of study entry. HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic (PK) interactions with lenalidomide, Bortezomib and/or dexamethasone. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy.

7. All study participants must be registered into the mandatory Revlimid REMS(RegisteredTM) program, and be willing and able to comply with the requirements of Revlimid REMS(RegisteredTM) program

8. Females of childbearing potential* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 x 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(RegisteredTM)) 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)

9. Females of childbearing potential must also agree to ongoing pregnancy testing.

10. 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. See Appendix II: Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

11. 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.

After registration and prior to randomization, participants will receive 1 cycle of RVD.
Participants are not required to meet additional eligibility or exclusion criteria prior to
randomization procedures.

Inclusion of Women, Minorities and Other Underrepresented Populations
Women, minorities and members of other underrepresented populations will have equal consideration for participation in this trial. Please note, however, that the prevalence of MM is more common among men than women, occurs more frequently with increasing age, and develops twice as often among black individuals than among white individuals. Inclusion and exclusion criteria are not expected to have a negative effect on recruitment or retention of these underrepresented populations.