eMedicine Specialties > Hematology > Plasma Cell Disorders
Amyloidosis, Immunoglobulin-Related: Treatment & Medication
Updated: Feb 12, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
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 surgery 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 (ie, melphalan, prednisone).
- Many more studies have been published on the treatment of myeloma than that 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. The first 2 randomized studies of melphalan and prednisone versus placebo or colchicine suggested a value to chemotherapy but did not reach statistical significance for improved survival.
- In the mid 1990s, 2 randomized placebo-controlled trials demonstrated a statistically significant survival benefit of melphalan and prednisone compared with colchicine. The colchicine arm in these trials essentially served as a placebo group, because colchicine is now known to be ineffective for L chain–type amyloidosis and is no longer used.
- Patients in 1 trial were randomized to 1 of 3 arms (melphalan and prednisone; melphalan, prednisone, and colchicine; or colchicine alone).8 The median survival rate was greater in patients in the melphalan, prednisone, and colchicine arm (18 mo) and those in the melphalan and prednisone (17 mo) arm than patients in the colchicine-alone arm (8.5 mo).8
- In another trial, 100 patients were randomized to receive either oral melphalan, prednisone, and colchicine or colchicine alone.9 The overall survival rate for the melphalan, prednisone, and colchicine group was 12.2 months compared with 6.7 months for the colchicine-alone group. This difference did not quite reach statistical significance (P = 0.087), reflecting the small sample size and several early deaths of patients with severe disease in both treatment groups. In addition, several patients did not receive the intended chemotherapy or were crossed over to chemotherapy by their physicians (analysis was performed on an intent-to-treat basis).9
- Taken together, these studies demonstrate a survival benefit of melphalan and prednisone compared with placebo in L chain–type amyloidosis.
- Patients whose conditions are most likely to respond to chemotherapy with objective improvement in end-organ damage are those 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.
- 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. In one randomized study, melphalan and prednisone use was compared with a 5-drug myeloma regimen (vincristine, carmustine, melphalan, cyclophosphamide, prednisone).10 Response rates and survival did not differ between the 2 groups. In a phase II trial, high-dose dexamethasone also produced occasional objective organ responses, including responses in some patients who had received previous chemotherapy. 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.
- Duration of initial chemotherapy and potential adverse effects are as follows:
- 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 1 study of patients with myeloma treated with melphalan was 17% at 50 months. In 2 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.
- 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 with better results respect to 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.11,12 In the first study, 10% of patients exhibited a complete/almost complete response; 18%, a partial response; and 7%, a minimal response. The median time to disease progression was 13 months for complete and partial responses. 72 patients who did not attain at least a minimal response were given dexamethasone in combination with bortezomib; 18 demonstrated some response. Phase III studies have confirmed the superiority of bortezomib compared with dexamethasone.
- Bortezomib has been investigated in a number of combination regimens (eg VMPT [bortezomib/melphalan/prednisone/thalidomide]; bortezomib and pegylated liposomal doxorubicin; bortezomib with corticosteroids, etc). In a phase II study, bortezomib with dexamethasone was compared with a standard-dose VAD regimen in patients with newly diagnosed myeloma.13 Complete response (20%) and objective response rate (82%) were higher in the bortezomib group than in the group that received standard-dose VAD (complete response, 9%; objective response rate, 67%).
- Several bortezomib-containing combinations are now being evaluated as induction therapy before high-dose therapy with autologous stem cell transplantation. The outcomes are sumarized in Table I, below.
