Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects.

  • Dubrey S
  • Reece D
  • Sanchorawala V
 et al. 
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BACKGROUND: Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL).

METHODS: In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response.

RESULTS: During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a ≥ 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment.

CONCLUSION: AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.

Author-supplied keywords

  • Aged
  • Amyloidosis
  • Amyloidosis: complications
  • Amyloidosis: drug therapy
  • Antineoplastic Agents
  • Antineoplastic Agents: administration & dosage
  • Boronic Acids
  • Boronic Acids: administration & dosage
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Electrocardiography
  • Female
  • Heart Diseases
  • Heart Diseases: drug therapy
  • Heart Diseases: etiology
  • Humans
  • Kidney Diseases
  • Kidney Diseases: drug therapy
  • Kidney Diseases: etiology
  • Liver Diseases
  • Liver Diseases: drug therapy
  • Liver Diseases: etiology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Paraproteinemias
  • Paraproteinemias: complications
  • Peripheral Nervous System Diseases
  • Peripheral Nervous System Diseases: drug therapy
  • Peripheral Nervous System Diseases: etiology
  • Prospective Studies
  • Pyrazines
  • Pyrazines: administration & dosage
  • Treatment Outcome

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  • S W Dubrey

  • D E Reece

  • V Sanchorawala

  • U Hegenbart

  • G Merlini

  • G Palladini

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