CLINICAL MANIFESTATIONS

 

 

EXTRAMEDULLARY DISEASE

An extramedullary plasmacytoma is a plasma cell neoplasm that arises outside the bone marrow, for example in skin, lymph nodes, pleural cavities, liver, pancreas, kidneys, and CNS.
It occurs in about 15% of myeloma patients, and it is associated with a highly aggressive course.
Although BRAF mutation is present in only 3% of patients with multiple myeloma, it is more frequent in patients with extramedullary disease.

The most frequent location of primary extramedullary plasmacytomas is the upper respiratory tract.

 

Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogenetics.
Haematologica. 2008 Apr;93(4):623-6.
Bink K, Haralambieva E, Kremer M, Ott G, Beham-Schmid C, de Leval L, Peh SC, Laeng HR, Jütting U, Hutzler P, Quintanilla-Martinez L, Fend F.
These authors performed FISH in 38 cases of primary extramedullary plasmacytoma. 14 cases (37%) contained IgH breaks. 6 patients had a t(4;14) translocation. Loss of 13q was present in 40%, and chromosomal gains in 82%. The cytogenetics in extramedullary plasmacytomas are similar to those of MM, except for the absence of t(11;14), is different.

Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients.
Ann Oncol. 2010 Feb;21(2):325-30.
Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M.
In this study of 1003 consecutive myeloma patients, EMD was present in 13% of cases, 7% at the time of diagnosis, and 6% during the course of the disease. EMD was associated with worse prognosis (shorter OS and EFS). The use of stem cell transplant and novel agents did not seem to increase the risk of EMD.

Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse.
Leuk Lymphoma. 2013 Jul;54(7):1459-64.
Papanikolaou X, Repousis P, Tzenou T, Maltezas D, Kotsopoulou M, Megalakaki K, Angelopoulou M, Dimitrakoloulou E, Koulieris E, Bartzis V, Pangalis G, Panayotidis P, Kyrtsonis MC.
In this retrospective series of 303 myeloma patients, there were 28 cases (9%) of relapse with extramedullary disease. These patients had a poor outcome, and their median overall survival was significantly less than in other patients (38 vs 59 months, p<0.01).

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse.
Haematologica. 2014 Feb;99(2):360-4.
Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, Sandecka V, Adam Z, Krejci M, Kuglik P, Hajek R.
Among 226 patients with relapsed myeloma, purely extramedullary disease was observed in 32 (14%). These patients had a poor prognosis, with median overall survival of 30 months from diagnosis.

Features of extramedullary disease of multiple myeloma: high frequency of p53 deletion and poor survival: a retrospective single-center study of 834 cases.
Clin Lymphoma Myeloma Leuk. 2015 May;15(5):286-91.
Deng S, Xu Y, An G, Sui W, Zou D, Zhao Y, Qi J, Li F, Hao M, Qiu L.
Among 834 consecutive MM patients in a single center in China, extrameduallary disease was found in 4.8% of cases at the time of diagnosis, and in 3.4% during the course of the disease. Patients with extrameduallary disease had a higher prevalence of p53 deletion at FISH (35% vs. 12%), worse time to progression (12 vs 25 months), and worse median survival (16.5 vs 40 months). At multivariate analysis, the presence of EMD remained an independent adverse prognostic factor.

 

SINONASAL

Sinonasal extramedullary plasmacytoma: a systematic review of 175 patients.
D'Aguillo C1, Soni RS, Gordhan C, Liu JK, Baredes S, Eloy JA.
Int Forum Allergy Rhinol. 2014 Feb;4(2):156-63.

 

THORACIC

Extramedullary plasmacytoma presenting with myasthenia gravis and mediastinal mass.
Ann Thorac Surg. 2000 Oct;70(4):1390-2.
Ahmed AR, Marchbank AJ, Nicholson AG, Wotherspoon AC, Ladas GP.
This is a case report of a 68-year-old woman who presented with myasthenia gravis and an anterior mediastinal mass. She was found to have an extramedullary plasmacytoma in the thymus with extracellular light chain deposition.

An unusual presentation of plasma cell dyscrasias: cardiac tamponade due to myelomatous infiltration.
Leuk Lymphoma. 2002 Jan;43(1):145-8.
Arat M, Ulusoy V, Demirer T, Uysal AV, Ozcan M, Dinçer S, Ilhan O, Koç H.
These authors report 3 cases of MM with pericardial involvement. The fluid obtained by pericardiocentesis showed infiltration with plasma cells in 1 of the 3 patients. In the other two patients the pericardial involvement was proven by biopsy. All these 3 patients died of progressive disease without any response to chemotherapy.

