# Waldenstrom Macroglobulinemia and Amyloidosis

## Waldenstrom Macroglobulinemia (WM)

### Introduction

Waldenstrom macroglobulinemia is defined as lymphoplasmacytic lymphoma (LPL) with bone marrow infiltration and the production of a monoclonal IgM protein. The disease is rare, with an incidence of approximately 3 to 5 per million per year, a median age at diagnosis of 70 years, and a male predominance. The diagnosis requires both bone marrow infiltration by lymphoplasmacytic lymphoma and the detection of an IgM monoclonal protein. A distinguishing molecular feature of WM is the MYD88 L265P mutation, which is present in more than 90% of cases and serves as a critical diagnostic and therapeutic biomarker separating WM from other IgM-secreting lymphoproliferative disorders.

### Molecular Biology

The MYD88 L265P mutation is a gain-of-function point mutation that constitutively activates NF-kappa-B signaling through the IRAK1/4 and Toll-like receptor (TLR) pathways. This mutation also drives constitutive Bruton tyrosine kinase (BTK) signaling, providing the molecular rationale for the efficacy of BTK inhibitors in WM. CXCR4 mutations are found in approximately 30 to 40% of WM patients and are characterized by WHIM-like (warts, hypogammaglobulinemia, infections, myelokathexis) frameshift or nonsense mutations. CXCR4 mutations are associated with higher IgM levels, greater bone marrow involvement, and resistance to ibrutinib, with S338X nonsense mutations conferring the most significant resistance. The combination of MYD88 and CXCR4 genotype is clinically informative and guides therapy and prognosis. Patients with MYD88 mutated and CXCR4 wild-type disease achieve the best responses to BTK inhibitor therapy. Those with MYD88 mutated and CXCR4 mutated disease demonstrate intermediate BTK inhibitor responses. The MYD88 wild-type genotype is associated with aggressive disease behavior and should prompt reconsideration of the diagnosis, as marginal zone lymphoma with IgM secretion is the principal differential diagnostic consideration.

### Clinical Manifestations

Hyperviscosity syndrome occurs in 10 to 30% of patients and manifests with blurred vision, headache, epistaxis, mucosal bleeding, and confusion. It typically develops when the IgM level exceeds 4 to 5 g/dL, although the threshold varies substantially between patients due to differences in IgM polymerization and intrinsic viscosity. Fundoscopic examination reveals characteristic "sausage-link" retinal veins, a hallmark finding that should be sought in any patient with WM presenting with neurologic or visual symptoms. Cytopenias result from bone marrow infiltration by the neoplastic lymphoplasmacytic population and from direct IgM-mediated effects on hematopoietic cells.

Peripheral neuropathy affects approximately 25% of WM patients and is most commonly caused by IgM antibodies directed against myelin-associated glycoprotein (anti-MAG antibodies). The neuropathy is characteristically distal, symmetric, and sensorimotor, with a demyelinating pattern on electromyography and nerve conduction studies. Cryoglobulinemia may be present as either Type I (monoclonal IgM) or Type II (mixed), manifesting with Raynaud phenomenon, purpura, renal disease, and neuropathy. Cold agglutinin disease results from IgM antibodies with anti-I specificity that cause autoimmune hemolytic anemia. AL amyloidosis is an uncommon but recognized complication of WM, resulting from IgM heavy chain or light chain deposition. Bing-Neel syndrome refers to direct central nervous system infiltration by lymphoplasmacytic lymphoma and is rare, presenting with headache, cranial nerve deficits, and positive cerebrospinal fluid cytology.

### Treatment Indications (IWWM Guidelines)

Treatment is indicated for symptomatic hyperviscosity, moderate-to-severe cytopenias (hemoglobin below 10 g/dL, platelet count below 100,000), bulky lymphadenopathy or organomegaly, symptomatic cryoglobulinemia or cold agglutinin disease, amyloidosis-related organ dysfunction, and constitutional symptoms. A fundamental principle of WM management is that treatment should never be initiated based on the IgM level alone, as many patients with elevated IgM remain asymptomatic and do not benefit from early intervention.

