Table of contents :

Epidemiology Aetiology Pathogenesis Localizations solitary plasmocytoma of bone extramedullary plasmocytoma / soft tissue myeloma indolent myeloma plasma cell leukemia Symptoms & signs Laboratory examinations Therapy  Prognosis Web resources

Epidemiology (USA) : after age 50; peak at age 60; diagnosed annually in approximately 15,000 new patients in the USA, with a prevalence of approximately 50,000 patients^ref; incidence and mortality rates (per 100,000) 1993-1997 :

	male		female
	African American	white	African American	white
incidence	11.4	5.1	8.6	3.3
mortality	7.4	3.6	5.4	2.4

year of diagnosis/death	1976	1977	1978	1979	1980	1981	1982	1983	1984	1985	1986	1987	1988	1989	1990	1991	1992	1993	1994	1995	1996	1997
SEER incidence	4.2	4.1	3.9	3.9	4.0	4.0	4.3	4.3	4.4	4.2	4.3	4.8	4.4	4.3	4.6	4.9	4.8	4.5	4.5	4.4	4.5	4.4
US mortality	2.5	2.5	2.5	2.6	2.6	2.6	2.7	2.7	2.8	2.8	2.8	2.9	2.9	2.9	3.0	3.0	3.0	3.1	3.1	3.2	3.1	3.1
SEER mortality	2.8	2.6	2.5	2.8	2.5	2.7	2.6	2.8	2.7	3.0	2.6	2.6	2.9	3.1	2.9	3.1	3.2	3.2	3.1	3.1	3.1	3.0
1-yr	65.4	70.2	70.0	69.8	69.8	69.5	73.2	72.6	69.6	72.3	72.0	75.6	73.9	71.8	72.8	75.9	69.1	72.5	72.9	73.4	69.3
2-yr	49.3	52.0	54.8	54.1	54.8	55.6	56.2	56.1	55.6	58.9	57.1	59.4	60.1	58.3	57.1	60.6	56.3	58.2	58.4	56.3
3-yr	36.7	38.7	42.4	43.4	44.4	43.0	44.8	44.1	44.0	46.8	44.7	48.5	47.1	44.8	44.7	48.6	45.2	45.8	47.1
4-yr	31.5	30.7	33.0	33.3	34.2	35.0	37.2	36.4	34.8	36.4	35.5	38.1	39.0	36.1	38.7	38.7	34.3	36.6
5-yr	24.6	25.0	27.3	26.1	27.0	27.8	29.7	28.7	27.6	27.7	29.8	28.8	29.8	27.0	30.7	31.2	26.4
6-yr	19.0	21.1	21.6	20.1	21.2	23.1	21.6	23.2	21.1	22.7	23.9	23.6	24.5	21.8	24.5	24.7
7-yr	15.9	17.7	17.8	18.0	18.8	16.8	17.8	17.6	18.3	19.3	19.2	19.6	18.4	17.0	19.2
8-yr	12.4	15.4	15.1	15.4	15.3	14.4	14.6	14.2	13.8	17.0	17.8	16.5	15.5	13.6
9-yr	10.6	12.7	13.1	12.3	13.8	12.2	12.1	12.2	11.7	13.2	13.1	14.1	12.5
10-yr	9.5	11.4	12.1	10.2	11.5	9.9	11.4	10.5	9.9	11.5	12.5	13.2
11-yr	8.7	9.3	10.9	9.1	10.4	8.8	9.7	9.9	9.7	10.2	10.8
12-yr	8.1	8.7	10.3	8.0	9.4	7.4	8.6	9.0	8.6	9.7
13-yr	6.1	8.2	8.2	6.5	7.8	6.9	8.3	8.0	7.4
14-yr	5.2	7.9	7.9	5.8	6.0	6.6	7.2	7.3
15-yr	5.0	7.6	6.3	4.5	5.8	6.2	7.2
16-yr	5.0	6.6	6.3	3.9	5.3	3.4
17-yr	5.0	5.7	5.5	3.9	4.7
18-yr	4.4.	4.6	5.0	3.7
19-yr	3.6	4.5	4.5
20-yr	2.3	4.4
21-yr	2.3