Malignant pleural effusion of multiple myeloma: prognostic factors and outcome.
Leuk Lymphoma. 2005 Aug;46(8):1137-42.
Kamble R, Wilson CS, Fassas A, Desikan R, Siegel DS, Tricot G, Anderson P, Sawyer J, Anaissie E, Barlogie B.
Approximately 80 cases of malignant pleural effusion (MPE) in MM have been reported. These authors reviewed 11 MM patients with MPE. All patients had high-risk disease and complex karyotype including -13 in 9 cases. Patients died at median of 4 months from onset of MPE despite aggressive therapeutic approaches such as stem cell transplant.

 

GI

CT features of abdominal plasma cell neoplasms.
Eur Radiol. 2005 Aug;15(8):1705-12.
Monill J, Pernas J, Montserrat E, Pérez C, Clavero J, Martinez-Noguera A, Guerrero R, Torrubia S.
This study describes the CT features of abdominal plasma cell neoplasms in 11 patients with plasma cell neoplasms and abdominal involvement. MM was found in 7 patients and extramedullary plasmacytoma in 4 patients. All patients with MM had other areas of extramedullary involvement, including the perirenal space (4), retroperitoneal and pelvic lymph nodes (3), peritoneum (3), liver (2), subcutaneous tissues (2) and kidney (1).

Clinical and biological features of multiple myeloma involving the gastrointestinal system.
Haematologica. 2006 Jul;91(7):964-7.
Talamo G, Cavallo F, Zangari M, Barlogie B, Lee CK, Pineda-Roman M, Kiwan E, Krishna S, Tricot G.

This study describes 24 cases of MM with involvement of the gastrointestinal system. MM involving the GI tract was associated with adverse biological features (high LDH levels, plasmablastic morphology, and unfavorable karyotype) and with short-lasting remissions, even after aggressive treatment. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, but the median progression-free survival was only 4 months.

 

GU

Case report: testicular secondary localization of a multiple myeloma.
Int Urol Nephrol. 2002;33(1):101-2.
de Rose AF, Giglio M, Naselli A, Truini M, Carmignani G.
This is a case report of a 61-year-old man who had recurrent MM and presented with a right testicular mass.

 

CNS

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.
Br J Haematol. 2002 Apr;117(1):103-8.
Fassas AB, Muwalla F, Berryman T, Benramdane R, Joseph L, Anaissie E, Sethi R, Desikan R, Siegel D, Badros A, Toor A, Zangari M, Morris C, Angtuaco E, Mathew S, Wilson C, Hough A, Harik S, Barlogie B, Tricot G.
Involvement of the CNS by MM is extremely rare. This study reports the characteristics of 18 such patients. Incidence was approximately 1%. There was an association with adverse biological features (unfavourable cytogenetic abnormalities, high tumour mass, plasmablastic morphology, additional extramedullary manifestations, and presence of circulating plasma cells). The outcome of these patients was very poor despite the use of aggressive treatment, including autologous stem cell transplant.

Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions.
Br J Haematol. 2004 Nov;127(3):280-4.
Chang H, Sloan S, Li D, Keith Stewart A.
These authors describe 9 patients with CNS MM. At FISH, 8 cases had p53 deletion and 4 had 13q deletion.

Myelomatous meningitis.
Cancer. 2008 Apr 1;112(7):1562-7.
Chamberlain MC, Glantz M.
This is a  case series of 14 patients with CSF-positive MM. Patients received intra-CSF chemotherapy + RT (to the brain in 5 patients and to the spine in 6 patients). There were 6 partial responses and 8 cases of progressive disease. The median duration of response was short, only 2.5 months (range: 0-6 months). 6 patients died because of progressive neurologic disease. 6-month neurologic disease progression-free survival rate was only 7%.

Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.
Br J Haematol. 2013 Aug;162(3):371-5.
Lee D, Kalff A, Low M, Gangatharan S, Ho P, Bajel A, Ritchie D, Grigg A, Spencer A.
The authors report 17 cases of myeloma involving the CNS. Interesting findings:
  - In 3 of 5 tested patients, free light chains in the CSF were found to be elevated.
  - Cytology of CSF became negative in 4 of 11 patients treated with intratechal chemotherapy.
  - Median overall survival from the diagnosis of CNS involvement was only 4 months.
  - Overall survival was better in 7 patients who received intratechal chemotherapy than in 10 patients who did not received it (20 vs 2 months, p=00.2).

Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents.
Br J Haematol. 2013 Aug;162(4):483-8.
Chen CI, Masih-Khan E, Jiang H, Rabea A, Cserti-Gazdewich C, Jimenez-Zepeda VH, Chu CM, Kukreti V, Trudel S, Tiedemann R, Tsang R, Reece DE.
The authors report 37 cases of myeloma with CNS involvement, either at diagnosis (24%) or at progression (76%). There was a high incidence of plasma cell leukemia (40%). Median overall survival was 4.6 months. Nine patients received a combination of intratechal chemotherapy (hydrocortisone, methotrexate/cytarabine), radiotherapy (cranial and/or spinal), and thalidomide/lenalidomide, and had a median OS of 17.1 months. The administration of D-PACE chemotherapy did not seem to improve survival. Of note, there is no evidence that bortezomib can cross the blood-brain barrier, but thalidomide certainly does, even because it is associated with sedative effects and CNS toxicity.

Patterns of central nervous system involvement in relapsed and refractory multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2014 Jun;14(3):211-4.
Abdallah AO, Atrash S, Shahid Z, Jameel M, Grazziutti M, Apewokin S, Kumar NS, Restrepo A, Waheed S, Van Rhee F, Heuck CJ, Johann D Jr, Barlogie B1, Usmani SZ.
This retrospective study identified 35 cases of myeloma involving the central nervous system (CNS) in a database of 3738 patients with multiple myeloma (= 0.9%) seen at the Myeloma Institute for Research and Therapy of the University of Arkansas between 1996 and 2012. The authors believe that the CNS involvement is due to either hematogenous spread of plasma cells, or direct spread of plasma cells from the lytic lesions in the skull. Prognosis was poor, because median survival after the diagnosis of CNS involvement was only 4 months.

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice.
Am J Hematol. 2016 Jun;91(6):575-80.
Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, Crusoe E, Silva Dias AL, Vij R, Fiala MA, Caers J, Rasche L, Nooka AK, Lonial S, Vesole DH, Philip S, Gangatharan S, Druzd-Sitek A, Walewski J, Corso A, Cocito F, Vekemans MC, Atilla E, Beksac M, Leleu X, Davila J, Badros A, Aneja E, Abildgaard N, Kastritis E, Fantl D, Schutz N, Pika T, Butrym A, Olszewska-Szopa M, Usnarska-Zubkiewicz L, Usmani SZ, Nahi H, Chim CS, Shustik C, Madry K, Lentzsch S, Swiderska A, Helbig G, Guzicka-Kazimierczak R, Lendvai N, Waage A, Andersen KT, Murakami H, Zweegman S, Castillo JJ.
This is a retrospective study conducted in 38 centers from 20 countries, and it included 172 patients with myeloma involving the CNS system. The median overall survival from the onset of CNS involvement was 7 months (2 months without treatment, and 8 months with treatment).

 

Malignant plasma cells in the cerebrospinal fluid (CSF) of a patient with myelomatous meningitis (my personal archive):

 

 

 

SKIN

Cutaneous plasmacytomas in myeloma. Relationship to tumor cell burden.
Arch Dermatol. 1978 Dec;114(12):1784-7.
Alberts DS, Lynch P.
These authors describe 2 MM patients who developed cutaneous plasmacytomas late in the course of their disease. Their systemic plasma cell tumor burden was large, estimated at approximately 3 kg in mass, corresponding to 2-3 x 10(12) cells. The development of cutaneous plasmacytomas in patients with multiple myeloma is usually a late event in the course of MM and it is an adverse prognostic sign.

Metastatic cutaneous plasmacytoma: a case report associated with IgA lambda multiple myeloma and a review of the literature of metastatic cutaneous plasmacytomas associated with multiple myeloma and primary cutaneous plasmacytomas.
J Dermatol. 1999 Sep;26(9):587-94.
Kato N, Kimura K, Yasukawa K, Aikawa K.
Among 83 cases of MM with metastatic cutaneous plasmacytomas, the secreted M protein was: IgG (52%), IgA (23%), IgD (16%), and Bence-Jones proteins (6%). There was a disproportionately high frequency of IgD lambda MM, because IgD MM represents only about 2% of MM cases. Among 18 cases of primary cutaneous plasmacytomas, the secreted M protein was: IgG (56%), IgA (11%), Bence-Jones proteins (17%), but no IgD.