### First-Line Treatment

BTK inhibitor therapy with ibrutinib at 420 mg daily or zanubrutinib at 160 mg twice daily represents a first-line treatment approach. The ASPEN trial compared zanubrutinib to ibrutinib and demonstrated similar efficacy, with combined complete and very good partial response rates of 28% versus 19%, respectively. Zanubrutinib was better tolerated, with fewer atrial fibrillation and bleeding events, establishing it as the preferred BTK inhibitor for WM. The best responses to BTK inhibitor therapy are observed in patients with MYD88 mutated and CXCR4 wild-type disease. BTK inhibitor therapy is administered continuously until disease progression. These agents should be used with caution in patients receiving strong CYP3A4 inhibitors or anticoagulation, with ibrutinib carrying a higher bleeding risk than zanubrutinib.

Rituximab-bendamustine (BR) is an alternative first-line regimen that achieves an overall response rate of 95% and a very good partial response rate of 40%, with the advantage of being time-limited therapy. An important caveat with rituximab-containing regimens is the IgM flare phenomenon, in which IgM may transiently increase by 25 to 50% after rituximab administration, potentially exacerbating or precipitating hyperviscosity. Rituximab should be avoided as first-line therapy when the IgM level exceeds 4 g/dL without prior plasmapheresis. DRC (dexamethasone, rituximab, and cyclophosphamide) is a lower-intensity regimen that is well tolerated in elderly patients. Bortezomib-based regimens such as BDR (bortezomib, dexamethasone, rituximab) are effective, particularly in amyloidosis-related WM, though peripheral neuropathy is a concern.

### Hyperviscosity Management

Emergent plasmapheresis is the immediate treatment for symptomatic hyperviscosity. IgM is an efficient target for plasmapheresis because approximately 80% resides in the intravascular compartment due to its large pentameric molecular size. A single plasma exchange removes 30 to 50% of circulating IgM. Definitive therapy should be initiated simultaneously, as plasmapheresis is a temporizing measure that does not address the underlying disease.

### Anti-MAG Neuropathy

Anti-MAG neuropathy often does not respond well to standard WM treatment regimens. Rituximab provides modest benefit, with approximately 30% of patients experiencing improvement, though the response is characteristically slow, developing over months. Ibrutinib may be considered, along with clinical trial enrollment. Intravenous immunoglobulin is generally ineffective for anti-MAG neuropathy.

## AL Amyloidosis

### Introduction

AL (light chain) amyloidosis is a systemic disease caused by the deposition of misfolded immunoglobulin light chain fibrils in tissues. Lambda light chains predominate, accounting for approximately 75% of cases, while kappa light chains account for the remaining 25%. The incidence is approximately 10 per million per year, with a median age at diagnosis of 63 years. The underlying plasma cell dyscrasia is typically of low tumor burden, with a median bone marrow plasma cell percentage of approximately 10%. Organ involvement determines prognosis, and cardiac involvement is the dominant predictor of survival.

### Pathophysiology

Clonal plasma cells produce structurally unstable light chains that undergo misfolding, aggregate into amyloid fibrils with a characteristic beta-pleated sheet conformation, and deposit in tissues. Beyond the mechanical effects of fibril deposition, pre-fibrillar oligomers exert direct cardiotoxicity, contributing to organ damage before significant amyloid accumulation occurs. Congo red staining of tissue biopsies produces the pathognomonic apple-green birefringence under polarized light microscopy. Mass spectrometry has become the gold standard for amyloid typing, as it reliably distinguishes AL amyloidosis from AA, ATTR, and other amyloid subtypes with a precision that immunohistochemistry cannot consistently match.

### Clinical Manifestations

Cardiac involvement is present in approximately 75% of patients and manifests as restrictive cardiomyopathy with diastolic dysfunction, the characteristic low-voltage electrocardiographic paradox (thickened ventricular walls on echocardiography but low voltage on ECG), arrhythmias, and heart failure. Renal involvement occurs in approximately 65% of patients, presenting with nephrotic syndrome (proteinuria often exceeding 3 g per day) and progressive chronic kidney disease. Hepatic amyloidosis causes hepatomegaly that may be massive, with elevated alkaline phosphatase as the characteristic laboratory finding while transaminases remain typically normal.

