Immunoglobulin-Related Amyloidosis Treatment & Management

Current choices for first-line treatment of systemic light-chain (AL) amyloidosis are autologous stem cell transplantation (ASCT) and combination chemotherapy. ^[22] Chemotherapy regimens include various combinations of the following:

• Dexamethasone
• Melphalan
• Cyclophosphamide
• Thalidomide
• Bortezomib
• Carfilzomib
• Lenalidomide
• Bendamustine 
• Daratumumab

 A hematologist with experience in administering chemotherapy should care for patients with L chain–type amyloidosis on an ongoing basis.

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. Therefore, 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. ^{[23, 24]} 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. ^[25] 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 kidney 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.

In patients whose disease responds to treatment but then progresses after treatment has been discontinued, chemotherapy (in 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 myeloid 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 (Velcade) 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 phase II studies confirmed the efficacy of bortezomib in patients with relapsed/refractory myeloma. ^{[26, 27]}

Subsequent studies demonstrated the benefit of bortezomib as part of combination therapy with melphalan and prednisone in the initial treatment of myeloma, ^{[28, 29]} and in combination with dexamethasone as induction treatment prior to autologous stem cell transplantation (ASCT) in patients with newly diagnosed myeloma. ^[30]

Drug resistance to bortezomib, probably related to high expression of heat-shock protein, led to the development of second-generation proteasome inhibitors (eg, carfilzomib, ixazomib). ^[31] These agents are approved for second-line therapy of myeloma.

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, an orally administered thalidomide analog, received US Food and Drug Administration (FDA) approval in 2006 for use with dexamethasone in patients with multiple myeloma who had received at least one prior therapy. In 2015, approval was expanded to include newly diagnosed multiple myeloma in patients who are not eligible for autologous stem cell transplantation. In 2017, the FDA approved lenalidomide as maintenance therapy for patients with multiple myeloma following ASCT. ^[32]

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 indicated 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 patients who 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 dexamethasone has demonstrated significant progression-free and overall survival benefits with a tolerable safety profile in relapsed/refractory cases. ^{[33, 34]}

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 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 those 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, 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.

Daratumumab

In 2021, the FDA granted accelerated approval to daratumumab plus hyaluronidase (Darzalex Faspro) in combination with bortezomib, cyclophosphamide, and dexamethasone (VCD) for newly diagnosed L chain amyloidosis. ^[35] Approval was based on the results of the ANDROMEDA (NCT03201965) study, an open-label, randomized, active-controlled trial in 388 patients, in which 42.1% of patients in the daratumumab/VCD arm achieved hematologic complete response, compared with 13.5% of those in the VCD arm (odds ratio4.8; 95% CI: 2.9, 8.1; P < 0.0001). ^[36] The most common adverse reactions (≥20%) in patients who received the daratumumab/VCD regimen are upper respiratory tract infection, diarrhea, peripheral edema, constipation, peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough. ^[35]

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. ^[37] 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 that Idox was insufficiently active at the dose administered in the protocol. ^[38]

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 or 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 kidney 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 kidney injury.

Carpal tunnel release

Involvement of the carpal ligament is observed not only in L chain–type amyloidosis but also in dialysis-related beta-2m amyloidosis i and in 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.

Kidney 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, kidney 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.

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

Complications of L chain–type amyloidosis reflect the organ systems involved. The most severe complication is extensive cardiac deposition, with consequent congestive heart failure, arrhythmias, or both. Cardiac involvement eventually occurs in most patients and appears to be the cause of death in more than 50% of patients with L chain–type amyloidosis.