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A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-Chain (AL) Amyloidosis Ineligible for Autologous Stem-Cell Transplantation

Phase 3
18 Years
Not Enrolling
Light Chain Deposition Disease, Primary Systemic Amyloidosis

Thank you

Trial Information

A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-Chain (AL) Amyloidosis Ineligible for Autologous Stem-Cell Transplantation


I. To compare hematologic overall response (partial response [PR], very good PR, amyloid
complete hematologic response [ACR], and stringent complete response [sCR]) after 3 courses
of therapy in patients with previously untreated systemic light-chain amyloidosis treated
with melphalan and dexamethasone with vs without bortezomib.


I. To evaluate the ACR rate after 3 courses of therapy and at completion of therapy.

II. To evaluate organ response rates after 3 courses of therapy and at 6, 9, and 12 months.

III. To evaluate treatment-related mortality. IV. To evaluate toxicity. V. To evaluate
progression-free and overall survival. VI. To evaluate PR or better at completion of
therapy. VII. To evaluate time to hematologic and organ response. VIII. To evaluate the
duration of hematologic and organ response. IX. To assess quality of life (QOL) at baseline,
at 3, 6, and 9 months during the therapy, at completion of therapy, and 3 and 6 months after


I. To determine the prognostic impact of t(11;14) translocation and cyclin D1 overexpression
on response and overall survival.

II. (Correlative) To compare sCR rates and to determine the impact of sCR on the outcomes.

III. (Correlative) To perform a descriptive analysis of amyloid typing and proteomic
composition of amyloid tissues.

OUTLINE: This is a multicenter study. Patients are stratified according to cardiac stage (I
vs II) and are randomized to 1 of 2 treatment arms.

ARM I: Patients receive melphalan orally (PO) and dexamethasone PO on days 1-4. Treatment
repeats every 28 days for up to 9 courses in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib
intravenously (IV) on days 1, 4, 8, and 11. Treatment repeats every 28 days for 2 courses.
Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on
days 1, 8, 15, and 22. Treatment repeats every 35 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity.

Blood, urine, bone marrow, and fat samples may be collected periodically for laboratory
analysis. Health-related quality of life is assessed periodically before, during, and after
therapy. After completion of study treatment, patients are followed up periodically for 5

Inclusion Criteria:

- Histologically confirmed diagnosis of systemic light-chain amyloidosis

- Histologic diagnosis of disease must be confirmed by pathology (positive Congo
red stain with green birefringence on polarized light microscopy)

- Genetic testing must be negative for transthyretin mutations associated with
hereditary amyloidosis (required in patients who are African-American or who present
with peripheral neuropathy as the dominant organ involvement)

- Measurable disease, defined by >= 1 of the following:

- Serum M-protein >= 1 g/dL by serum protein electrophoresis (SPEP)

- Serum kappa or lambda free light chain of >= 7.5 mg/dL allowed provided the
kappa to lambda free light chain ratio is abnormal

- Symptomatic organ involvement* (heart, kidney, liver/gastrointestinal tract,
peripheral nervous system, or soft tissue), defined as any of the following:

- NOTE: *Carpal tunnel syndrome skin purpura or the presence of vascular amyloid
on a bone marrow biopsy alone are not sufficient to meet criteria for
"symptomatic organ involvement"

- Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day
by 24-hour urine collection

- Cardiac involvement is defined as the presence of a mean left ventricular wall
thickness of > 12 mm by ECHO in the absence of a history of hypertension or
valvular heart disease or in the presence of unexplained low voltage (< 0.5 mV)
by ECG

- Hepatic involvement is defined as hepatomegaly or an alkaline phosphatase > 1.5
times upper limit of normal (ULN)

- Peripheral nerve involvement is defined by clinical history or abnormal sensory
and/or motor findings on neurologic exam

- Gastrointestinal (GI) involvement is defined as gross GI bleeding or diarrhea
(at least 4 stools per day over baseline); a positive GI biopsy is not
sufficient to document clinical involvement

- Autonomic nerve involvement is defined as orthostasis, symptoms of nausea or
dysgeusia, gastric atony by gastric emptying scan, diarrhea, or constipation

- Soft tissue and lymphatic involvement may be ascertained based on classic
physical exam findings (macroglossia, shoulder pad sign, raccoon eyes, carpal
tunnel syndrome, synovial enlargement, firm enlarged lymph nodes) or biopsy

- Amyloid cardiac biomarker stage I or II disease

- Staging defined by NT-proBNP and troponin T cut-offs of < 332 pg/mL and < 0.035
ng/mL, respectively, as thresholds: stage I, both under threshold; stage II,
either troponin or NT-proBNP (but not both) over threshold (if troponin T is not
available at local institution, troponin I may be used, but the threshold must
be < 0.1 ng/mL)

- No clinically overt myeloma (hypercalcemia or lytic bone lesions)

- Ineligible for autologous stem cell transplantation with melphalan 200 mg/m^2 or
refuses to undergo transplantation

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) > 1,500/mm^3

- Platelet count > 140,000/mm^3

- Hemoglobin > 11 g/dL

- Total bilirubin < 2.5 mg/dL

- Alkaline phosphatase < 5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) < 3 times ULN

- Creatinine clearance > 30 mL/min

- Bone marrow plasma cells < 30%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No repetitive ventricular arrhythmias on 24-hour Holter electrocardiogram (ECG) (in
spite of antiarrhythmic treatment)

- The absence of supine systolic blood pressure < 100 mmHg and difficult to
managesymptomatic orthostatic hypotension

- No symptomatic orthostatic hypotension that is difficult to manage

- No cardiac syncope

- No uncompensated NYHA class III or IV congestive heart failure

- No uncontrolled infection

- No active malignancy within the past 5 years except for adequately treated basal cell
or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I
cancer currently in complete remission

- No serious medical or psychiatric illness likely to interfere with study
participation, including recent myocardial infarction (within the past 6 months) or
poorly controlled diabetes mellitus

- No peripheral neuropathy >= grade 2

- Human immunodeficiency virus (HIV)-positivity allowed provided the following criteria
are met:

- No history of acquired immunodeficiency syndrome (AIDS)-defining events
including history of CD4 cell count < 200/mm^3

- Current CD4 cell count >= 350/mm^3

- Not receiving zidovudine or stavudine

- No secondary amyloidosis

- No known hypersensitivity to bortezomib, boron, or mannitol

- No prior chemotherapy or radiotherapy for the treatment of myeloma or systemic
light-chain amyloidosis

- More than 3 weeks since radiotherapy

- Enrollment of subjects who require radiotherapy (which must be localized in
field size) should be deferred until the radiotherapy is completed and 3 weeks
have elapsed since the last date of therapy

- More than 14 days since prior and no concurrent participation in clinical trials with
other investigational agents not included in this trial

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Hematologic overall response (PR+VGPR+ACR+sCR)

Outcome Description:

Will be performed using Mantel-Haenszel test stratified on cardiac stage with an overall one-side type I error of 2.5%. The Mantel-Haenszel estimator is used to estimate the common odds ratio (BMDex/MDex), and a two-sided 95% confidence interval is also calculated.

Outcome Time Frame:

84 days (3 courses)

Safety Issue:


Principal Investigator

Angela Dispenzieri

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

November 2010

Completion Date:

Related Keywords:

  • Light Chain Deposition Disease
  • Primary Systemic Amyloidosis
  • Amyloidosis
  • Multiple Myeloma



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