Immunoglobulin-Related Amyloidosis Medication

  • Author: Slavomir Urbancek, MD, PhD; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Apr 8, 2011
 

Medication Summary

Melphalan plus prednisone is considered standard therapy for L chain–type amyloidosis, with any myeloma regimen offering a reasonable therapeutic choice.

An anthracycline analogue of 4'-iodo-4'-deoxydoxorubicin is the first small molecule found with in vivo activity to solubilize L chain–type amyloid deposits. The antiamyloid activity of 4'-iodo-4'-deoxydoxorubicin was discovered fortuitously when it was being evaluated as a chemotherapy agent in multiple myeloma. A patient with myeloma and L chain–type amyloidosis excreted L chains into the urine and improved symptomatically within days. 4'-Iodo-4'-deoxydoxorubicin was then demonstrated to bind to amyloid fibrils, although the parent compound, doxorubicin, does not.

Five of 8 patients in the first pilot trial of 4'-iodo-4'-deoxydoxorubicin responded with clinical improvement unrelated to any cytotoxic effect on the plasma cell clone.[23] From 1995 to 1997, 4'-iodo-4'-deoxydoxorubicin was administered to another 42 patients in Europe. Of the 42 patients, 13 had disease responses and 15 demonstrated stabilized disease. However, the clinical responses were transient, and the disease typically progressed after a period of months. From 1999 to 2000, 4'-iodo-4'-deoxydoxorubicin was studied for treatment of L chain–type amyloidosis in a phase II trial at 2 US centers. Results from this trial are not yet available.

The ideal use of small molecule amyloid inhibitors, such as 4'-iodo-4'-deoxydoxorubicin, likely lies in combination with cytotoxic chemotherapy, both to decrease clonal L-chain production and to mobilize deposited L chains. Various small molecules that bind to amyloid fibrils of the L chain – type amyloid and other types are under investigation.

Diuretics are the mainstay of therapy for L chain – type amyloidosis – related congestive heart failure. The optimal degree of diuresis is often difficult to judge. When edema is troubling and symptomatic postural hypotension is not present, fluid can be removed with careful diuresis. Conversely, hypotension resulting from a low ejection fraction and/or autonomic neuropathy may limit diuretic use.

Digoxin and calcium channel blockers are contraindicated in cardiac amyloidosis, because these agents bind to amyloid fibrils, which may worsen heart failure and produce arrhythmias.

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Immunosuppressive Agents

Class Summary

Two slightly different regimens of melphalan and prednisone have been used in 2 large studies. Either regimen can be used to treat this condition.

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Melphalan (Alkeran) and prednisone (Deltasone, Orasone, Meticorten)

 

Melphalan reduces clonal plasma cell population. Inhibits mitosis by cross-linking DNA strands. Individual tolerance to melphalan varies. Adjust dosage after the first cycle, based on the degree of cytopenia in the previous cycles. Nadir counts appear 2-3 wk following administration. Should be taken on an empty stomach. Prednisone reduces clonal plasma cell population.

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Antineoplastic Agent, Proteasome Inhibitor

Class Summary

Proteasome inhibitors are antineoplastic agents that inhibit cell growth and proliferation.

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Bortezomib (Velcade)

 

First drug approved of anticancer agents known as proteasome inhibitors. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreases cancer cell survival.

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Immunosuppressant Agents

Class Summary

Immunosuppressant agents may suppress the production of factors that mediate immune reactions.

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Thalidomide (Thalomid)

 

Immunomodulatory agent that may suppress excessive production of tumor necrosis factor-alpha (ie, TNF-alpha) and may downregulate selected cell-surface adhesion molecules involved in leukocyte migration. Because of concerns regarding teratogenicity, thalidomide can only be prescribed by registered physicians and dispensed by registered pharmacists. Patients must participate in ongoing surveys to receive therapy, and only a 28-day supply can be prescribed at a time. Indicated in conjunction with dexamethasone to treat newly diagnosed multiple myeloma.

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Lenalidomide (Revlimid)

 

Indicated for transfusion-dependent MDS subtype of deletion 5q cytogenetic abnormality. Structurally similar to thalidomide. Elicits immunomodulatory and antiangiogenic properties. Inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

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Contributor Information and Disclosures
Author

Slavomir Urbancek, MD, PhD  Head, Department of Dermatology, FD Roosevelt Hospital, Slovakia; Scientific Secretary, Slovak Dermatovenereological Society

Slavomir Urbancek, MD, PhD is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, Slovak Dermatovenereological Society, and Slovak Society of Allergology and Clinical Immunology

Disclosure: Nothing to disclose.

Coauthor(s)

Pere Gascon, MD, PhD  Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Daniel R Jacobson, MD  Professor of Medicine, Boston University School of Medicine; Chief of Oncology, Veterans Affairs Boston Healthcare System

Disclosure: Nothing to disclose.

Joel Buxbaum, MD  Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute

Joel Buxbaum, MD is a member of the following medical societies: American Society for Clinical Investigation, American Society of Human Genetics, and Association of American Physicians

Disclosure: Foldrx pharmaceuticals Consulting fee Consulting; Isis pharmaceuticals Consulting fee Consulting

Carol A Bogdan, MD  Consulting Staff, Coastal Cancer Center, Myrtle Beach, SC

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert E Wolf, MD, PhD  Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD  Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching; UCB Speaking and teaching; Omnicare Consulting fee Consulting; Centocor Consulting fee Consulting

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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The relationship among light chain–type amyloidosis (AL), the other monoclonal plasma cell disorders, and the other amyloidoses. Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance.
Table I. Phase II trials of bortezomib-based therapies in newly diagnosed patients with myeloma.[17]
TrialNORR %CR/Near CR %Very good PR %
Bortezomib Monotherapy



Jagannath et al[18]



Anderson et al[14]



Dispenzieri et al[15]



49



63



42



49



40



52



10



10



0



2



NR



5



Bortezomib/Dexamethasone



Jagannath et al[18]



Harousseau et al[16]



49



48



88



67



18



21



20



10



Bortezomib/ Doxorubicin/ Dexamethasone



Oakervee et al (standard dose)[19]



Popat et al (reduced dose)[20]



21



19



95



89



29



16



33



26



Bortezomib/PLD/Dexamethasone



Jakubowiak et al[21]



28893221
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