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Advances in Systemic Amyloidosis: A Spotlight on New Disease-Modifying Therapies Across the Clinical Spectrum
  • CME
  • CE

Beth Faiman, PhD, MSN, APRN-BC, AOCN
Shaji K. Kumar, MD
Released: October 21, 2021

AL Amyloidosis (Light-Chain Amyloidosis)

Monoclonal Gammopathies: A Spectrum

Shaji K. Kumar, MD:
Given that AL amyloidosis is associated with MGUS, it is helpful to briefly review the monoclonal gammopathies. These disorders lie on a spectrum with MGUS at one end, where patients exhibit a relatively small amount of monoclonal protein, fewer than 10% plasma cells in bone marrow, and no end-organ damage.10 At the other end of the spectrum is multiple myeloma (MM), with high levels of monoclonal protein, a high percentage of plasma cells in bone marrow, and end-organ damage. In between is smoldering MM, and patients with this condition have a greater risk of progression to active MM vs those with MGUS.11

Most patients with AL amyloidosis are in the MGUS phase, with a minority having coexisting smoldering MM and an even smaller proportion having active MM.10

Distribution of Monoclonal Gammopathies: Mayo Clinic, Rochester, Minnesota

Shaji K. Kumar, MD:
In this analysis of 56,391 patients with monoclonal gammopathies who presented to Mayo Clinic Rochester from 1960-2017, most had MGUS (57%), whereas only 9.4% had AL amyloidosis. We should bear in mind that this is a referral center, and the frequency of AL amyloidosis will be lower in the community.

MGUS/Amyloidosis: Early Detection

Shaji K. Kumar, MD:
One of the greatest challenges to detecting AL amyloidosis is that most patients will have no preexisting history of a plasma cell disorder such as MGUS or smoldering myeloma. Most patients will instead present with systemic amyloidosis with organ involvement, which then leads to identification of the underlying monoclonal gammopathy. Thus, there has been a lot of interest in attempting to detect AL amyloidosis much earlier in patients with and without a known diagnosis of monoclonal gammopathy.

One of these approaches is aimed at earlier detection in individuals with MGUS. These patients should be monitored for markers of cardiac amyloid, such as N-terminal prohormone B-type natriuretic peptide (NT‑proBNP), or markers that indicate renal or liver involvement, such as albuminuria and alkaline phosphatase, respectively.12

The graph shown here comes from a study by Dispenzieri and colleagues13 characterizing which patients with MGUS are more likely to progress to AL amyloidosis. Patients with N-glycosylated monoclonal light chain proteins had a much higher risk of progression to AL amyloidosis (20-yr incidence: 21.4% vs 3.1% in those without glycosylated light chain). These data indicate that patients with MGUS and N-glycosylated light chains should be watched much more closely than those without N-glycosylated light chains.

AL Amyloidosis: Clinical Presentation

Shaji K. Kumar, MD:
To elaborate on the discussion earlier about clinical presentation, most patients with AL amyloidosis present with nonspecific symptoms such as fatigue and weight loss.14 These symptoms would not necessarily point a primary care provider toward the rare diagnosis of AL amyloidosis. However, if a patient presents with an enlarged tongue and/or periorbital purpura, the index of suspicion for AL amyloidosis greatly increases, and the patient is likely to be diagnosed sooner than someone presenting with only nonspecific symptoms.

Once AL amyloidosis is suspected in a patient, the first step is to screen for monoclonal light chains.14 The next step is to demonstrate that there is tissue deposition of amyloid. The third step is to identify the protein forming the amyloid fibrils. We will now go through these steps in more detail.

Light-Chain Amyloidosis: Screening for Monoclonal Protein

Shaji K. Kumar, MD:
If a patient is suspected to have AL amyloidosis or has been determined to have amyloidosis based on clinical symptoms and/or imaging, it is important to first screen for underlying monoclonal gammopathy. Screening for monoclonal protein can be done using serum protein electrophoresis with immunofixation, urine protein electrophoresis with immunofixation, and a serum free light chain (FLC) assay.15

If all 3 assays are performed, only 1% of patients would have a false negative for monoclonal protein. Indeed, 99% would be correctly identified by this series of tests in patients with underlying monoclonal gammopathy and AL amyloidosis.15 In 1 study, when urine immunofixation was not performed, approximately 6% of amyloidogenic clones were missed.16 

Detecting and Typing Amyloid Protein

Shaji K. Kumar, MD:
The next step is to detect amyloid deposits in tissue.4 The standard workup for a patient who has been identified as positive for monoclonal protein would include a bone marrow biopsy and a fat aspirate.

As shown here, at least one of those 2 samples would be positive for amyloid protein in 87% of patients, which can be sufficient to perform typing and diagnose AL amyloidosis. The remaining patients who are negative by bone marrow and fat aspirate will have to undergo an organ‑directed biopsy determined by the type of organ involvement.

As we discussed, tissue samples can then be analyzed using immunohistochemistry and/or mass spectrometry to identify the type of protein responsible for amyloidosis. Here is an example of a glomerulus biopsy that is apple-green birefringent with immunohistochemistry staining demonstrating that this is λ light chain–associated amyloid.