Neurologic involvement includes peripheral neuropathy that is axonal and painful, autonomic neuropathy manifesting as orthostatic hypotension, gastrointestinal dysmotility, and erectile dysfunction, and bilateral carpal tunnel syndrome, which may be an early presenting sign. Gastrointestinal manifestations include macroglossia, which is present in 10 to 15% of patients and is pathognomonic when present, as well as GI bleeding, malabsorption, and dysmotility. Soft tissue involvement produces periorbital purpura (the classic "raccoon eyes," especially after coughing or Valsalva maneuver), the shoulder pad sign from amyloid infiltration of periarticular tissues, and cutaneous papules. Coagulopathy may result from factor X deficiency caused by adsorption of factor X onto amyloid fibrils, acquired von Willebrand syndrome, and hyperfibrinolysis.

### Diagnosis

The diagnosis of AL amyloidosis should be suspected based on the constellation of clinical features described above. Screening begins with an abdominal fat pad aspirate with Congo red staining, which has a sensitivity of 70 to 80%. Definitive diagnosis requires tissue biopsy of the involved organ, such as endomyocardial biopsy for cardiac amyloidosis or renal biopsy for renal amyloidosis. Amyloid typing by mass spectrometry of the deposited material is essential to distinguish AL from ATTR and other amyloid types, as immunohistochemistry is less reliable and mistyping can lead to fundamentally incorrect treatment. Exclusion of ATTR amyloidosis is critical and can be accomplished with a technetium-99m pyrophosphate cardiac scan, which is positive in ATTR but negative in AL amyloidosis, along with genetic testing for hereditary ATTR (TTR gene mutations).

### Staging (Mayo 2012 System)

The Mayo 2012 staging system is based on cardiac biomarkers and stratifies patients into four stages. One point each is assigned for BNP of 81 pg/mL or greater (or NT-proBNP of 332 pg/mL or greater), troponin T of 0.025 ng/mL or greater (or elevated high-sensitivity troponin), and a difference between involved and uninvolved free light chain (dFLC) of 18 mg/dL or greater. Stage I (0 points) carries a median overall survival of approximately 95 months. Stage II (1 point) has a median overall survival of approximately 60 months. Stage III (2 points) has a median overall survival of approximately 24 months. Stage IV (3 points) has a median overall survival of only approximately 6 months, underscoring the urgency of early diagnosis and rapid treatment initiation.

| Mayo 2012 Stage | Points | Criteria (1 point each) | Median OS |
|---|---|---|---|
| I | 0 | BNP <81 pg/mL (NT-proBNP <332), TnT <0.025 ng/mL, dFLC <18 mg/dL | ~95 months |
| II | 1 | One elevated biomarker | ~60 months |
| III | 2 | Two elevated biomarkers | ~24 months |
| IV | 3 | All three elevated | ~6 months |

<image>A comprehensive diagnostic and clinical presentation diagram for AL amyloidosis. In the center, show a plasma cell producing misfolded light chains that form amyloid fibrils (depict the fibril structure with beta-sheet conformation). Radiating outward, show the major organ systems affected: Heart (thickened walls on echocardiogram, low voltage on ECG, diastolic dysfunction, BNP elevation), Kidneys (nephrotic syndrome, proteinuria), Liver (hepatomegaly, elevated alk phos), Nervous System (peripheral neuropathy, autonomic dysfunction, carpal tunnel), GI (macroglossia, malabsorption), Soft Tissue (periorbital purpura, shoulder pad sign). For each organ, include a small clinical image or diagram showing the characteristic finding. At the bottom, show the diagnostic pathway: Congo red stain (apple-green birefringence under polarized light) → mass spectrometry typing → distinguish from ATTR (Tc-99m PYP scan). Include the Mayo 2012 staging system with biomarker cutoffs. Medical education poster format with anatomical illustrations.</image>

### Treatment

#### Transplant-Eligible (Stage I-II, Age <70, Adequate Organ Function)

High-dose melphalan at 140 to 200 mg/m2 followed by autologous hematopoietic stem cell transplantation is an effective treatment for eligible patients, with the melphalan dose adjusted based on cardiac and renal function. This approach achieves complete response rates of 30 to 40%, and transplant responders enjoy a median overall survival exceeding 10 years. Transplant-related mortality has improved substantially to 2 to 5% at experienced centers, compared to historical rates of 10 to 15%, reflecting improved patient selection criteria. Strict eligibility requirements exclude patients with advanced cardiac amyloidosis (NYHA class IV, troponin T above 0.06), estimated GFR below 30 mL/min (relative contraindication), and severe autonomic neuropathy.