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Table
| Trial | N | ORR % | CR/Near CR % | Very good PR % |
| Bortezomib Monotherapy Jagannath et al 15 Anderson et al 11 Dispenzieri et al 12 | 49 63 42 | 49 40 52 | 10 10 0 | 2 NR 5 |
| Bortezomib/Dexamethasone Jagannath et al 15 Harousseau et al 13 | 49 48 | 88 67 | 18 21 | 20 10 |
| Bortezomib/ Doxorubicin/ Dexamethasone Oakervee et al (standard dose) 16 Popat et al (reduced dose) 17 | 21 19 | 95 89 | 29 16 | 33 26 |
| Bortezomib/PLD/Dexamethasone Jakubowiak et al 18 | 28 | 89 | 32 | 21 |
| Trial | N | ORR % | CR/Near CR % | Very good PR % |
| Bortezomib Monotherapy Jagannath et al 15 Anderson et al 11 Dispenzieri et al 12 | 49 63 42 | 49 40 52 | 10 10 0 | 2 NR 5 |
| Bortezomib/Dexamethasone Jagannath et al 15 Harousseau et al 13 | 49 48 | 88 67 | 18 21 | 20 10 |
| Bortezomib/ Doxorubicin/ Dexamethasone Oakervee et al (standard dose) 16 Popat et al (reduced dose) 17 | 21 19 | 95 89 | 29 16 | 33 26 |
| Bortezomib/PLD/Dexamethasone Jakubowiak et al 18 | 28 | 89 | 32 | 21 |
N = number of patients; ORR = objective response rate; CR = complete response; PR = partial response; PLD = pegylated liposomal doxorubicin.
- Drug resistance to bortezomib, probably related to heat-shock high protein expression 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.
- In a phase III study, thalidomide plus dexamethasone produced a significant improvement in the overall response rate (63%) compared with dexamethasone alone (41%; P = 0.0017).
- Combination melphalan/prednisone/thalidomide (MPT) therapy has been demonstrated to have superiority over melphalan/prednisone (MP) alone. The MPT regimen has become one of the standard therapeutic combinations for elderly patients with myeloma.
- Phase I and II studies in relapsed/refractory myeloma have confirmed a 29% partial response rate with lenalidomide. Similarly, a phase III trial confirmed the superiority of combination lenalidomide/dexamethasone therapy (complete response, 12,9%; objective response rate, 59%) versus dexamethasone alone (complete response, 0,6%; objective response rate 21%) (P <0.001). These results led to the approval of lenalidomide as a second-line therapy for multiple myeloma.
- 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. Phase 1 clinical studies confirmed that patients whose condition has relapsed or progressed following multiple therapies can still achieve durable antitumor responses with carfilzomib. In addition to the two phase 2 single-agent trials in myeloma and ongoing studies in lymphoma, a clinical trial in solid tumors and a trial exploring carfilzomib in combination with a Federal Drug Administration (FDA)-approved agent is pending.
- 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, desipeptide, valproic acid
- Inhibitors of vascular-endothelial growth factor (VEGF): Bevacizumab and others
- Inhibitors of p38 mitogen-activated protein kinase
- Targeting cell surface molecules
- High-dose chemotherapy followed by stem cell or autologous bone marrow rescue is as follows:
- 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. Similar to 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 phase II trials of high-dose chemotherapy in selected patients have demonstrated favorable responses and survival rates compared with historical controls. One phase III trial randomized patients younger than 65 years to either a standard dose, 6-drug regimen or high-dose therapy (4-6 cycles of the same 6-drug regimen, followed by 140 mg/m2 of melphalan and total body irradiation) with autologous bone marrow transplantation. This trial found a 5-year survival benefit for high-dose therapy. 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.
- In L chain–type amyloidosis, the indication for high-dose chemotherapy 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 ciclosporine A, mycophenolate mofetil, tacrolimus) were 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.
- 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
- Treatment of cardiac involvement is as follows:
- 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.
- Treatment of cardiac involvement is as follows:
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 TTR amyloidosis (see Amyloidosis, Overview and Amyloidosis, Transthyretin-Related).
- 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 about organ transplantation in L chain–type amyloidosis are available to guide the decision-making process, but patients have received heart or kidney transplants.
- Cardiac transplantatio
- 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
- 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.19
Consultations
A hematology and/or oncology, cardiology, nephrology, or other subspecialty consultation may be indicated, depending on the disease's organ involvement.
Diet
No known diet changes affect L chain–type amyloidosis directly. Patients with nephrotic syndrome, renal failure, or congestive heart failure arising from L chain–type amyloidosis should receive appropriate dietary treatment for those conditions.