• SEER (1973-1997) Incidence and Mortality
• Racial and Ethnic patterns of multiple myeloma (SEER 1973-1992)

• benzene
• chronic antigenic stimulation (CAS)
• HHV-8 DNA has been identified in phenotypically normal^ref bone marrow and peripheral blood adherent stromal cells (dendritic cells)^{ref1, ref2} but not in the neoplastic MM plasma cell population. It has been suggested that the cytokines expressed by HHV-8 gene, such as vIRF, vIL-8R and vIL-6, may play a role in the pathogenesis of multiple myeloma. In detection of HHV-8, nested-PCR is more sensitive than fluorescence quantitative PCR^ref. However, the majority of European investigators failed to find evidence to confirm this observation^{ref1, ref2, ref3}. Different explanations have been offered to account for inconsistencies in seroepidemiologic and virologic studies searching for an association of KSHV with MM, including the presence of viral variants. Indeed, Ma et al^ref reported unique KSHV open reading frame (ORF) 65 sequences that were detected exclusively in patients with MM but not in patients without MM who were seropositive for KSHV. Interestingly, in some MM patients, a mutation at the C-terminal end of ORF65 resulted in an extension of the ORF by 33 amino acids. These sequences were found only in samples from patients with MM and were suggested as a possible unique target of KSHV serologic immune responses in such patients, who lack seroreactivity against the "conventional" ORF65 protein : however these possibilities are unlikely, because very sensitive RT-PCR analyses, with a detection limit of 1 viral copy in 10 × 10³ cells, was performed by using primers specific for 3 different KSHV genes^{ref1, ref2}. To avoid detection by this RT-PCR, the virus in patients with MM would have to be changed in all these locations and represent a very distant relative of KSHV. Moreover, if all those KSHV proteins that have been shown to be targeted by humoral or cellular immune responses were either altered or completely absent in the virus associated with MM, the elusive infectious agent would likely be unrelated to the KSHV described by Chang et al in 1994^ref. Nevertheless, when the recently described ORF65 sequence unique to patients with MM was included in the ELISPOT analyses no specific responses were detected in any patient with MM. Although we cannot rule out the possibility that ongoing viral replication was insufficient to maintain detectable memory CTL responses against the lytic ORF65 protein, one would expect to detect at least some responses against the latent gene product of ORF73, which is required for viral genome persistence^{ref1, ref2}. The level of viral replication may be very low and not detectable with the sensitive RT-PCR method used. Such low-level viral replication could also lead to an antigenic load insufficient for induction of humoral and cellular immune responses. It remains unclear whether HHV-8 is consequentially associated with MM or only a regional opportunistic infection. Controversy still focuses on the role of specific HHV-8 strains involved in pathogenesis of MM^ref
• adiposity  : RR= 1.5 for BMI, 1.9 for weight, 2.0 for waist circumference, and 1.8 for hip circumference^ref
• familial MM : RR= 3.23 in first-degree relatives of female sex and also a 2-fold risk for other hematologic malignancies. Although evidence for an increased risk for MGUS was not documented in this series as it has been in other reports, this may be due to the fact that the relatives of MM patients were not systematically screened for the presence of paraproteins. Therefore the inference in this report about the familial risk of MGUS is rather weak. On the other hand, the authors identified 8 families in which the propositus had myelomatosis and at least one relative had MGUS and another gammopathy^{ref1, ref2}.

• translocations of the IgH gene locus, which leads to dysregulation of oncogenes at translocation partner regions (cyclin D1 at 11q13, FGFR3/MMSET at 4p16.3, c-MAF at 16q23, and cyclin D3 at 6p21)
• deletions of 13q14 (assessed with double color FISH), the site of a putative tumour suppressor gene, which is an adverse prognostic indicator (worse EFS and OS, higher relapse rate  patients with deletion 13q had a nearly 2 times higher risk of non surviving (HR: 1.94; 95% CI: 0.95-3.98, p=0.07) after dose-reduced allogeneic stem cell transplantation)
• epigenetic changes and activating mutations of oncogenes are usually associated with disease progression :
• mutations of N-RAS and K-RAS