#### Transplant-Ineligible or Deferred

Dara-VCd (daratumumab plus bortezomib, cyclophosphamide, and dexamethasone) is the current standard of care for first-line treatment of AL amyloidosis, as established by the ANDROMEDA trial. This regimen demonstrated a hematologic complete response rate of 53% compared to 18% with VCd alone, along with markedly superior organ response rates: cardiac response of 42% versus 22% and renal response of 53% versus 24%. Dara-VCd is the standard both for transplant-eligible patients as induction therapy and for transplant-ineligible patients as definitive treatment. The regimen consists of subcutaneous daratumumab (Darzalex Faspro) combined with VCd for 6 cycles, followed by daratumumab maintenance every 4 weeks. VCd (bortezomib, cyclophosphamide, and dexamethasone) was the prior standard and remains an option if daratumumab is unavailable. Melphalan-dexamethasone is reserved for frail patients who cannot tolerate VCd.

#### Response Assessment

Hematologic response is measured by the reduction in the difference between involved and uninvolved free light chains (dFLC). A complete response requires a normal free light chain ratio, negative immunofixation electrophoresis, and negative bone marrow plasma cells. A very good partial response requires a dFLC below 40 mg/L. Hematologic response is the driver of organ improvement. Organ responses are assessed by specific criteria: cardiac response requires a decrease in NT-proBNP of at least 30% and at least 300 pg/mL, while renal response requires a decrease in proteinuria of at least 30% or 50% without a decline in creatinine clearance. A critically important concept is that organ responses lag behind hematologic responses by months, and clinicians must exercise patience in assessing treatment efficacy.

#### Relapsed/Refractory

Treatment options for relapsed or refractory AL amyloidosis include immunomodulatory agent-based regimens such as lenalidomide-dexamethasone and pomalidomide-dexamethasone, with the caveat that lenalidomide can elevate NT-proBNP independently of cardiac worsening, complicating response assessment. Ixazomib-dexamethasone provides an oral proteasome inhibitor-based alternative. Investigational anti-fibril antibodies represent an emerging approach: birtamimab, an anti-amyloid fibril antibody, was evaluated in the VITAL trial, which was negative overall, although subset analysis suggested potential benefit in Mayo stage IV disease. CAEL-101, another anti-amyloid fibril antibody, is undergoing clinical trials for cardiac AL amyloidosis.

## Key Clinical Pearls
- MYD88 L265P is present in >90% of WM; its absence should prompt reconsideration of the diagnosis (marginal zone lymphoma with IgM is the main mimic)
- IgM flare with rituximab can precipitate hyperviscosity crisis; plasmapheresis first if IgM >4 g/dL before starting rituximab-containing therapy
- Zanubrutinib is preferred over ibrutinib for WM based on the ASPEN trial (comparable efficacy, fewer cardiovascular and hemorrhagic complications)
- AL amyloidosis typing by mass spectrometry is ESSENTIAL; IHC mistyping can lead to incorrect treatment (e.g., treating ATTR amyloidosis with chemotherapy)
- Dara-VCd (ANDROMEDA) is the new standard first-line for AL amyloidosis; the addition of daratumumab has dramatically improved hematologic and organ response rates
- Cardiac stage IV AL amyloidosis has a median survival of ~6 months; early recognition and rapid initiation of effective therapy is critical

## References
1. Castillo JJ, et al. Consensus treatment recommendations from the tenth International Workshop for Waldenstrom Macroglobulinaemia. Lancet Haematol. 2020;7(11):e827-e837.
2. Tam CS, et al. Zanubrutinib versus ibrutinib in patients with Waldenstrom macroglobulinaemia (ASPEN). Lancet Haematol. 2020;7(12):e946-e957.
3. Kastritis E, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis (ANDROMEDA). N Engl J Med. 2021;385(1):46-58.
4. Dispenzieri A, et al. Mayo staging system for light chain amyloidosis. J Clin Oncol. 2004;22(18):3751-3757.
5. Quock TP, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv. 2018;2(10):1046-1053.