Medication
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.20 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.
Immunosuppressive Agents
Two slightly different regimens of melphalan and prednisone have been used in 2 large studies. Either regimen can be used to treat this condition.
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.
Adult
2 regimens have been studied:
Regimen 1 (Mayo Clinic): 0.15 mg/kg melphalan PO plus 0.8 mg/kg prednisone PO qd for 7 d; increase melphalan dose by 2 mg in each 6-wk cycle until midcycle leukopenia or thrombocytopenia develops; repeat cycle q6wk for 2 y or until serious toxicity develops
Regimen 2 (Boston University): 0.15 mg/kg melphalan PO plus 1.5 mg/kg prednisone PO qd for 4 d; repeat cycle q6wk for 1 y; increase melphalan dose by 2 mg in each 6-wk cycle until leukopenia or thrombocytopenia develops (not to exceed 0.25 mg/kg/dose); limit total melphalan dose over entire treatment regimen to 600 mg
Pediatric
Not established
Concurrent administration of melphalan with cyclosporine increases nephrotoxicity; cimetidine and H2 antagonists increase gastric pH, decreasing effects of melphalan; coadministration of prednisone with estrogens may decrease prednisone clearance; concurrent use of prednisone with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing the maintenance dose); monitor for hypokalemia with the coadministration of diuretics.
Documented hypersensitivity; severe bone marrow depression; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI disease
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Amenorrhea may occur; caution in patients with previously diagnosed myelosuppression; perform CBC count before each treatment course and 2-3 wk after beginning treatment in the first cycle and selected cycles thereafter to monitor nadir counts; if severe thrombocytopenia or leukopenia develops, delay the next cycle or reduce the dose; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, and infections may occur with glucocorticoid use.
Antineoplastic Agent, Proteasome Inhibitor
Proteasome inhibitors are antineoplastic agents that inhibit cell growth and proliferation.
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.
Adult
1.3 mg/m2 IV bolus 2 times/wk for 2 wk (ie, days 1, 4, 8, and 11); rest for 10 d (ie, days 12-21), then repeat cycle
Pediatric
Not established
Substrate of CYP450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4; may inhibit CYP450 2C19, therefore caution with coadministration of isoenzyme 2C19 substrates (eg, barbiturates, phenytoin, valproic acid, imipramine, lansoprazole, warfarin)
Documented hypersensitivity to bortezomib, boron, or mannitol
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Common adverse effects include nausea, fatigue, diarrhea, constipation, headache, decreased appetite, thrombocytopenia, anemia, fever, vomiting, or peripheral neuropathy (modify the dose if neuropathy occurs); may cause hypotension; caution in patients with hepatic impairment; at least 72 h should elapse between each dose
Immunosuppressant Agents
Immunosuppressant agents may suppress the production of factors that mediate immune reactions.
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.
Adult
200 mg PO qhs; administer at least 1 h pc
Pediatric
Not established
May increase sedation of alcohol, barbiturates, chlorpromazine, and reserpine
Documented hypersensitivity; sexually active males not using latex condom (risk to the fetus from the semen of patients taking thalidomide is unknown), women of childbearing potential not using 2 forms of contraception
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Perform pregnancy test within 24-h period before initiating therapy (weekly during the first month, followed by monthly tests in women with regular menstrual cycles or q2wk in those with irregular menstrual cycles); bradycardia may occur; decrease the dose or temporarily discontinue if constipation, oversedation, or peripheral neuropathy occur; use protective measures (eg, sunscreens, protective clothing) against exposure to sunlight or UV light (eg, tanning beds); prescribing physician must register with the "System for Thalomid Education and Prescribing Safety" (STEPS) program established by the manufacturer.
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.
Adult
10 mg PO qd initially; dose adjustment required if renal impairment, thrombocytopenia, or neutropenia occurs
Pediatric
<18 years: Not established
>18 years: Administer as in adults.