study	KRAS2 mutations (expecially codon 12)		NRAS mutations (expecially mutations at codon 61 in a subset representing 12-100%ref)
	medullary disease, at diagnosis [at relapse] (%)	extramedullary disease	medullary disease, at diagnosis [at relapse] (%)	extramedullary disease
Neri et alref (1989)	2/43 [2/13]  (7)	NA	11/43 [4/13]  (26)	NA
Paquette et alref (1990)	0/17  (0)	NA	2/17  (11)	NA
Matozaki et alref (1991)	0/15  (0)	NA	4/15  (26)	NA
Tanaka et alref (1992)	0/10  (0)	NA	5/10  (50)	NA
Portier et alref (1992)	2/13  (15)	6/15  (40)	2/13  (15)	6/15  (40)*
Corradini et alref (1993)	0/77  (0)	1/13  (7)	7/77  (9)	3/13  (29)*
Millar et alref (1995)	0/18  (0)	NA	0/18  (0)	NA
Liu et alref (1996)	23/139  (16.5)	NA	29/129  (23)	NA
Bezieau et alref (2001)	35%		25%

• changes in c-MYC
• SHP1 methylation leading to epigenetic activation of the Jak/STAT pathway^ref
• c-MAF is overexpressed in 50% of MM : the expresson of integrin b₇ (which binds E-cadherin on the surface of stromal cells upregulating expresion of VEGF, which is important for MM cell growth and enhances the proliferation through the production of cyclin D1) and the cell-cycle regulator cyclin D2, and the chemokine receptor CCR1 is increased in the presence of c-MAF^ref

circulating ECs (CECs)

a correlation was documented between the level of CECs/EPCs and response to thalidomide treatment

• micromolecular myeloma / light chain myeloma / Bence Jones myeloma (10%) : only monoclonal Ig light (L) chains are produced. Such chains are found minimally in plasma as they can pass glomerular filters, precipitate within renal tubules and be recovered in urine as dimers (Bence Jones (BJ) protein (BJP) (Bence Jones Henry. On a new substance occurring in the urine of a patient with mollities ossium. Phil.Transact.Roy.Soc 138:55-62 (1847))), leading to glomerulonephritis and renal failure. It has unusual solubility properties : on heating it precipitates at 50°-60°C and redissolves at 90°-100°C, and on cooling it again precipitates and redissolves (Bence Jones reaction)
• IgD myeloma
• non-secretory myeloma (0.1-5%) : absence of detectable M-protein in serum and urine. The presenting features of nonsecretory myeloma are similar to those in patients with a detectable M-protein, except for the absence of renal function impairment. The response to therapy and survival of patients with nonsecretory myeloma are similar to those of patients with measurable M-protein. Coexistence of nonsecreting and nonproducing light chain multiple myeloma has been reported^ref
• non-producing myeloma : no cytoplasmic immunoglobulin chains are synthetized

