Waldenström macroglobulinemia: biology, genetics, and therapy

Figures & data

Table 1 Comparison of IgM monoclonal gammopathiesa

Characteristic	IgM MGUS	Smoldering WM	WM	IgM multiple myeloma	IgM amyloidosis	Splenic marginal zone lymphoma
Serum IgM gammopathy	<3 g/dL	≥3 g/dL	Any level	Any level	Any level	Low level
Bone marrow LPL infiltrate	<10%	≥10%	≥10%b	≥10%; predominantly plasmacytic PCs	Normal or slight increase of PC or LPL	Intertrabecular and intrasinusoidal infiltrate
End-organ damage/symptoms	No	No	Yesc	Yesd	Yese	Yesf
Hyperviscosity	No	No	Yes	Uncommon	Uncommon	Uncommon
Differentiating genetic features and markers	6q deletion absent, MYD88 L265P (up to 80%)	6q deletion, MYD88 L265P (90%) CD56^−	6q deletion (30%–50%), IgH translocations absent, MYD88 L265P (90%) CD56^− CD25^+ (88%) CD103^−	May have t(11;14) or other IgH translocations, MYD88 L265P negative CD56^+, CD138^+ CD19^–, CD45^−	May have t(11;14)	+3q (19%) and +5q (10%); MYD88 L265P negative CD22^+, CD11c^+, CD25^– Del 7q (19%) CD25^+ (44%) CD103^+ (40%)
Risk of transformation	1.5% per year	12% per year for the first 5 years, 68% within 10 years	5%–10% risk for DLBCL	N/A	N/A	13%–19% lifetime risk in small series

Notes:

a The table lists a few important differential characteristics of IgM monoclonal gammopathies. IgM paraprotein can be present in virtually all B-cell lymphoproliferative disorders;

b Mayo Clinic criteria requires at least 10% of bone marrow involvement by LPL, whereas the Second International Workshop on WM (IWWM-2) eliminated the requirement for a minimum amount of marrow involvement.

c Constitutional symptoms: hepatosplenomegaly, lymphadenopathy, anemia, hyperviscosity, solid organ involvement, rarely lytic lesions.

d CRAB features (hyperCalcemia, Renal failure, Anemia, and Bone lesions);

e Organs typically involved are kidneys, heart, nerves, tongue, gastrointestinal tract, and liver. Patients with IgM amyloid light-chain (AL) amyloidosis have higher frequency of pulmonary, lymph node, peripheral nerve involvement, and lower cardiac involvement. Concentration of free light chain tends to be lower than in non-IgM AL amyloidosis;

f Primarily involves spleen; lymphadenopathy is rare. Reprinted from Blood Rev, 29(5), Kapoor P, Paludo J, Vallumsetla N, Greipp PR, Waldenstrom macroglobulinemia: what a hematologist needs to know, 301–319,¹⁵ copyright 2015, with permission from Elsevier.

Abbreviations: DLBCL, diffuse large B-cell lymphoma; IgM, immunoglobulin M; LPL, lymphoplasmacytic lymphoma; MGUS, monoclonal gammopathy of undetermined significance; N/A, not applicable; PC, plasma cell; WM, Waldenström macroglobulinemia; IgH, immunoglobulin heavy locus.

Table 2 Characteristics of IgM or direct Waldenström macroglobulinemia cell infiltration–related morbidities

Pathophysiology	Clinical feature
Cell infiltration related
Bone marrow (100%)	Anemia
	Thrombocytopenia
	Neutropenia
Extramedullary hematopoietic tissues (25%)	Lymphadenopathy
	Hepatomegaly
	Splenomegaly
Lung (4%)	Nodules or diffuse infiltrates
	Pleural effusion
CNS (rare)	Bing–Neel syndrome
Cell infiltration + IgM paraprotein mediated
Kidney (4%)	Infiltration of neoplastic cells
	Perirenal mass
	Bence Jones proteinuria
	Cast nephropathy
	Amyloidosis
	Light-chain deposition disease
	Cryoglobulinemia
GI (4%)	Malabsorption
	Diarrhea
	Mucosal bleeding
Skin (3%)	Cutaneous plaques
	Schnitzler syndrome
IgM paraprotein mediated
Hyperviscosity (35%)	Bleeding
	Abnormal funduscopy
	Visual symptoms
	Headaches
	Altered mental status (rare)
	Stroke (rare)
IgM-related neuropathy (up to 40%)	Typical phenotype includes peripheral symmetric, predominantly sensory, with pronounced vibration but mild pin prick loss, ataxia, and tremor
Cryoglobulinemia (asymptomatic in up to 20% of WM; symptomatic ≤5%)	Raynaud phenomenon/acrocyanosis
	Peripheral neuropathy
	Purpura
	Skin ulceration or necrosis
	Arthralgia
	Glomerulonephritis-related hematuria
Cold agglutinin hemolytic anemia (10%)	Hemolytic anemia (usually hemoglobin is >7 g/dL)

Notes: Reprinted from Blood Rev, 29(5), Kapoor P, Paludo J, Vallumsetla N, Greipp PR, Waldenstrom macroglobulinemia: what a hematologist needs to know, 301–319,¹⁵ copyright 2015, with permission from Elsevier.

Abbreviations: CNS, central nervous system; GI, gastrointestinal; WM, Waldenström macroglobulinemia; IgM, immunoglobulin M.

Table 3 Selected trials in Waldenström macroglobulinemia

Therapy	Patient population	N	OS	PFS (months)	TTP (months)	Response rates (%)
						ORR	CR	VGPR	PR	MR
Rituximab^Citation46,Citation48	TN	34	85% at 5 years	51% at 2 years	30	53	0	–	35	18
	R/R	35	48% at 5 years	46% at 2 years	32	51	0	–	20	31
Rituximab-extended dose schedule^Citation47	R/R	29	–	–	14	66	0	–	48	17
Bendamustine–rituximab R-CHOP^Citation50	R/R	17	–	–	–	100	53	–	30	–
Bendamustine–rituximab	TN	22	–	70	–	95	–	–	–	–
R-CHOP^Citation51		19		28		95
DRC^Citation52,Citation53	TN	72	90% at 2 years, 47% at 8 years	67% at 2 years, 45% at 3 years	35	83	7	–	67	9
Bortezomib^Citation54	TN and R/R	27	–	–	7	85	0	–	48	37
Bortezomib + rituximab^Citation55	TN	26	96% at 1 years	NR	NR	89	4	4	58	23
Bortezomib + rituximab^Citation56	R/R	37	94% at 1 years	16	16	81	3	3	46	30
BDR^Citation57	TN	59	82% at 3 years	42	–	85	3	7	58	17
BDR^Citation58	TN	23	100% at 2 years	78% at 2 years	NR	96	13	22	48	13
Idelalisib^Citation59	R/R	10	–	–	–	80	–	–	–	–
ABT-199^Citation60	R/R	4	–	–	–	100	–	–	100	–
Ibrutinib^Citation70	R/R	63	95% at 2 years	69% at 2 years	9.6	90	0	16	57	17

Abbreviations: BDR, bortezomib, dexamethasone, rituximab; CR, complete response; DRC, dexamethasone, rituximab, cyclophosphamide; m, months; MR, minor response; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R/R, relapsed or refractory; TN, treatment naïve; TTP, time to progression; VGPR, very good partial response; NR, not reached.

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