Data limited; none reported
Documented hypersensitivity; pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Available only through RevAssist, a risk-management plan to prevent fetal exposure; only pharmacists and prescribers registered with the program may prescribe and dispense (program requires mandatory pregnancy testing and limits prescription to 1-mo supply via mail); male patients, including those with vasectomy, must use latex condom during sexual contact with a female of childbearing potential; women must not become pregnant 4 wk before starting lenalidomide and 4 wk after discontinuing lenalidomide; may cause anemia, DVT, pulmonary embolism, thrombocytopenia, neutropenia, diarrhea, pruritus, rash, and fatigue; renal excretion is substantial: caution in elderly patients or those with renal impairment (may need to decrease the dose); do not break, chew, or open capsules
More on Amyloidosis, Immunoglobulin-Related |
| Overview: Amyloidosis, Immunoglobulin-Related |
| Differential Diagnoses & Workup: Amyloidosis, Immunoglobulin-Related |
 Treatment & Medication: Amyloidosis, Immunoglobulin-Related |
| Follow-up: Amyloidosis, Immunoglobulin-Related |
| Multimedia: Amyloidosis, Immunoglobulin-Related |
| References |
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References
UAMS researchers ID 17 genes that lead to high-risk myeloma. Updated: April 9, 2007. Fox16.com. Available at http://www.fox16.com/news/local/story/UAMS-researchers-ID-17-genes-that-lead-to-high/km2T2OFQGEKoCaRCIcjv3Q.cspx. Accessed February 11, 2009.
Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. Jan 1995;32(1):45-59. [Medline].
Leibovitch I, Selva D, Goldberg RA, et al. Periocular and orbital amyloidosis: clinical characteristics, management, and outcome. Ophthalmology. Sep 2006;113(9):1657-64. [Medline].
Cross TJ, Wendon JA, Quaglia A, et al. Myeloma associated amyloidosis presenting as subacute liver failure. Postgrad Med J. Jul 2006;82(969):e13. [Medline].
Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood. Apr 15 2006;107(8):3378-83. [Medline]. [Full Text].
Porrata LF, Gertz MA, Litzow MR, et al. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis. Clin Cancer Res. Feb 1 2005;11(3):1210-8. [Medline]. [Full Text].
Pan WH, Li NP. Clinical pathological feature of early tongue amyloidosis. Chin Med Sci J. Jun 2006;21(2):104-6. [Medline].
Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. Apr 24 1997;336(17):1202-7. [Medline]. [Full Text].
Skinner M, Anderson J, Simms R, et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. Mar 1996;100(3):290-8. [Medline].
Gertz MA, Lacy MQ, Lust JA, et al. Prospective randomized trial of melphalan and prednisone versus vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of primary systemic amyloidosis. J Clin Oncol. Jan 1999;17(1):262-7. [Medline]. [Full Text].
Anderson K, Richardson P, Chanan-Khan A, et al. Single-agent bortezomib in previously untreated multiple myeloma (MM): results of a phase II multicenter study [abstract 7504]. J Clin Oncol. 2006;24:423s.
Dispenzieri A, Zhang L, Fonseca R, et al. Single agent bortezomib is associated with a high response rate in patients with high risk myeloma. A phase II study from the Eastern Cooperative Oncology Group (E2A02) [abstract 3527]. Blood. 2006;108(11):1006s. [Full Text].
Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica. Nov 2006;91(11):1498-505. [Medline]. [Full Text].
Lee AI, Munshi NC. Integration of novel agents into treatment of myeloma. Clin Lymphoma Myeloma. Aug 2007;7(suppl 5):S215-21. [Medline].
Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. Jun 2005;129(6):776-83. [Medline].
Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. Jun 2005;129(6):755-62. [Medline].
Popat R, Oakervee HE, Curry N, et al. Reduced dose PAD combination therapy (PS-341/bortezomib, Adriamycin and dexamethasone) for previously untreated patients with multiple myeloma [abstract 2554]. Blood. 2005;106:171a-718a. [Full Text].
Jakubowiak AJ, Al-Zoubi A, Kendall T, et al. High rate of complete and near complete responses (CR/nCR) after initial therapy with bortezomib (Velcade®), Doxil®, and dexamethasone (VDD) is further increased after autologous stem cell transplantation (ASCT) [abstract 3093]. Blood. 2006;108:882a. [Full Text].
