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Immunoglobulin-Related Amyloidosis Treatment & Management

  • Author: Slavomir Urbancek, MD, PhD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jan 29, 2015
 

Medical Care

Standard treatment of L chain–type amyloidosis aims to reduce production of the monoclonal immunoglobulin precursor via chemotherapy or, occasionally, via radiation therapy or surgical resection of a localized amyloidogenic plasmacytoma. Experimental drugs that bind to amyloid fibrils, leading to their resorption, are also being studied. Supportive therapy to maintain organ function is equally important.

Chemotherapy

Chemotherapy is based on the principle that, as in myeloma, proliferation of a plasma cell clone causes L chain–type amyloidosis. Regimens most likely to benefit patients with this disease are the same as those that are useful for myeloma (eg, melphalan plus prednisone).

Many more studies have been published on the treatment of myeloma than of L chain–type amyloidosis, because myeloma is more common and the response to therapy can be more easily monitored. In myeloma, the level of serum or urine monoclonal protein usually serves as a quantitative marker of tumor burden. In L chain–type amyloidosis, determining the response to therapy is difficult and requires indirect measurements of end-organ damage, serial biopsies, or serial P component scans when available.

After melphalan and prednisone were demonstrated to be useful for myeloma, the regimen was tried for L chain–type amyloidosis.[13, 14] Taken together, these studies demonstrated a survival benefit of melphalan and prednisone compared with placebo in L chain–type amyloidosis.

Many experts consider melphalan plus prednisone to be standard therapy for L chain–type amyloidosis for patients not enrolled in a clinical trial, and it is the only regimen that has been shown to prolong survival compared with no chemotherapy. No regimen has been shown in a randomized trial to be superior to melphalan plus prednisone.[15] Nevertheless, other chemotherapeutic regimens used for multiple myeloma are also expected to benefit patients with L chain–type amyloidosis and are reasonable therapeutic options for this disease.

Chemotherapy is most likely to produce objective improvement in end-organ damage in patients with renal involvement and nephrotic syndrome. Approximately 25% of this group has at least a 50% decrease in proteinuria, with most of these patients experiencing complete resolution of proteinuria. Improvement can occur in nearly any organ, but improvement in L chain–type amyloidosis neuropathy is rare.

Duration of initial chemotherapy and potential adverse effects

No data indicate the optimal treatment duration in patients whose conditions respond to chemotherapy. In patients in whom a response occurs with objective improvement in organ function and in whom toxicity does not develop, chemotherapy is usually continued for 1-2 years.

When the disease initially responds and then progresses off treatment, chemotherapy, whether the same or a different regimen, can be resumed. Little information exists regarding whether any maintenance therapy, such as alpha interferon, is useful, again mirroring the situation in myeloma.

When contemplating the duration of therapy, keep in mind the leukemogenic potential of melphalan. The actuarial risk of acute myelogenous leukemia (AML) in one study of patients with myeloma treated with melphalan was 17% at 50 months. In two studies of patients with L chain–type amyloidosis treated with melphalan-containing regimens, 5% of patients developed myelodysplasia within 3 years of treatment. Some patients' conditions progressed to AML.

Therapeutic advances

During the past decade, understanding of the molecular and cellular pathophysiology of myeloma has improved significantly, allowing identification of novel molecular pathways and targeting development of several new therapeutic possibilities. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted initially in refractory-relapsed patients and then as first-line treatment, providing better results than vincristine/doxorubicin/dexamethasone (VAD) or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients.

In 2003, bortezomib became the first proteasome inhibitor approved for the treatment of relapsed myeloma. Inhibition of proteasome activity appears to have greater cytotoxicity in malignant cells than in normal cells. Two phases II studies confirmed the efficacy of bortezomib in patients with relapsed/refractory myeloma.[16, 17]

Subsequent studies demonstrated the benefit of bortezomib as part of combination therapy with melphalan and prednisone in the initial treatment of myeloma,[18, 19] and in combination with dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed myeloma.[20]

Drug resistance to bortezomib, probably related to high expression of heat-shock protein, led to the development of second-generation proteasome inhibitors (eg, salinosporamide A).

The immunomodulatory drugs thalidomide, lenalidomide, and carfilzomib affect myeloma through pleiotropic effects. Twenty-five to thirty percent of patients exhibit at least a partial response when these agents are given as monotherapy. In combination with other drugs (dexamethasone, cyclophosphamide, melphalan), the response rate is considerably higher.

Thalidomide has a well-established role as first-line therapy, either as a single agent or in combination with steroids. The combination regimen of melphalan, prednisone, and thalidomide (MPT) has become one of the standard therapeutic combinations for elderly patients with myeloma.

Lenalidomide has been approved as a second-line therapy for multiple myeloma. It is indicated in combination with dexamethasone for patients who have received at least one prior therapy.