By mass spectrometry, λ light chain amyloidosis would be confirmed by the presence of λ light chain protein and the absence of κ light chain protein in the sample.

Amyloidosis: Initial Workup

Shaji K. Kumar, MD:
We will turn now to the initial workup of AL amyloidosis. First to be determined should be how many organs are involved; second should be the severity of involvement.

As shown here, approximately one half of patients will have just 1 organ involved, one third will have 2 organs, and the remainder will have more than 2 organs involved. Looking at the specific organs involved, the most common is the heart (37% of patients), followed by the kidneys (28%) and peripheral nerves (15%).

Considerations for Amyloidosis Workup

Shaji K. Kumar, MD:
Obviously, cardiac amyloidosis is the most concerning manifestation of this disease. There are several key considerations when performing the workup for this condition. First, if the serum NT-proBNP is normal, it is unlikely that the patient has cardiac amyloidosis—meaning that elevated NT-proBNP provides some discriminatory value in identifying this condition.17

Second, electrocardiogram may show low voltages and arrythmias.

Third, echocardiogram (ECHO) typically shows increased septal thickness but also can show diastolic dysfunction and abnormal strain patterns.

Fourth, MRI scans can demonstrate cardiac nulling.18

Fifth, PYP scans can help identify ATTR amyloidosis, which we will discuss later in this activity.4

Biopsy can definitively identify organ involvement, although other considerations can help determine the organ system(s) involved.

In terms of renal involvement, the typical presentation is nephrotic range proteinuria.19 Elevated creatinine is more common in advanced stages.20

Liver involvement is characterized by elevated alkaline phosphatase, with elevated bilirubin usually noted in the very late stages of the disease.21

Nerve conduction studies can demonstrate abnormality in both sensory and motor nerves, more commonly in the sensory nerves.22

Gastrointestinal involvement can be identified through decreased serum carotene, abnormal motility, and the presence of increased fecal fat.23,24

The presence of amyloid can be associated with deficiencies in factor X deficiency and other coagulation factors; workup should examine these coagulopathy parameters.19

AL Amyloidosis: OS by Mayo Clinic Stage

Shaji K. Kumar, MD:
Once the patient has been diagnosed and organ involvement determined, it is important to stage the disease. Different staging systems have been developed.

The most recent Mayo Clinic staging system, Mayo Clinic 2012, uses cardiac troponin-T (cTnT), NT-proBNP, and FLC difference—the absolute difference between κ and λ FLC—to categorize patients into 4 distinct stages with very different outcomes in terms of OS.25 In this prognostic staging system, patients are assigned 1 point for each of the following parameters: cTnT ≥0.025 ng/mL, NT-proBNP ≥1800 pg/mL, and FLC difference ≥180 mg/dL. Patients with 0, 1, 2, and 3 points are divided into stage I, II, III, and IV, respectively.

The OS from diagnosis for each of these stages is shown in the graph, which is from the study where we originally developed this prognostic staging system. In this study population of 810 patients with newly diagnosed AL amyloidosis, 758 patients were included in the survival analysis. We found a median OS from diagnosis in stage I that was not reached; stage II: 68.8 months; stage III: 16.7 months; and stage IV: 6.7 months.

As I mentioned, other risk stratification systems have been proposed or developed.26 These include a primarily cardiac-focused staging system that uses just NT-proBNP and cTnT, which is good at determining the short-term outcomes.27 By contrast, the Mayo Clinic 2012 system incorporates serum FLC and is better at predicting both short-term and long-term outcomes. Other organ-specific staging systems (eg, renal staging systems) also have been developed.

Newly Diagnosed AL Amyloidosis: Changes in Survival Over Time

Shaji K. Kumar, MD:
Even though the staging systems predict patient outcome, it is important and unfortunate to mention that a notable number of patients with amyloidosis die early. As shown in the graph of a single-institution retrospective analysis of 1551 patients newly diagnosed with AL amyloidosis, the 2-year mortality rate has improved over the years, from 42% among those diagnosed in 2000-2004 to 60% in 2010-2014.28 This improvement suggests that patients are benefiting from advances in therapy, as well as earlier diagnosis and intervention.

What Are the Goals of Therapy for Amyloidosis?

Shaji K. Kumar, MD:
Now that the patient has been diagnosed with AL amyloidosis and undergone risk stratification, what are the goals of treatment for AL amyloidosis?

The first is to achieve a deep response, as reflected in normalization or near normalization of serum FLC so that minimal FLC is available for amyloid fibril formation.

Second, the response needs to be durable because, although the amyloid that has already been deposited can be cleared, this clearance can take quite a while. The median time to organ response is anywhere from 6-12 months.29,30

Third, we want to minimize toxicity. This is particularly relevant to the population of patients with amyloidosis because extensive organ involvement can increase the risk for treatment-related toxicity compared with patients with MM receiving the same therapies.31

Finally, supportive care is especially important for patients with multiorgan involvement and is critical for survival. These supportive care considerations will be discussed later in more detail by my colleague, Beth Faiman, PhD, MSN, APRN-BC, AOCN.