Tran Thang NN, Abdo G, Martin JB, et al. Percutaneous cementoplasty in multiple myeloma: a valuable adjunct for pain control and ambulation maintenance. Support Care Cancer. Aug 2008;16(8):891-6. [Medline].
Gianni L, Bellotti V, Gianni AM, Merlini G. New drug therapy of amyloidoses: resorption of AL-type deposits with 4'-iodo-4'-deoxydoxorubicin. Blood. Aug 1 1995;86(3):855-61. [Medline]. [Full Text].
Biehn SE, Moore DT, Voorhees PM, et al. Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin. Ann Hematol. Mar 2007;86(3):211-6. [Medline].
Browning MJ, Banks RA, Tribe CR, et al. Ten years' experience of an amyloid clinic--a clinicopathological survey. Q J Med. Mar 1985;54(215):213-27. [Medline].
Buxbaum J, Gallo G. Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am. Dec 1999;13(6):1235-48. [Medline].
Camoriano JK, Greipp PR, Bayer GK, Bowie EJ. Resolution of acquired factor X deficiency and amyloidosis with melphalan and prednisone therapy. N Engl J Med. Apr 30 1987;316(18):1133-5. [Medline].
Davern S, Tang LX, Williams TK, et al. Immunodiagnostic capabilities of anti-free immunoglobulin light chain monoclonal antibodies. Am J Clin Pathol. Nov 2008;130(5):702-11. [Medline]. [Full Text].
Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. Nov 20 2008;epub ahead of print. [Medline].
Gertz MA, Kyle RA, Greipp PR. Response rates and survival in primary systemic amyloidosis. Blood. Jan 15 1991;77(2):257-62. [Medline]. [Full Text].
Harousseau JL. The allogeneic dilemma. Bone Marrow Transplant. Dec 2007;40(12):1123-8. [Medline]. [Full Text].
Jagannath S, Durie BGM, Wolf JL, et al. Long-term follow-up of patients treated with bortezomib alone and in combination with dexamethasone as frontline therapy for multiple myeloma [abstract 796]. Blood. Nov 2006;108:238a. [Full Text].
Kyle RA. High-dose therapy in multiple myeloma and primary amyloidosis: an overview. Semin Oncol. Feb 1999;26(1):74-83. [Medline].
Pelosi F Jr, Capehart J, Roberts WC. Effectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol. Feb 15 1997;79(4):532-5. [Medline].
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. Jun 26 2003;348(26):2609-17. [Medline]. [Full Text].
Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation. Jun 1981;63(6):1285-8. [Medline].
Simons M, Isner JM. Assessment of relative sensitivities of noninvasive tests for cardiac amyloidosis in documented cardiac amyloidosis. Am J Cardiol. Feb 1 1992;69(4):425-7. [Medline].
Solomon A, Weiss DT, Murphy C. Primary amyloidosis associated with a novel heavy-chain fragment (AH amyloidosis). Am J Hematol. Feb 1994;45(2):171-6. [Medline].
van Gameren II, Hazenberg BP, Bijzet J, van Rijswijk MH. Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum. Jun 2006;54(6):2015-21. [Medline]. [Full Text].
Yood RA, Skinner M, Rubinow A, Talarico L, Cohen AS. Bleeding manifestations in 100 patients with amyloidosis. JAMA. Mar 11 1983;249(10):1322-4. [Medline].
Further Reading
Keywords
immunoglobulin-related amyloidosis, amyloidosis, immunoglobulin, AL, light chain amyloidosis, primary amyloidosis, primary systemic amyloidosis, myeloma-associated amyloidosis, Ig-related amyloidosis, monoclonal plasma cell dyscrasias, monoclonal plasma cell disorder, amyloid deposits, amyloid L chain type, multiple myeloma, monoclonal gammopathy of undetermined significance, MGUS, nonamyloid monoclonal immunoglobulin deposition disease, MIDD, lymphoproliferative disorders