• plasmacytoma (< 5% of patients with a plasma cell dyscrasia) present with a single bone (SBP) or extramedullary plasmacytoma (EMP) without evidence of systemic disease (normocalcemia, absence of anemia, preservation of uninvolved immunoglobulins, or renal disease attributable to myeloma). Diagnosis requires biopsy confirmation of a monoclonal plasma cell infiltrate from a single site. The treatment of choice for both entities is radiotherapy given with curative intent (> 4000 cGy) resulting in long term disease-free survival in approximately 30% of patients with SBP and 65% of patients with EMP.
• solitary plasmacytoma of bone (SPB) / bone localized or solitary myeloma : diagnosis requires
• biopsy-proven monoclonal plasma cell infiltration of a single lytic bone lesion
• no additional lesions on bone survey : the role of MRI of the thoracic and lumbosacral spine in the diagnosis of SBP was prospectively evaluated by Moulopoulos et al in 12 consecutive patients with SBP : MRI detected additional abnormalities in 4 patients who, after radiotherapy for the solitary lesion (of curative intent), had persistent paraprotein (> 50% of the pretreatment value), compared with only 1 of 6 similarly treated patients without an abnormality by pretreatment spinal MRI^ref. In a follow-up report of 23 patients with thoraco-lumbar spine disease from one center, 7 of 8 patients who had SBP by radiographs alone developed MM, compared with only 1 of 7 patients with only 1 lesion confirmed by MRI^ref. Thus, most investigators agree that a negative MRI of the thoraco-lumbar spine is a prerequisite for the diagnosis of SBP
• absence of clonal plasma cells on a random marrow sample : 33% of patients considered to have a SPB according to standard criteria have bone marrow abnormalities consistent with MM on MRI^ref
• no evidence of systemic MM (normocalcemia, absence of anemia or renal disease attributable to MM)
• presence of monoclonal protein (M protein) in the serum or urine has been noted in 24-72% of patients in various series^{ref1, ref2, ref3}. Among 63 consecutive previously untreated patients with SBP, 62% had a serum M protein, 13% had only Bence Jones protein (BJP), and 25% had non-secretory disease^ref. Paraprotein values were usually very low, with only 11 of 37 patients with a serum M protein > l g/dL (high value 2.2 g/dL) and the highest urine BJP was 0.7 g/day
• serum immunoglobulin free light chain (FLC) assays have provided a measurable parameter to follow in approximately 65% of patients previously diagnosed with "non-secretory" MM by standard electrophoretic studies^ref. It is likely that these assays will also be useful in a similar percentage of patients with SBP. Like MRI, this would improve the precision of monitoring SBP and provide more sensitive identification of patients who achieve complete disappearance of paraprotein after radiation therapy and are most likely to be cured. An abnormal FLC ratio at diagnosis may identify risk of progression to MM in patients with solitary bone plasmacytoma (SBP). In the cohort of 116 patients, 43 have progressed to MM; with a median time to progression of 1.8 years. The FLC ratio was determined in all 116 patients on serum collected at time of diagnosis, and was abnormal in 54 patients (47%). An abnormal FLC ratio was associated with a higher risk of progression to myeloma (p=0.039). The risk of progression at 5 years was 44% in patients with an abnormal serum FLC ratio at diagnosis compared to 26% in those with a normal FLC ratio. 1-2 years following diagnosis, a persistent serum M protein 0.5 g/dL was an additional risk factor for progression. Risk stratification^ref :
• patients with a normal FLC ratio at baseline and M protein <0.5 g/dL 1-2 years following diagnosis (low-risk; n=31) => 5-yr PFS = 13%
• either risk factor abnormal (intermediate-risk, n=26) => PFS = 26%
• both an abnormal FLC ratio and M protein 0.5 g/dL (high-risk, n=18) => PFS = 62%
• levels of uninvolved immunoglobulins are usually preserved, and in our series of 63 patients, only 3 had suppressed levels. These 3 patients had disease progression at 12, 18 and 74 months, indicating the presence of systemic disease^ref.
Therapy : radiotherapy with curative intent is the treatment of choice, resulting in local control in > 80% of patients and prolonged cause-specific disease-free survival in approximately 35% of patients with SBP. Strict dosing guidelines are difficult to recommend due to the limited number of patients and the absence of prospective phase I-II and randomized studies. Despite this, some recommendations are reasonable based on multiple single institution studies. Tsang et al report no dose-response above 35 Gy in 32 patients; however, a retrospective review by Mendenhall et al noted that among 81 patients treated with > 40 Gy of radiation, there was only 6% local progression of disease, which was superior to 31% for those who received < 40 Gy^{ref1, ref2}. Similarly, no local failure was seen for doses > 50 Gy^ref. While no dose-response was noted by Tsang et al, size of the tumor appeared predictive for local recurrence. That report indicated that SBP < 5 cm was 100% controlled for local recurrence, while nearly 40% of patients with bulky disease (>= 5 cm) had local progression or recurrence of disease^ref. Outcome after treatment for solitary plasmacytoma (selected studies) :

series	no. of patients	radiotherapy dose (Gy)	10-year DFS (%)	OS (yrs)	10-year OS (%)
Wilderref	60	3-70	38	11	-
Frassicaref	46	< 12-70	25	9.3	-
Tsangref	32	< 30-0	36	10	-
Bolekref	27	28.3-60	46	10	-