How can we determine if the treatments are effective? There are 2 ways to approach measuring response in AL amyloidosis. The first is to look at hematologic response, which involves measuring reduction in the monoclonal protein.32 Hematologic response can be assessed accurately after 1-2 cycles of therapy.

However, the more important endpoint is organ response. This can be measured using a various tests dependent on the organ, such as NT-proBNP or ECHO for septal thickness to assess cardiac response.29,33 Liver response is determined by measuring alkaline phosphatase, and renal response involves measuring urine protein and creatinine. As I mentioned earlier, organ response can take some time, and in the short term we must rely entirely on measuring hematologic response.

Hematologic response in patients with AL amyloidosis is graded similarly to response in patients with MM. An amyloid CR is defined as achieving a normal FLC ratio and having negative serum and urine immunofixation results, a very good partial response (VGPR) is defined as having an FLC difference <40 mg/L, and a partial response (PR) is defined as an FLC difference >50%.34

OS in Amyloidosis by Hematologic and Organ Response

Shaji K. Kumar, MD:
Both hematologic and organ responses are important because they are strong predictors of outcome. Shown here are data from a large, multicenter analysis evaluating survival in 816 patients with AL amyloidosis stratified by the hematologic and organ responses just discussed.34 The left graph shows that hematologic responses at 6 months predicted significant differences in OS (all P ≤.01), with the highest OS in those achieving a CR, followed by VGPR, PR, and then no response. Comparable results were observed when hematologic response was assessed earlier at 3 months.

The right graph shows that in patients with cardiac involvement, assessing cardiac response in terms of NT-proBNP at 6 months also predicted significant differences in OS (both P <.001). The highest OS was observed in those with a 6-month NT-proBNP response, defined as a decrease >300 ng/L with a >30% decrease from baseline, followed by those with stable NT-proBNP. The lowest OS was found in those with NT-proBNP progression, defined as an increase >300 ng/L with a >30% increase from baseline. Again, comparable results were found when cardiac response was assessed at 3 months.

More recently, my colleagues and I have developed a composite approach integrating hematologic and organ response—known as the composite hematologic organ response (CHOR) model—which may better predict survival.35

Treatment Strategies for AL Amyloidosis

Shaji K. Kumar, MD:
Turning now to treatment strategies, 1 approach involves plasma cell–directed therapies aimed at reducing the abnormal plasma cells producing excess FLC.36,37 The second approach aims to slow or stop the process of amyloid fibril formation and protein misfolding using fibril inhibitors such as doxycycline. Other approaches aim to clear the fibrils once they are deposited using various fibril-directed therapies.

We will first review data on plasma cell–directed therapies, which have been borrowed extensively from treatments for patients with MM.

Overall Survival by ASCT in AL Amyloidosis Treatment

Shaji K. Kumar, MD:
Is ASCT beneficial to patients with AL amyloidosis? Historically, there were few prospective trial data testing this approach, forcing healthcare professionals to turn to retrospective studies. In this retrospective case-control study of 126 patients with AL amyloidosis, Dispenzieri and colleagues38 compared OS in those who underwent peripheral blood stem cell transplantation (PBSCT) after high-dose chemotherapy vs matched controls who did not undergo PBSCT. As shown in the graph, the patients who underwent PBSCT experienced significantly improved OS from diagnosis vs those who did not undergo PBSCT, with 4-year OS rates of 71% vs 41%, respectively (P <.001).

Melphalan Plus Dexamethasone vs HD Melphalan Plus ASCT in AL Amyloidosis: Reponses and Survival

Shaji K. Kumar, MD:
Based on these and other supportive retrospective data, the IFM Intergroup performed a randomized phase III trial comparing transplant vs nontransplant approaches that was published in The New England Journal of Medicine in 2007.39 The trial randomized 100 adults with newly diagnosed AL amyloidosis to high-dose IV melphalan followed by ASCT vs standard-dose oral melphalan plus high-dose oral dexamethasone.

The trial did not show superiority of high-dose IV melphalan with autologous stem cell rescue over a standard dose of oral melphalan plus dexamethasone. In fact, median OS with oral melphalan plus dexamethasone was significantly longer than with high-dose IV melphalan with autologous stem cell rescue (56.9 vs 22.2 months, respectively; P = .04). However, there was an extremely high rate of transplant‑related mortality (24%), which we do not see with current transplant approaches, making these data less applicable.

Stem Cell Transplantation vs Melphalan Plus Dexamethasone in AL Amyloidosis: Survival

Shaji K. Kumar, MD:
More recently in 2016, Gertz and colleagues40 published results from a nonrandomized phase III trial evaluating melphalan plus dexamethasone in 1 arm and high-dose melphalan plus ASCT in another arm. All 89 patients had AL amyloidosis and were eligible for transplant; the arm assignment was determined by patient preference. This resulted in imbalanced baseline characteristics such that the patients in the transplant arm were younger and fitter with less-advanced disease where the heart was not the dominant disease site. The investigators attempted to account for the nonrandomized treatment allocation by comparing outcomes between arms in which patient cohorts were matched by risk and performance status.