Cutaneous involvement in multiple myeloma: a clinicopathologic, immunohistochemical, and cytogenetic study of 8 cases.
Arch Dermatol. 2003 Apr;139(4):475-86.
Requena L, Kutzner H, Palmedo G, Calonje E, Requena C, Pérez G, Pastor MA, Sangueza OP.
This is a case series of 8 patients with MM and cutaneous involvement. The cutaneous lesions consisted of multiple erythematous or violaceous nodules or plaques. 2 different histopathologic patterns were identified: nodular and diffuse interstitial. At IHC, neoplastic plasma cells were positive for CD79a, CD138, and epithelial membrane antigen, and variably positive for VS38c and CD43. 5 cases produced IgA-lambda proteins, 2 cases IgG-kappa; and 1 case IgA-kappa. Prognosis was poor, because all 8 patients died a few months after the development of cutaneous involvement, despite aggressive chemotherapy.

Skin involvement in immunoglobulin E multiple myeloma.
J Clin Oncol. 2009 Feb 1;27(4):637-8.
Wozney JL, Ahmed F, Bayerl MG, Ehmann WC, Talamo G.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.
J Am Acad Dermatol. 2016 May;74(5):878-84.
Malysz J, Talamo G, Zhu J, Clarke LE, Bayerl MG, Ali L, Helm KF, Chung CG.

 

Extramedullary involvement of the skin by multiple myeloma. The lesion enlarged over a few weeks (my personal archive):

 

 


PLASMA CELL LEUKEMIA

 

Plasma cell leukemia (PCL) is defined by the following findings in the peripheral blood:
  - Absolute plasma cell count of at least 2,000/
mL
  - >20% plasma cells in the differential white cell count

It occurs in about 2% of newly diagnosed myeloma.
Primary PCL
: leukemia present at diagnosis.
Secondary PCL
: leukemic transformation of a previously diagnosed myeloma
.

Clinical manifestations are similar to those of multiple myeloma, but they can also include splenomegaly and hepatomegaly.

Compared with MM, PCL cells have reduced expression of CD56 (NCAM, neural cell adhesion molecule).

The incidence of chromosomal abnormalities such as -13 is very high.

Prognosis of PCL is significantly worse than in myeloma, and survival is often measured in weeks or months instead of years.
Patients with primary PCL have a better prognosis than patients with secondary PCL.

 

Plasma cell leukemia: an evaluation of response to therapy.
Am J Med. 1987 Dec;83(6):1062-8.
Noel P, Kyle RA.
This is a report of a series of 43 patients with plasma cell leukemia, The 25 patients with primary plasma cell leukemia had a median survival of 6.8 months, and the 18 patients with secondary plasma cell leukemia had a median survival of 1.3 months.

Genetic aberrations and survival in plasma cell leukemia.
Leukemia. 2008 May;22(5):1044-52.
Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA, Chng WJ, Ketterling RP, Gertz MA, Henderson K, Greipp PR, Dispenzieri A, Lacy MQ, Rajkumar SV, Bergsagel PL, Stewart AK, Fonseca R.
This study reports the cytogenetic findings of 80 patients with plasma cell leukemia. Patients with primary PCL had a median age at presentation younger than those with secondary plasma cell leukemia (55 vs 65 years). The survival of patients with primary plasma cell leukemia was better than that in secondary plasma cell leukemia (11.1 vs 1.3 months).

How I treat plasma cell leukemia.
Blood. 2012 Sep 20;120(12):2376-89.
van de Donk NW, Lokhorst HM, Anderson KC, Richardson PG.
[Review]
This publication proposed response criteria for PCL.

Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients.
Clin Lymphoma Myeloma Leuk. 2014 Apr;14(2):131-139.e1.
Vij R, Mazumder A, Klinger M, O'Dea D, Paasch J, Martin T, Weng L, Park J, Fiala M, Faham M, Wolf J.
With a sequencing-based method, the authors could detect malignant plasma cells in the peripheral blood of myeloma patients with very high sensitivity, at levels <1:1,000,000 WBC. The vast majority of patients (44/46, 96%) of patients has detectable circulating plasma cells, and the levels in the peripheral blood were approximately 11 times lower than levels in the bone marrow.

Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.
Haematologica. 2017 Jun;102(6):1099-1104.
Granell M, Calvo X, Garcia-Guiñón A, Escoda L, Abella E, Martínez CM, Teixidó M, Gimenez MT, Senín A, Sanz P, Campoy D, Vicent A, Arenillas L, Rosiñol L, Sierra J, Bladé J, de Larrea CF; GEMMAC (Grup per l’estudi del mieloma i l’amiloïdosi de Catalunya).
In this study, 482 patients with newly diagnosed myeloma were stratified into 4 groups, based on the review of the peripheral blood smear:
  - 0% circulating plasma cells (382 patients, 79%). Median survival was 47 months.
  - 1-4% circulating plasma cells (83 patients, 17%). Median survival was 50 months.
  - 5-20% circulating plasma cells (12 patients, 2.5%). Median survival was 6 months.
  - >20% circulating plasma cells (5 patients, 1%). This group represents those patients who are traditionally diagnosed with plasma cell leukemia. Median survival was 14 months.
 Of note, the prognosis of patients with 5-20% circulating plasma cells was similar to that of patients with plasma cell leukemia (i.e., >20%). Instead, the presence of 1-4% circulating plasma cells had no adverse impact on prognosis. 

