IMMUNE SUPPRESSION

Increased susceptibility to infections, especially from encapsulated organisms.
Streptococcus pneumoniae infection is common.
Haemophilus infection and herpes zoster are common among myeloma patients.

The immune suppression is due to:
 1. Impaired production of normal immunoglobulins
 2. Decreased CD4 counts
Immune suppression is very important, since two thirds of patients ultimately die of infections.

 

Pictures of herpes zoster (shingles) in patients with multiple myeloma (my personal archive):

 

         

 

 

Infections in patients with multiple myeloma.
Semin Hematol. 2009 Jul;46(3):277-88.
Nucci M, Anaissie E.
[Review]

Risks, severity and timing of infections in patients with multiple myeloma: a longitudinal cohort study in the era of immunomodulatory drug therapy.
Br J Haematol. 2015 Oct;171(1):100-8.
Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA.

 

 


 

AMYLOIDOSIS (10%)

See specific section

 

EXTRAMEDULLARY DISEASE

PLASMA CELL LEUKEMIA

See specific section.

 

ACUTE LEUKEMIA

It complicates the course of MM in 5% of treated patients.

 

 


 

Systemic manifestations of monoclonal gammopathy:
  - Hyperviscosity syndrome
  - Neuropathy
       Anti-MAG syndrome
  - Skin disorders
  - POEMS syndrome
  - Interference with assay methods
       Pseudohyponatremia

 

 

HYPERVISCOSITY SYNDROME (<5%)

Hyperviscosity syndrome is caused by high concentrations of paraproteins, typically with IgG >6,000 mg/dL or IgA >4,000 mg/dL.
More common with IgG3 paraprotein.

1) Mucosal bleeding

The tendency to bleed is the most common symptom of hyperviscosity syndrome.
 - Spontaneous ecchymoses
 - Spontaneous gum bleeding
 - Epistaxis
 - Rectal bleeding
 - Menorrhagia
 - Persistent bleeding after minor procedures

2) Visual changes

Visual changes range from blurred vision to vision loss.
Ophthalmologist may detect dilated retinal veins, with sausage-like segmentation, and retinal hemorrhages.

3) Neurologic symptoms

Neurologic manifestations are frequent and varied.
 - Headaches
 - Vertigo
 - Ataxia
 - Nystagmus

 - Hearing loss
 - Paresthesias
 - Altered mental status: confusion, somnolence, stupor, coma
 - Seizures

4) Systemic and cardiorespiratory symptoms

 - Fatigue
 - Anorexia
 - Dyspnea, hypoxia
 - CHF
 - Volume overload: lower extremity edema, pulmonary edema, elevated JVP

 

 

POEMS SYNDROME (1%)

  Polyneuropathy
  Organomegaly
  Endocrinopathy
  M protein
  Skin changes: thickening, hyperpigmentation, hypertrichosis

POEMS syndrome is also called osteosclerotic myeloma.
The diagnosis is made with 2 major criteria + 1 minor criterion.
Major criteria:
  - Plasma cell dyscrasia (almost always lambda)
  - Polyneuropathy
Minor criteria:
  -Organomegaly, including lymphadenopathy
  - Endocrinopathy
  - Skin changes: thickening, hyperpigmentation, hypertrichosis
  - Osteosclerotic bone lesions
  - Castleman's disease
  - Papilledema
  - Peripheral edema, pleural effusion, ascites

 

POEMS syndrome: definitions and long-term outcome.
Blood. 2003 Apr 1;101(7):2496-506.
Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA, Fonseca R, Lust JA, Gertz MA.
This study describes 99 patients with POEMS syndrome. Clinical manifestations that appeared to be part of the syndrome included CHF, pulmonary hypertension, renal insufficiency, and thrombotic events. Median survival was 165 months.

Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome.
Blood. 2008 Aug 1;112(3):836-9.
Abe D, Nakaseko C, Takeuchi M, Tanaka H, Ohwada C, Sakaida E, Takeda Y, Oda K, Ozawa S, Shimizu N, Masuda S, Cho R, Nishimura M, Misawa S, Kuwabara S, Saito Y.

 

 


 

OTHER

 

Immunoglobulin A multiple myeloma presenting with Henoch-Schönlein purpura associated with reduced sialylation of IgA1.
Br J Haematol. 2003 Sep;122(6):915-7.
Van Der Helm-Van Mil AH, Smith AC, Pouria S, Tarelli E, Brunskill NJ, Eikenboom HC.
Henoch-Schönlein purpura is characterized by IgA1 depositions in blood vessels of the skin or in renal glomeruli. Serum IgA levels may be very high. These authors report 2 patients with IgA1 myeloma presenting with Henoch-Schönlein purpura.

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma.
Blood. 2004 Jul 1;104(1):40-2.
Ma CX, Lacy MQ, Rompala JF, Dispenzieri A, Rajkumar SV, Greipp PR, Fonseca R, Kyle RA, Gertz MA.
Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. These authors reviewed 32 patients with adult-acquired FS. At diagnosis, most patients had MGUS or smoldering myeloma. Their median serum creatinine was 2.0 mg/dL. Afteer a median follow-up of 65 months, 5 patients developed ESRD, and only 1 of 14 patients with MGUS progressed to MM. Therefore, FS associated with monoclonal gammopathy does not seem to increase the risk of progression to MM.