As shown here, median OS was significantly prolonged in the transplant arm vs the nontransplant arm (not reached vs 6.53 years, respectively; P = .02). Median progression-free survival (PFS) was also significantly prolonged (4 vs 1.63 years; P = .008).

Both of these phase III trials have disadvantages, such as high transplant-related mortality in the first and a nonrandomized design in the second. This means that we do not have large, prospective, randomized comparative trials of transplant vs nontransplant approaches in similar patient populations. Nonetheless, we do have retrospective data suggesting the outcomes associated with ASCT in this disease. 

CIBMTR Experience Treating Amyloidosis: Responses and Long-Term Survival

Shaji K. Kumar, MD:
This study analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry on outcomes in 1536 patients with AL amyloidosis who underwent ASCT from 1995-2012.41 The patients were divided into cohorts defined by the year of transplantation: 1995-2000, 2001-2006, and 2007-2012.

Data were available from the 2 most recent cohorts, enabling determination of hematologic and renal response. A best hematologic response of CR was achieved in 37% of those treated from 2001-2006 and in 37% of those from 2007-2012. Renal response was observed in 31% and 32%, respectively.

Another notable finding from the CIBMTR study was that early mortality was significantly higher in centers that performed <4 vs ≥4 AL transplantations per year.41 This is important to consider when comparing results.

Overall, there were significant declines over time in early mortality at 30 and 100 days, which were 11% and 20%, respectively, in the 1995-2000 cohort and 3% and 5% in the 2007-2012 cohort (P <.001). OS rates correspondingly improved over time, with the 5-year OS rate climbing from 55% in the 1995-2000 cohort to 77% in the 2007-2012 cohort (P <.001).

These improvements in mortality partly reflect improved patient selection, as well as better management of transplant-related complications.

Long-Term Survival in Amyloidosis

Shaji K. Kumar, MD:
As we just noted, the OS of patients undergoing ASCT has continued to improve, and we now have data on long-term survival. This single-institution analysis evaluated long-term outcomes in 159 patients with AL amyloidosis who underwent ASCT from 1996-2003.42 In the entire cohort, the median OS was 6.7 years, with a 15-year OS rate of 33%.

This analysis found that long-term outcomes were strongly associated with the degree of response and whether there was cardiac involvement or not. Patients achieving a CR had a median OS of 19.3 years vs 5.4 years in those who did not achieve a CR (P <.001). Those without cardiac involvement had much better long-term outcomes: the median OS was 4.0 years in those with cardiac involvement vs 11.1 years in those without (P = .006).

Both the CIBMTR study and this analysis noted better outcomes in patients who received a full dose of melphalan conditioning (defined as ≥180 mg/m2 in the CIBMTR study and 200 mg/m2 in the single-institution analysis).41,42 However, this observation is clouded by confounding factors behind the decision to administer lower vs higher doses of melphalan.

Transplant Eligibility in Amyloidosis: Mayo Criteria

Shaji K. Kumar, MD:
Over time, we have learned to better select patients with AL amyloidosis who are more likely to benefit from ASCT. At the Mayo Clinic, we consider patients eligible for transplantation if they meet the following criteria.43

  • Aged 70 years or younger
  • Good performance score (≤2)
  • Systolic blood pressure ≥90 mm Hg
  • TnT <0.06 ng/mL
  • Creatinine clearance ≥30 mL/min, unless on chronic dialysis
  • Good New York Heart Association class (I/II)

Is Induction Required Prior to ASCT in AL Amyloidosis?

Shaji K. Kumar, MD:
Once a patient is planned to undergo ASCT, an important question is whether they should receive induction therapy. Prospective data are lacking, so we must turn to retrospective analyses such as the one shown here. In this retrospective study of 415 patients who underwent ASCT within 12 months of diagnosis at the Mayo Clinic, we compared outcomes between those who did vs did not receive induction therapy.44 In this cohort, 35% received induction therapy, with approximately half receiving corticosteroids only and half receiving chemotherapy.

Induction therapy was beneficial in those with baseline bone marrow plasma cells >10%. The overall hematologic response rates were significantly higher in this group for those who did vs did not receive induction therapy (P = .048), whereas there was no significant difference by induction therapy status in the group with baseline bone marrow plasma cells ≤10%.

Although we lack prospective data, it is not uncommon for patients with a very low degree of plasmacytosis in their bone marrow to undergo stem cell collection and proceed directly to stem cell transplantation without induction therapy.

We do know that patients who receive induction therapy and achieve a good response are more likely to have improved PFS and OS. Shown here are data from another retrospective analysis of 128 patients with newly diagnosed AL amyloidosis who received induction therapy, most commonly based on bortezomib (73%), before undergoing ASCT at the Mayo Clinic from 2007-2017.45

The hematologic overall response rate was 87% with induction therapy, and the depth of response before transplant was associated with PFS and OS. Those who achieved a VGPR or better before transplant with induction therapy had a median PFS that was not reached vs 34.1 months in those who achieved a PR or less (P = .0009). The median OS was also significantly prolonged in those who achieved a VGPR or better before transplant vs a PR or less (not reached vs 128 months, respectively; P = .02). Comparable results were observed for PFS and OS based on depth of response after transplant.

