A Trial for Systemic Light-chain (AL) Amyloidosis

Design In this multi-center phase III trial, untreated patients diagnosed with AL who are not candidates for stem cell transplant with melphalan 200 mg/m2 are the target population. Patients who are eligible for SCT with melphalan 200 mg/m2 but who decline to undergo transplantation will be enrolled in the study as a subgroup with stratified randomization. Because many newly diagnosed AL patients present with limited organ reserve, the eligibility criteria take into consideration the impact of cardiac involvement on overall survival using cardiac biomarker staging. Stage I and II patients will be eligible. Stage III patients will be enrolled in an ancillary phase II study. Eligible patients will be stratified as cardiac stage I or stage II and then randomized to receive MDex or BMDex.

Intervention Untreated patients with AL amyloidosis will be offered treatment on this study. After being screened and found eligible, patients will be stratified based on cardiac stage as stage I or stage II. Thresholds for cTnT, cTnI, and NT-proBNP are <0.035 microg/L, <0.1 microg/L, and <332 ng/L respectively. For stage I patients both cTnT or cTnI and NT-proBNP are below the threshold. For stage II patients either troponin or NT-proBNP are above the threshold.

Patients eligible for SCT with melphalan 200 mg/m2 who decline transplant will be considered an additional stratum and randomized separately.

Thus, there will be the following strata:

0.patients eligible for SCT with melphalan 200 mg/m2 who decline transplant,

1. cardiac stage I,
2. cardiac stage II.

After stratification, patients will then be randomized to receive either A: MDex:oral melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days (MDex) or B: BMDex:cycles 1 and 2 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle,cycles 3 - 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.

Treatment will start within 2 weeks after randomization.

Treatment is continued until

• completion of MDex cycle 9 or BMDex cycle 8 or
• achievement of a complete hematologic response after cycle 6 or
• achievement of a partial hematologic response and an organ response after cycle 6 or
• less than a partial hematologic response after cycle 3 or
• progression of clonal plasma cell disease.

On the first day of each new treatment cycle and before each bortezomib dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. Dose modifications or delays will be made based on the toxicity experienced during the previous cycle of therapy or newly encountered on Day 1 of a cycle. Dose reduction steps are presented.

The start of a new cycle can be delayed on a weekly basis (for a maximum of 3 weeks)until recovery from toxicity to a level allowing continuation of therapy. Delay of a new cycle for more than 3 weeks can only occur if a clear clinical benefit has been observed. Otherwise, if there is a delay in the start of a new cycle of more than 3 weeks due to insufficient recovery from toxicity, subjects will discontinue study drug and have procedures performed as outlined for the End of Treatment Visit in the Schedule of Events.

During treatment, prophylactic medications will include acyclovir 400 mg twice daily with dose adjusted for renal function, ciprofloxacin 250 mg twice a day on days 1-7 of each cycle, and a proton-pump inhibitor. Supportive measures will be used. Patients will be seen in clinic by their physicians prior to beginning each cycle of therapy.