 

COAGULOPATHY

Thrombosis in multiple myeloma.
Expert Rev Anticancer Ther. 2007 Mar;7(3):307-15.
Zangari M, Elice F, Fink L, Tricot G.
[Review]

Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor.
Thromb Haemost. 2005 May;93(5):889-96.
Shinagawa A, Kojima H, Berndt MC, Kaneko S, Suzukawa K, Hasegawa Y, Shigeta O, Nagasawa T.
This study describes a patient with IgD-lambda MM who had a significant bleeding tendency. Both bleeding time and APTT were prolonged. Thee purified protein responsible for the aPTT prolongation was found to be a homodimer of the lambda light chain. The lambda dimer protein bound to the region of the A1 domain of vWF and interfered with the vWF-GPIb-alpha interaction.

A possible link between Trousseau's syndrome and tissue factor producing plasma cells.
Am J Hematol. 2009 Jun;84(6):382-5.
Shimizu K, Itoh J.
These authors described a patient with Trousseau's syndrome (recurrent, migratory superficial thrombophlebitis), and demonstrated elevated plasma tissue factor antigen levels and tissue factor production by the bone marrow clonal plasma cells.

Multiple myeloma presenting with acquired factor VIII inhibitor.
Int J Hematol. 2009 Sep;90(2):166-9.
Sari I, Erkurt MA, Ifran A, Kaptan K, Beyan C.

High incidence of arterial thrombosis in young patients treated for multiple myeloma: results of a prospective cohort study.
Blood. 2010 Jul 8;116(1):22-6.
Libourel EJ, Sonneveld P, van der Holt B, de Maat MP, Leebeek FW.
Among 195 patients with multiple myeloma, 11 (6%) developed arterial thrombosis. Most cases were seen during induction chemotherapy.

Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias.
Ann Hematol. 2016 May;95(6):945-57.
Dicke C, Schneppenheim S, Holstein K, Spath B, Bokemeyer C, Dittmer R, Budde U, Langer F.

Identification of a new potential mechanism responsible for severe bleeding in myeloma: immunoglobulins bind the heparin binding domain of antithrombin activating this endogenous anticoagulant.
Haematologica. 2016 Oct;101(10):e423-e426.
Martínez-Martínez I, González-Porras JR, Cebeira MJ, de Arriba F, Espín S, Bohdan N, Corrales FJ, Corral J, Vicente V.

 

SKIN

Cutaneous manifestations of multiple myeloma.
Arch Dermatol. 1991 Jan;127(1):69-74.
Kois JM, Sexton FM, Lookingbill DP.
This retrospective study reviews the cutaneous manifestations in 115 MM patients with skin biopsy. 5 patients had extramedullary plasmacytomas, 12 patients had ecchymoses without thrombocytopenia (2 of them had amyloidosis), and 1 patient had pyoderma gangrenosum.

The spectrum of cutaneous disease in multiple myeloma.
J Am Acad Dermatol. 2003 Apr;48(4):497-507.
Bayer-Garner IB, Smoller BR.
Dermatologic disorders associated with MM are:
 - Amyloidosis
 - Cryoglobulinemia
 - POEMS syndrome
 - Normolipemic plane xanthoma
 - Plasmacytoma
These authors reviewed 472 skin biopsy specimens form patients with MM. Diagnoses included: GVHD (120), neoplastic lesions (111; 73 malignant, 38 benign), nonspecific lesions (77), drug-related lesions (46), infectious lesions (41), papulosquamous lesions (18), bullous diseases (17), vasculitis (11), thrombocytopenia-related lesions (9), Sweet's syndrome (7), granulomatous dermatitis (6), cutaneous eruption of lymphocyte recovery (3), unrelated lesions (2), normolipemic plane xanthoma (1), amyloidosis (1), panniculitis (1), and alopecia cicatrisata (1).

Sweet syndrome in multiple myeloma: a series of six cases.
J Cutan Pathol. 2003 Apr;30(4):261-4.
Bayer-Garner IB, Cottler-Fox M, Smoller BR.
Sweet syndrome (SS) is a paraneoplastic syndrome characterized by fever, neutrophilia, erythematous painful plaques, and dermal neutrophilic infiltration. It is usually associated with acute myelogenous leukemia. These authors reviewed the pathology reports of 2357 patients with multiple myeloma, and they found 6 cases of SS. 5 of the 6 patients received G-SCF, and the sixth received GM-CSF. SS may be secondary to elevated levels of G-CSF.

Leukocytoclastic (small vessel) vasculitis in multiple myeloma.
Clin Exp Dermatol. 2003 Sep;28(5):521-4.
Bayer-Garner IB, Smoller BR.
The hallmark of leukocytoclastic vasculitis is palpable purpura. Its association with MM is rare. These authors reviewed the pathology reports of 2357 patients with MM, and they found 8 cases of leukocytoclastic vasculitis.

 

EYES

Ophthalmic manifestations of multiple myeloma.
Ophthalmologica. 2005 Jan-Feb;219(1):43-8.
Fung S, Selva D, Leibovitch I, Hsuan J, Crompton J.
Ophthalmic manifestations of MM are very rare. These authors describe 8 MM patients with ophthalmic manifestations: 4 patients had neuro-ophthalmic symptoms resulting in diplopia or visual disturbances, 3 patients had orbital involvement, and 1 patient had hyperviscosity retinopathy.

Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations.
Ophthalmology. 2015 Sep;122(9):1748-56.
Milman T, Kao AA, Chu D, Gorski M, Steiner A, Simon CZ, Shih C, Aldave AJ, Eagle RC Jr, Jakobiec FA, Udell I.

 

 


Giampaolo Talamo, M.D.