Although useful, the retrospective nature of this analysis limits our ability to draw clinical conclusions from these data.

SCT in AL Amyloidosis: 1-Year OS by Weight Gain

Shaji K. Kumar, MD:
Cardiac and renal complications present another challenge to patients undergoing transplantation for AL amyloidosis. An important observation on the prognostic significance of weight gain due to edema came from this 2005 retrospective analysis of 126 patients who underwent treatment with high-dose melphalan plus ASCT from 1997-2003.46 Those who experienced a weight gain ≥2% during stem cell mobilization exhibited worse survival vs those who did not, with a 1-year mortality rate of 33.9% vs 9.8%, respectively (P = .002). The 1-year mortality rate was even higher at 66.7% among those who were in the top 10% for weight gain, defined as an increase of >8.3% in weight.

Because weight gain and fluid retention during stem cell mobilization are associated with poor outcomes, we can use this as a good clinical discriminatory marker when deciding whether to proceed to ASCT.

Retrospective Analysis: Amyloidosis OS From Transplant With Melphalan Conditioning

Shaji K. Kumar, MD:
Many patients with AL amyloidosis benefit from ASCT; however, the optimal dose of melphalan has been a point of contention. This retrospective study compared reduced-dose (<180 mg/m2; 86% received 140 mg/m2) to full-intensity (200 mg/m2) melphalan conditioning.47 In total, 314 patients received the higher dose, and 143 patients received the lower dose.

Patients who received full-intensity melphalan conditioning had a longer 4-year PFS (55% vs 31%; P <.001) and 4-year OS (86% vs 54%; P <.001) than patients who received the reduced dose. For patients achieving ≥VGPR, the 4-year OS was 94% vs 83% for full-intensity vs reduced-dose melphalan (P <.001), respectively.

In this study, some of the critical factors identified as contributing to OS outcomes of patients undergoing ASCT for AL amyloidosis included the number of organs involved, the degree of plasmacytosis, and the Mayo stage.

Unfortunately, there are no clear prospective data identifying which patients should receive a full dose of melphalan vs a reduced dose.

Retrospective Analysis: PFS With Posttransplant Consolidation in AL Amyloidosis

Shaji K. Kumar, MD:
After dosage, a related question arises: Should additional consolidation therapy be given after ASCT?

A retrospective analysis of 471 patients with AL amyloidosis examined responses in relation to post-ASCT consolidation therapy.48 Consolidation regimens consisted of immunomodulatory drugs (mainly lenalidomide), proteasome inhibitors (PIs; mainly bortezominb), or a combination of the two. A small percentage of patients received daratumumab plus immunomodulatory drugs, alkylators, or rituximab as consolidation therapy. In the total population, there was no median PFS benefit to consolidation therapy (38 months with consolidation vs 39 months without consolidation; P = .002), and there was no PFS or OS benefit to post-ASCT consolidation therapy for patients with ≥VGPR at Day 100 after transplant. For patients with <VGPR at Day 100 after transplant, there was a higher median PFS with consolidation (22.4 months) than without it (8.8 months; P <.001). The study results also suggest that consolidation therapy may improve OS among patients with <VGPR. Again, in the absence of good prospective data, treatment must be individualized.

Response-Adapted Strategy to Determine Which Patients With AL Amyloidosis Benefit From ASCT

Shaji K. Kumar, MD:
Basset and colleagues49 took a response-adapted approach to compare treatment results of patients treated with cyclophosphamide plus bortezomib plus dexamethasone (CyBorD) alone and those who received CyBorD followed by ASCT.

In total, 139 patients with AL amyloidosis received CyBorD and were eligible for an ASCT; 63 patients (45%) had a satisfactory response (defined as a CR, or a PR or VGPR with organ response) and did not undergo ASCT. Of the remaining patients (n = 76) with an unsatisfactory response (no response or VGPR or PR without organ response), 55 proceeded to ASCT. For this group, the overall hematologic response was 80%, with 21 patients (38%) attaining a CR and 15 (27%) reaching VGPR.

Despite having a suboptimal response to CyBorD, patients who underwent ASCT fared well compared with those who had initial success with CyBorD. There were no differences in 6- and 12-month survival or duration of response, suggesting that this is a reasonable approach. But these treatments clearly need to be compared in phase III settings.

mSMART: Newly Diagnosed AL Amyloidosis, SCT Eligible

Shaji K. Kumar, MD:
The mSMART (Stratification for Myeloma and Risk-Adapted Therapy) approach for transplant-eligible patients with AL amyloidosis is to offer induction therapy with daratumumab (Dara) plus CyBorD followed by stem cell collection, 200 mg/m2 melphalan (or 140 mg/m2 for patients with creatinine clearance <30mL/min), and ASCT.50 If these patients do not achieve a hematologic VGPR, we certainly consider giving them additional therapy. Patients who reach CR or ≥VGPR can be observed thereafter. In patients with high-risk characteristics (such as overt MM or ≥20% bone marrow plasma cells and high-risk cytogenetics), we consider maintenance therapy. 