 

PRIMARY PLASMA CELL LEUKEMIA

Primary plasma cell leukaemia.
Br J Haematol. 1994 Dec;88(4):754-9.
Dimopoulos MA, Palumbo A, Delasalle KB, Alexanian R.
This is a report of a series of 27 patients with primary plasma cell leukemia. Compared with patients with myeloma, patients with PCL had more frequent:
  - Thrombocytopenia
  - High LDH
  - Extraosseous involvement
  - Hypodiploidy
  - Complex cytogenetic abnormalities
Treatment with melphalan-prednisone was ineffective (median survival: 2 months). Treatment with more intensive chemotherapy produced a median survival of 20 months.

Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics.
Blood. 1999 Feb 1;93(3):1032-7.
García-Sanz R, Orfão A, González M, Tabernero MD, Bladé J, Moro MJ, Fernández-Calvo J, Sanz MA, Pérez-Simón JA, Rasillo A, Miguel JF.
This is a report of a series of 26 patients with primary plasma cell leukemia.

Primary plasma cell leukaemia: a report of 18 cases.
Leuk Res. 2001 Feb;25(2):103-7.
Costello R, Sainty D, Bouabdallah R, Fermand JP, Delmer A, Diviné M, Marolleau JP, Gastaut JA, Olive D, Rousselot P, Chaïbi P.

Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myélome and the Groupe Français de Cytogénétique Hématologique.
Blood. 2001 Feb 1;97(3):822-5.
Avet-Loiseau H, Daviet A, Brigaudeau C, Callet-Bauchu E, Terré C, Lafage-Pochitaloff M, Désangles F, Ramond S, Talmant P, Bataille R.
Cytogenetic analysis of patients with primary plasma cell leukemia showed an abnormal karyotype in 23 of 34 patients, usually with numerous numerical and structural abnormalities. Monosomy 13 was present in 68% of cases.

Intermediate doses of melphalan and dexamethasone are better than vincristine, adriamycin, and dexamethasone (VAD) and polychemotherapy for the treatment of primary plasma cell leukemia.
Ann Hematol. 2002 Jul;81(7):362-7.
Vela-Ojeda J, García-Ruiz Esparza MA, Rosas-Cabral A, Padilla-González Y, García-Chávez J, Tripp-Villanueva F, Sánchez-Cortés E, Ayala-Sánchez M, García-León LD, Montiel-Cervantes L, Rubio-Borja ME.
In this study of 24 patients with primary plasma cell leukemia, 12 patients received treatment with VAD (vincristine, adriamycin, and dexamethasone), 8 with M-80 (melphalan 80 mg/m2 PO + dexamethasone), and 4 with VMCPA (vincristine, melphalan, cyclophosphamide, prednisone, and adriamycin). Median overall survival was 60 days.

Primary plasma cell leukemia: report of 17 new cases treated with autologous or allogeneic stem-cell transplantation and review of the literature.
Am J Hematol. 2005 Apr;78(4):288-94.
Saccaro S, Fonseca R, Veillon DM, Cotelingam J, Nordberg ML, Bredeson C, Glass J, Munker R.

Primary plasma cell leukemia: a Surveillance, Epidemiology, and End Results database analysis between 1973 and 2004.
Cancer. 2009 Dec 15;115(24):5734-9.
Ramsingh G, Mehan P, Luo J, Vij R, Morgensztern D.
This is a case series of 291 patients with PCL. Median age was 67 years (range, 19-98 years). Median overall survival was 4 months. The long-term outcome was poor: the 2-year survival was 14%, and the 5-year survival was 6.4%.

Primary plasma cell leukemia and autologous stem cell transplantation.
Haematologica. 2010 May;95(5):804-9.
Drake MB, Iacobelli S, van Biezen A, Morris C, Apperley JF, Niederwieser D, Björkstrand B, Gahrton G; European Group for Blood and Marrow Transplantation and the European Leukemia Net.
This is a retrospective analysis of 272 patients with primary plasma cell leukemia treated with autologous stem cell transplantation between 1980 and 2006. Median overall survival was 25.7 months, inferior to that of 20,844 myeloma patients (62.3 months).

 

 


Giampaolo Talamo, M.D.