Lenalidomide has also been investigated as first-line combination therapy for myeloma. In a phase II trial, 91% of patients exhibited at least a partial response, with 32% exhibiting a complete or almost complete response. Thalidomide and lenalidomide are also being evaluated as maintenance therapy after autologous transplantation.

Carfilzomib is a structurally and mechanistically novel proteasome inhibitor that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. Carfilzomib is similar to bortezomib in that it is a potent inhibitor of the proteasome chymotrypsinlike activity; but, unlike bortezomib, carfilzomib has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Carfilzomib is ndicated for the treatment of patients who have received at least two prior therapies including bortezomib and an immunomodulatory agent, and have experienced disease progression during or within 60 days of completion of the last therapy.

In the past few years, a number of agents have been developed to target specific aspects of myeloma cell biology. Major strategies are disruption of molecular pathways of myeloma cell growth and impairment of the drug-resistance mechanism. These agents target myeloma cells and the microenvironment. Among these agents, many of which are in early phases of clinical trials in relapsed myeloma, the most important include the following:

  • Inhibitors of the PI3KI/Akt/mTOR pathway: Perifosine
  • Inhibitors of the heat-shock protein 90: Tanespimycin
  • Mitogen-activated protein kinase (MAPK) and farnesyl transferase inhibitors: Tipifarnib, lonafarnib
  • Histone deacetylase inhibitors: Vorinostat, depsipeptide, valproic acid
  • Inhibitors of vascular-endothelial growth factor (VEGF): Bevacizumab and others
  • Inhibitors of p38 mitogen-activated protein kinase

Pomalidomide is a distinct oral immunomodulatory agent with direct anti-myeloma, stromal cell-support inhibitory, and immune modulatory effects. It is approved for patientswho have received two or more prior therapies, including lenalidomide and bortezomib, and have experienced progressive disease during or within 60 days of completion of the last treatment. Pomalidomide combined with low-dose dexamethazone has demonstrated significant progression-free and overall survival benefits with a tolerable safety profile in relapsed/refractory cases.[21]

High-dose chemotherapy with rescue transplantation

In both L chain–type amyloidosis and myeloma, standard-dose regimens rarely, if ever, completely eradicate the plasma cell clone. Therefore, high-dose chemotherapy followed by autologous bone marrow or peripheral blood stem cell rescue has been studied in selected patients. As with standard-dose regimens, studies of high-dose therapy for myeloma predate similar studies for L chain–type amyloidosis, and more data are available on myeloma.

In myeloma, several trials of high-dose chemotherapy in selected patients have demonstrated favorable responses and survival rates compared with historical controls. However, even in myeloma, indications for high-dose therapy remain controversial; no consensus exists about which patients should be offered high-dose therapy with rescue.

The indication for high-dose chemotherapy in L chain–type amyloidosis is even less established. Several centers have reported phase II trials of high-dose chemotherapy, followed by rescue with autologous bone marrow or peripheral blood stem cells.

In one highly selected group of patients (median age 48 y; patients with severely impaired cardiac, pulmonary, or renal function were excluded), 11 (65%) of 17 patients exhibited a response, as assessed by objective improvement in end-organ function. Based on these data, high-dose chemotherapy regimens have become the recommended therapy in some centers for patients who are deemed able to tolerate the conditioning regimen.

In early studies of high-dose therapy with peripheral blood stem cell rescue, patients with severe cardiac involvement experienced very high early mortality. This complication is attributed to intolerance of fluid shifts that occur with peripheral blood stem cell harvesting. Therefore, patients with severe cardiac involvement are now generally deemed ineligible for high-dose chemotherapy. Another concern with high-dose therapy followed by stem cell rescue is that the autologous stem cells collected for reinfusion generally contain the clonal cells that produce the amyloidogenic L chain.

Diseases in which high-dose chemotherapy has the most significant impact are those in which the malignant cell population is dividing rapidly. However, this criterion does not apply to L chain–type amyloidosis. Until standard-dose chemotherapy is compared with high-dose chemotherapy with rescue in a phase III randomized trial, deciding which therapy to use in individual patients will remain difficult and controversial.

The place of allogeneic stem cell transplantation in the management of myeloma remains controversial. Although it may induce long-term clinical and molecular remissions, high transplant-related toxicity after myeloablative preparative regimens has limited the role of allogeneic stem cell transplantation as first-line treatment.

Moreover, the toxicity related to infections and to graft versus host disease (GVHD) is very high. As a consequence of this toxicity, allogeneic stem cell transplantation could not be proposed for those older than 50-55 years, whereas the median age at diagnosis was over 65 years.

Some reduced-intensity conditioning regimens (including the addition of immunosuppressive agents as cyclosporine A, mycophenolate mofetil, tacrolimus) have been developed. Allogeneic stem cell transplantation should be considered for patients with chemosensitive disease and a low tumor burden, which can be obtained after high-dose chemotherapy plus autologous stem cell transplantation. Results of ongoing trials will determine the place of these remedies related to the introduction of the novel therapeutic agents listed above.