Survival With Melphalan/Dex in Advanced AL Amyloidosis Not Eligible for ASCT

Shaji K. Kumar, MD:
So, what are the treatment options for patients who are ineligible to go to a stem cell transplant?

Palladini and colleagues51,52 assessed the combination of melphalan plus high-dose dexamethasone (MDex) in patients with advanced AL amyloidosis who were not eligible for ASCT.

The study enrolled 46 patients who were ineligible for high-dose chemotherapy or ASCT due to age, number of involved organs, cardiac or respiratory conditions, or creatinine levels. They received melphalan 0.22 mg/kg plus dexamethasone (Dex) 40 mg for up to 9 courses (median 4 courses). A hematologic response was obtained in 31 patients (67%), with a median time to response of 4.5 months. Fifteen of these patients (33%) achieved CR. Median PFS was 3.8 years, and the median OS was 5.1 years.52 The data show that patients who get a good response with MDex do very well long term.

Phase III EMN-03: MDex vs BMDex in Untreated Systemic AL Amyloidosis

Shaji K. Kumar, MD:
Another approach to treating AL is the use of PIs. Several studies have looked at bortezomib with either Dex53,54 or alkylating agents such as melphalan55,56 and cyclophosphamide.57 All of these trials clearly demonstrated that patients can get deep hematologic response associated with clinically relevant organ response with PI monotherapy or PI combination therapy.

The EMN-03 study is a randomized, open-label, multicenter phase III trial that prospectively compared the current standard of care (MDex) with the combination of bortezomib plus MDex (BMDex) for patients with newly diagnosed AL amyloidosis who were not eligible for high-dose melphalan and ASCT. Between 2011 and 2016, the study enrolled 110 eligible patients who received ≥1 dose of therapy.

Treatment was given in 28-day cycles until patients either completed the maximum allowed number of cycles (9 for MDex, 8 for BMDex) or completed cycle 6 and achieved hematologic CR or PR and organ response, or completed cycle 3 but achieved <PR or the progression of clonal plasma cell disease.58 The primary endpoint was the overall hematologic response rate after 3 cycles. Secondary endpoints included CR, VGPR, organ response rates, and quality of life (QoL) after 3 cycles. In addition, CR, VGPR, overall hematologic response rate, organ response rate, OS, and PFS were also compared at the completion of therapy. 

MDex vs BMDex in Untreated Systemic AL Amyloidosis (EMN-03): Survival

Shaji Kumar, MD:
The 2 graphs on this slide clearly illustrate that the addition of bortezomib to MDex improved the PFS and OS for patients who were otherwise considered ineligible for ASCT.

The EMN-03 study met its primary endpoint, showing that the hematologic response rate after 3 cycles was significantly higher in the BMDex arm (79%) vs the MDex arm (52%; log-rank test P = .002).58 In addition, patients treated with BMDex experienced a 50% decrease in mortality rate. At a median follow-up of 50 months, the median OS was not reached in the BMDex arm vs 34 months in the MDex arm.

In the EMN-03 trial, there were no significant differences in cardiac and renal responses at 3, 6, or 9 months after treatment in the BMDex and MDex arms.58

TOURMALINE-AL1: Ixazomib Plus Dexamethasone vs Physician’s Choice

Shaji Kumar, MD:
The TOURMALINE-AL1 trial was a randomized, open-label, international phase III trial.13 This was the first phase III study of patients with relapsed or refractory AL amyloidosis with cardiac and renal involvement. Between December 2012 and August 2018, 168 patients were randomized into 2 study arms: MDex plus the PI ixazomib (Ixa; n = 85) or the physician’s choice of Dex plus another non–PI-based drug (n = 83). Patients were treated in 28-day cycles until progressive disease, death, unacceptable toxicity, or termination of the study.

The 2 primary endpoints were overall hematologic response rate (≥PR) and 2-year heart or kidney deterioration or mortality rate. OS and hematologic CR were the key secondary endpoints. The primary endpoints were not met for this trial, but the data favored the Ixa plus Dex regimen. This regimen showed a hematologic response rate of 53% vs 51% with the physician’s choice of treatments (P = .76). Ixa plus Dex also showed a CR rate of 26% vs 18% for the other arm (P = .22).

Immunomodulatory Drugs: Considerations in Amyloidosis Treatment

Shaji K. Kumar, MD:
Immunomodulatory drugs are very successful in treating patients with MM, but they have limited value in treating AL amyloidosis. These drugs are significantly more toxic (especially thalidomide) for patients with AL amyloidosis compared with those with MM. Lenalidomide and pomalidomide have been studied alone, and trials with combined lenalidomide plus Dex and lenalidomide plus Dex plus cyclophosphamide are active and certainly can be considered for patients who do not get good responses with other treatments.

