An Open-label Phase II Study of the Efficacy of Combination Bortezomib-containing Regimens in the Treatment of Newly Diagnosed Patients With t (4; 14) Positive Multiple Myeloma
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 36
- Locations
- 7
- Primary Endpoint
- To determine the time to progression (TTP) with this treatment regimen
Study Overview
Brief Summary
Given the disappointing results with routine ASCT in t(4;14) patients, we propose this open label phase II study of bortezomib along with dexamethasone and pegylated liposomal doxorubicin (Doxil/Caelyx), referred to as the DBd regimen, for 4 cycles, followed by post-induction therapy with cyclophosphamide + bortezomib + prednisone (referred to as the CyBorP regimen) for 8 cycles. Since patients with t(4;14) remain at high risk for relapse, maintenance therapy with dexamethasone weekly will be given until disease progression.
Detailed Description
PROTOCOL SYNOPSIS A. TITLE: An Open-Label Phase II Study of the Efficacy of Combination Bortezomib-containing Regimens in the Treatment of newly diagnosed patients with t (4;14) positive Multiple Myeloma.
B. RATIONALE: Between 15 and 20% of myeloma patients exhibit a t(4;14), which results in translocation of the receptor tyrosine kinase (TK) fibroblast growth factor receptor 3 (FGFR3) from chromosome 4 to the Immunoglobulin H (IgH) locus. The presence of a t(4;14) appears to confer an extremely poor prognosis. Patients with this abnormality do not experience prolonged remissions after a single autologous stem cell transplant (ASCT) using high-dose melphalan, and the optimal therapy of this group has not yet been defined. Specifically, data from Princess Margaret Hospital and the Mayo Clinic both indicate that the median progression-free survival (PFS) is only about 8 months and overall survival 18-22 months after ASCT. Unpublished data from the French Francophone Myeloma Intergroup (IFM) studies suggest that tandem transplants may improve these results modestly, but the outcome is still inferior compared with other cytogenetic subgroups.
Initial unpublished observations suggested that t(4;14) patients with relapsed/refractory disease were uniquely sensitive to the new agent bortezomib. More recent information in larger numbers of patients indicates that responses to single agent bortezomib are seen in up to 50-65% of t(4;14) patients; the duration of response is similar to that seen in other subsets, i.e. in the range of 5-7 months. Combinations of bortezomib with agents such as doxorubicin, pegylated liposomal doxorubicin, thalidomide, cyclophosphamide, melphalan, thalidomide and corticosteroids have been evaluated in a number of clinical studies in recurrent myeloma, and the response rates (RR) appear to be improved compared to single agent bortezomib, and toxicity has been acceptable.
In newly diagnosed myeloma patients, combinations such as vincristine, doxorubicin, dexamethasone (VAD) and thalidomide + dexamethasone are often utilized before ASCT. A study by Hussein et al. substituted pegylated liposomal doxorubicin for the conventional formulation of doxorubicin and noted a similar response rate with less grade 3/4 neutropenia, alopecia and sepsis; in addition, patients do not necessarily require a central venous catheter. More recently, Cavenagh et al. has reported remarkable activity with the so-called PAD regimen of bortezomib, doxorubicin and dexamethasone, with a combined Complete Remission (CR) + Partial Response (PR) rate of 67% following 1 cycle, and 93% after 4 cycles, with no impairment of the ability to collect blood stem cells for ASCT. Preliminary data from an ongoing Canadian phase II study of Doxil/Caelyx + Bortezomib + Dexamethasone (DBd), in which pegylated liposomal doxorubin, bortezomib and dexamethasone are combined, has produced encouraging results to date with minimal toxicity. In that study, DBd therapy was given for 4 cycles before ASCT independently of cytogenetic classification.
Given the disappointing results with routine ASCT in t(4;14) patients, we propose this open label phase II study of bortezomib along with dexamethasone and pegylated liposomal doxorubicin (Doxil/Caelyx), referred to as the DBd regimen, for 4 cycles, followed by post-induction therapy with cyclophosphamide + bortezomib + prednisone (referred to as the CyBorP regimen) for 8 cycles. Since patients with t(4;14) remain at high risk for relapse, maintenance therapy with dexamethasone weekly will be given until disease progression. This approach will test the hypothesis that bortezomib-based therapy can improve the outcome of newly diagnosed t(4;14) multiple myeloma patients.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients previously diagnosed with MM based on criteria from the International Myeloma Working Group (IMWG)
- •Patients who have 'measurable' disease
- •Age 18 years at the time of signing Informed Consent
- •A patient may have received up to 4 months of other anti myeloma therapy, as part of the induction therapy, prior enrollment and still be considered eligible to participate in the study, as long as the patient's multiple myeloma has not progressed on the current regimen and the other eligibility criteria are met.
- •Patient is t(4;14) positive on screening assay.
Exclusion Criteria
- •Concomitant therapy medications that include corticosteroids (> 10 mg per day of prednisone or equivalent) or other therapy that is or may be active against myeloma prior to day 1 (with the exception of radiation therapy or induction therapy as described under the above inclusion criteria section
- •Peripheral neuropathy of Grade 2 or greater.
- •Patients with evidence of mucosal or internal bleeding and/or refractoriness to platelet transfusions (i.e., unable to maintain a platelet count 50 x 109 /L).
- •Patients with an absolute neutrophil count (ANC) < 1.0 x 109/L. Treatment to raise the ANC, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is not allowed within 14 days of study entry.
- •Patients with hemoglobin < 80 g/L despite transfusion.
- •Pregnant or lactating women
Arms & Interventions
Single Arm
Please see intervention description for Bortezomib (Velcade)
Intervention: Bortezomib (Drug)
Outcomes
Primary Outcomes
To determine the time to progression (TTP) with this treatment regimen
Time Frame: Patients were followed monthly until disease progression and subsequently every six months for up to five years to assess OS.
Measured from the date of enrollment to the date of disease progression. Otherwise, censored at the time of last disease assessment. Responses were assessed using the International Myeloma Working Group criteria, involving a modified version of the European Group for Blood and Marrow Transplantation (EBMT) criteria, where the category of stringent complete response (sCR) was included for patients with normalization of the free light chain ratio.10,11 Bone marrow aspirate and biopsy were obtained routinely after induction therapy to confirm CR or sCR. Serum free light chain assay and serum and/or urine electrophoresis were performed monthly; immunofixation was performed when confirmation of very good partial response (VGPR), CR, or sCR was necessary.
Secondary Outcomes
- To determine overall survival(5 years)
- To determine the safety profile of this regimen(5 years)
- To determine the objective response rate/duration following DBd induction and Cybor P post induction therapy(Patients were followed monthly until disease progression)
- To determine PFS(5 years)