Pharmacologic therapy to solubilize amyloid fibrils

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

Five of eight patients in the first pilot trial of Idox responded with clinical improvement unrelated to any cytotoxic effect on the plasma cell clone.[22] In a subsequent European trial in 42 patients, 13 had disease responses and 15 had disease stabilization. However, the clinical responses were transient, and the disease typically progressed after a period of months. In a multicenter phase II trial in 40 US patients, six patients responded and 12 died; the investigators concluded thatIdox was insufficiently active at the dose administered in the protocol.[23]

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

Treatment of localized amyloid L-chain type

Treatment of localized L chain–type amyloidosis (most often found in the pulmonary tract or the genitourinary tract) has not been studied systematically. Because progression to systemic disease does not occur often, treatment with chemotherapy is not indicated.

Localized radiation therapy aimed at destroying the local collection of plasma cells producing the L chain–type amyloid can be administered when a plasma cell collection can be identified.

Local collections of L chain–type amyloid in the genitourinary tract, even in the absence of an identified clonal plasma cell collection, can cause hematuria. In these patients, surgical resection of amyloidomas may be required to control the bleeding.

Supportive care

Diuretics are the mainstay of therapy for L chain–type amyloid–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, autonomic neuropathy, or both 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. Pacemakers are of use in some patients with symptomatic bradycardia.

Treatment of renal involvement is as follows:

  • Hemodialysis and peritoneal dialysis can stabilize the course of patients with extensive kidney involvement
  • Hemodialysis should be offered to patients developing renal failure
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Surgical Care

Carpal tunnel release

Involvement of the carpal ligament is observed not only in L chain–type amyloidosis but also in B2M amyloidosis in patients undergoing dialysis and in patients with transthyretin-related amyloidosis (see Amyloidosis and Transthyretin-Related Amyloidosis).

Treatment is surgical. At the time of carpal tunnel release, perform a biopsy if a definitive diagnosis has not been established, so that both Congo red staining and immunostaining can be performed. Why the carpal ligament is a favored location for amyloid deposition remains unknown.

Organ transplantation

No randomized trials of organ transplantation in L chain–type amyloidosis are available to guide the decision-making process, but patients have received heart or kidney transplants. A few patients with L chain–type amyloidosis have received heart transplants. This therapy may be life saving for patients with severe disease, but, in the absence of effective systemic therapy to eliminate production of the amyloidogenic L chain, amyloidosis can recur in the transplanted organ.

For young patients with severe cardiac involvement, cardiac transplantation followed by high-dose chemotherapy and autologous stem cell or autologous bone marrow reinfusion has occasionally been considered.

Renal transplantation has been reported often in patients with amyloidosis, but most such cases have not been of the L chain–type amyloidosis. Because L chain–type amyloidosis is generally a systemic disease and hemodialysis is generally effective and available, renal transplantation is rarely indicated in L chain–type amyloidosis, except perhaps in the occasional patient whose condition has had particularly good responses to chemotherapy and in whom long-term survival may be expected.

Percutaneous cementoplasty

A study by Tran Thang et al confirmed the beneficial effect of percutaneous cementoplasty on bone pain and functional improvement.[24]

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Consultations

A hematology and/or oncology, cardiology, nephrology, or other subspecialty consultation may be indicated, depending on the disease's organ involvement.

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Contributor Information and Disclosures
Author

Slavomir Urbancek, MD, PhD Head, Department of Dermatology, FD Roosevelt Hospital, Slovakia; Member of executive commitee - 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, Slovakian Dermatovenerological Society, Slovak Society of Allergology and Clinical Immunology

Disclosure: Received honoraria from Abbott for speaking and teaching; Received honoraria from Pfizer for none; Received honoraria from Janssen for speaking and teaching; Received honoraria from MSD for speaking and teaching; Received consulting fee from Roche for speaking and teaching.

Coauthor(s)

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

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

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

Disclosure: Nothing to disclose.

Carol A Bogdan, MD Consultant in Hematology-Oncology, Myrtle Beach, SC

Disclosure: Nothing to disclose.

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

Joel N Buxbaum, MD is a member of the following medical societies: American Association for the Advancement of Science, American Society for Clinical Investigation, American Society of Human Genetics, Association of American Physicians, Association of Black Cardiologists, Henry Kunkel Society

Disclosure: Received consulting fee from Foldrx pharmaceuticals for consulting; Received consulting fee from Isis pharmaceuticals for consulting; Received consulting fee from alnylam pharmaceutical for consulting; Received consulting fee from Pfizer Pharmaceuticals for consulting.

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, Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, American College of Rheumatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Janssen<br/>Serve(d) as a speaker or a member of a speakers bureau for: Abbvie; Genentech; Pfizer; Questcor.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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 Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University School of Medicine in Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Affairs Medical Center

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

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.
 
 
 
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