ANDROMEDA: Daratumumab Plus VCd vs VCd Alone in Newly Diagnosed AL Amyloidosis

Shaji K. Kumar, MD:
Dara is a human monoclonal antibody that targets CD38 on the plasma cells. The ANDROMEDA study is a randomized, open-label phase III trial that enrolled 388 newly diagnosed adults with AL amyloidosis who had 1 or more organs affected, no prior treatment for MM or AL amyloidosis, cardiac stage I-IIIa, and eGFR ≥20 mL/min.59,60

Patients were randomized to receive either six 28-day cycles of treatment with bortezomib plus cyclophosphamide plus Dex (VCd), or SC Dara plus VCd or 6 cycles. After the initial 6 cycles, the Dara group continued to receive single-agent Dara for up to 24 cycles.

The primary endpoint of the ANDROMEDA study was a hematologic CR in the intention-to-treat population. Secondary endpoints were major organ deterioration PFS, organ responses, time to hematologic response, OS, and safety.

ANDROMEDA: Overall Confirmed Hematologic, Cardiac, and Renal Responses at 6 Months

Shaji K. Kumar, MD:
The ANDROMEDA study met its primary endpoint with more 53% of patients in the Dara plus VCd arm achieving a hematologic CR vs 18% in the VCd arm (relative risk ratio: 2.9, 95% CI: 2.1-4.1, P <.001; odds ratio: 5.1, 95% CI: 3.2-8.2, P <.001).59

The addition of Dara significantly improved the overall response rate and the depth of response, which is critical for this population. Almost 80% of the patients receiving Dara plus VCd achieved a ≥VGPR vs 49% in the control group (relative risk ratio: 1.6, 95% CI: 1.4-1.9; OR: 3.8, 95% CI: 2.4-5.9).

In terms of clinical relevance, you also can see that a higher proportion of patients receiving Dara plus VCd vs VCd alone were able to achieve a renal response (53% vs 24%) and a cardiac response (42% vs 22%), respectively.

ANDROMEDA: Most Common Adverse Events

Shaji K. Kumar, MD:
The addition of Dara to VCd increased the overall rate of adverse events (AEs), but only by a relatively small margin. The most common grade 3 or 4 AEs occurred more often in the Dara group: lymphopenia (13% vs 10%), pneumonia (8% vs 4%), cardiac failure (6% vs 5%), and diarrhea (6% vs 5%).59 Most of the toxicities that were seen appeared to be comparable between the 2 arms, suggesting that adding Dara to VCd  had very limited negative impact.

ANDROMEDA: Survival Free From Major Organ Deterioration or Hematologic Progression in ITT Population

Shaji K. Kumar, MD:
An important composite secondary endpoint in the ANDROMEDA trial was event-free survival from major organ deterioration, hematologic progression, or death. The graph on this slide suggests the positive influence of Dara on this endpoint (HR: 0.58l; 95% CI: 0.36-0.93; P = .02).59

ANDROMEDA: Assessing QoL

Shaji K. Kumar, MD:
QoL was assessed for patients in both study groups, with standardized surveys at the start of each cycle.61 Patients in the Dara plus VCd arm did not see a decline in QoL during the study period and reported improvement in global health status and fatigue following cycle 6.

Based on the results of the ANDROMEDA trial, SC Dara was approved in combination with VCd for newly diagnosed patients with AL amyloidosis. At this time, it is the only approved agent in this setting.

mSMART: Relapsed/Refractory AL Amyloidosis

Shaji K. Kumar, MD:
Now, let’s focus on relapsed/refractory AL amyloidosis. When considering treatment of patients with relapsed or refractory AL amyloidosis, the first consideration is whether the patient is refractory to Dara.50  For patients who are not refractory to Dara, other Dara-based combinations may be used in the second line. However, for patients who are refractory to Dara, second-line options vary. For patients who are also refractory to bortezomib, pomalidomide-Dex or lenalidomide-Dex combinations may be used. For patients who are not bortezomib refractory, CyBorD may be used in the second line if there is no significant neuropathy. In the case of significant neuropathy, MDex or Ixa-Dex are more suitable options. In the third line, ASCT, carfilzomib, venetoclax, or bendamustine may be considered. However, there are insufficient data to fully support these treatment options.

Phase I/II Trial of Birtamimab in Previously Treated AL Amyloidosis: Cardiac Biomarkers and Best Responses

Shaji K. Kumar, MD:
A phase I/II trial explored the use of the birtamimab (NEOD001), an investigational monoclonal antibody targeting aggregated amyloid, in patients with previously treated AL amyloidosis.62 Patients in this trial (N = 69) received ≥1 prior systemic therapy for AL amyloidosis. In the final expansion cohort, the NT-proBNP change from baseline with treatment was assessed in 36 evaluable patients. Of these, 19 met the response criteria, and the remaining 17 were considered stable.34,63

Phase I/II Trial of Birtamimab in Previously Treated AL Amyloidosis: Renal Biomarkers, Best Responses

Shaji K. Kumar, MD:
In total, 36 evaluable patients with baseline proteinuria >0.5 g/24 hour also were assessed for renal response (change from baseline).63 In addition, 23 (64%) patients met the response criteria, and the remaining 13 (36%) patients were stable.

These results suggest the positive contribution of birtamimab to improvements in cardiac and renal function in patients with previously treated AL amyloidosis. However, these studies were done in the context of other therapies that effectively control the amyloidogenic clone. Hence, it is difficult to assess the individual impact of this fibril-directed therapy. In fact, the phase III VITAL trial of birtamimab in newly diagnosed patients with AL amyloidosis failed to meet its initial endpoint.64,65 Ongoing studies are looking at various subgroups, such as patients with cardiac involvement, where we might see the maximum benefit.

AL Amyloidosis Management Summary

Beth Faiman, PhD, MSN, APRN-BC, AOCN:
Managing AL amyloidosis requires a multidisciplinary team of doctors, nurses, social workers, physicians, and advanced practice professionals. When managing patients with amyloidosis, it is most important to understand the different body systems that can be affected, including the kidneys, skin, liver, gastrointestinal tract, or heart.5

When we are working with patients with kidney amyloid, we want to make sure they are responding to treatment. To do this, we test their serum and urine M-protein on a monthly basis and collect a 24-hour urine sample to measure total protein.33 In addition to watching for kidney organ response, we also look for improvement in serum FLC levels over time.

Patients with kidney amyloid often excrete lots of protein, and this can lead to low serum albumin levels, which can result in swelling.66 This swelling is one of the primary concerns for patients with kidney amyloid, and it is typically seen in the lower extremities. The swelling is worse at the beginning of treatment and improves over time as the proteinuria subsides and the kidney organ response occurs. Patients with kidney amyloidosis typically require diuretics and will require comanagement with the nephrology team. They also need a lot of emotional support, because struggling with considerable weight gain can be distressing.

It is very difficult to care for patients with cardiac amyloidosis. Heart failure tends to be a diastolic dysfunction; that is, a restrictive pattern in the heart and systolic ejection fraction is often normal until late in the disease.4 In essence, the amyloid has embedded itself in the heart wall, which results in the thickening of the myocardium. Patients with cardiac amyloidosis often present with heart failure with preserved ejection fraction and are frequently misdiagnosed. If misdiagnosed, these patients can become very sick by the time we see them. Therefore, it is important to manage the heart failure with appropriate use of diuretics and make sure that the patient’s ECHO and electrocardiogram are evaluated.

For patients with cardiac amyloidosis, we monitor NT-proBNP, hematologic response, and serum FLC levels.34

The morbidity and mortality can be quite high for patients with cardiac amyloidosis, but with aggressive supportive care, comanagement with cardiology, and disease monitoring, treatment can be very effective. When patients are receiving active treatment, it is important to make sure all their other needs are addressed. Patient needs could include transportation to treatment centers, home care, counseling, etc. Often, I will involve a social worker to help patients get assistance.

When educating patients on the types of available therapy, I typically mention that VCd is a common standard of care.67 When appropriate, we can now add Dara, which is given as an SC injection about 3 inches from the abdomen and over a period of approximately 3-5 minutes.68

A major potential adverse events of Dara in patients with amyloidosis is the risk of systemic administration-related reactions or local injection site reactions.68  In the ANDROMEDA trial, 7% and 25% of patients experienced a grade 1 or 2 systemic administration-related reaction or local injection-site reaction related to Dara, respectively.59

Premedication with acetaminophen and diphenhydramine is recommended for patients receiving Dara plus VCd.68 I explain to my patients that they will have an IV started even though they will receive an SC injection. For the first month of treatment, I typically order an IV to be started in case the patient has an infusion-related reaction and needs antihistamines, diphenhydramine, or IV fluids. Patients are more likely to experience an infusion-related reaction on the first 2 injections. If there are no reactions after the first 2 injections, premedications are often discontinued, and patients are released almost immediately after that injection is given. After premedication with diphenhydramine, acetaminophen, and famotidine, I often observe my patients for about 4 hours after the first dose to make sure they don’t have a reaction to that SC injection.

There are adverse events related to the VCd combination. Cyclophosphamide is commonly given and may cause nausea.69 To curb that, I make sure that patients have an antiemetic available. When administering bortezomib, we monitor for peripheral neuropathy. Dex is often given with the CyBorD regimen, and it can cause problems such as hyperglycemia and additional fluid retention. Especially for our patients with heart failure or kidney amyloidosis, we want to keep a close eye on fluid status. A timely organ response in the heart or kidney may allow us to discontinue the Dex within the first 2 months of therapy.

One of the final topics I discuss with my patients and caregivers on the Dara plus VCd regimen is the risk for blood type and crossmatch interference. Patients with MM and other plasma cell disorders might need to have blood transfusions more often than those with the AL amyloidosis. However, we make sure patients are aware of their blood type to expedite efficient handling, cleaning, and crossmatching of the blood for the patient.

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