Thus, in the absence of a large cooperative group study, our practice has been to recommend 45 Gy in 25 fractions over 5 weeks. Recently, evidence-based guidelines of the United Kingdom Myeloma Forum (UKMF) recommend radiotherapy of at least 40 Gy in 20 fractions and ports that encompass the tumor volume plus a margin of at least 2 cm beyond disease detectable by MRI^ref. For bulkier disease (> 5 cm), a higher dose (up to 50 Gy in 25 fractions) was recommended.Surgical resection of SBP is rarely necessary, but occasional patients may require decompressive laminectomy in the presence of cord compression. When possible, an anterior approach is preferred and radiotherapy is generally delayed, but ports may be somewhat compromised due to hardware^ref. Adjuvant chemotherapy has been administered with inconclusive results. Although some studies have found that adjuvant therapy may prevent or delay progression to myeloma, most have noted no benefit with the early administration of chemotherapy^{ref1, ref2, ref3}. More recently, even myeloablative therapy with stem cell support has been evaluated in high-risk patients with solitary bone plasmacytoma, but results are too premature to draw any conclusions given the long natural history of this disease^ref. It is unclear whether the risk of early therapy for SBP may predispose to development of either resistant plasma cell clones or to secondary leukemia. Thus, given the lack of consistent data proving benefit from chemotherapy, we and others believe that there is no current role for adjuvant chemotherapy in the initial treatment of SBP.
Prognosis : while the majority of patients with solitary plasmacytoma of bone develop myeloma after a median of 2-3 years, the overall median survival of 7-12 years is longer than for patients in early phases of symptomatic myeloma. Approximately 15-45% of patients remain disease free at 10 years, and although the majority of these appear to be cured, rare late recurrences have been reported. In our experience, prolonged stability ensued only in patients with complete disappearance of paraprotein by one year, indicating the absence of occult disease outside the radiotherapy port, in contrast to patients with either persistence of paraprotein (after 1 year) or non-secretory disease in whom myeloma usually evolved^ref. Others have reported that neurologic problems associated with SBP, spinal disease, soft tissue masses, bulky disease (>= 5 cm), age > 55 years, radio-therapy dose, and M protein level were important prognostic factors^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11}. In a series of 63 patients researchers were unable to confirm any of these factors, although no patient with a serum M protein > l.0 g/dL had complete disappearance of paraprotein.

Myeloma-free survival (A) and cause-specific survival (B), both in terms of response of myeloma. (M) protein in the blood and/or urine to radiotherapy, for solitary bone plasmacytoma patients.
As further advances in diagnostic testing are evaluated (PET scans, free light chains) occult disease should be more easily recognizable. Consequently, SBP will be diagnosed less, complete disappearance of paraprotein should occur more frequently and the fraction of cured patients should rise.
• solitary extramedullary or extraosseous plasmacytoma (EMP) / soft tissue myeloma is less common than SBP and occurs when there is soft tissue infiltration of clonal plasma cells. There should be no evidence of bone destruction or occult disease elsewhere. EMP must be distinguished from reactive plasmacytoma, plasma cell granuloma and lymphoma (MALT, marginal zone, and immunoblastic)^{ref1, ref2}. This is probably best accomplished by phenotypic studies positive for CD38 and monoclonal cytoplasmic light chain expression of malignant plasma cells obtained by biopsy or fine needle aspiration of the solitary lesion. Similar to SBP, there should be no evidence of clonal marrow plasmacytosis. Approximately 85% of lesions occur in the head and neck mucosa, and underlying bone involvement, particularly in the sinuses, may be noted. Gastrointestinal involvement, although significantly less common, is the next most frequent site and other areas of involvement reported infrequently include lung, bladder, thyroid, testis, ovary, and tonsil among others^{ref1, ref2, ref3}. There are limited data regarding the diagnosis and staging of this disorder, and while CT or MRI is required to document the extent of the solitary lesion, no prospective data exist regarding the role of spinal MRI in staging this entity, but similar to SBP, we find it useful for the accurate staging of EMP. < 25% of patients have evidence of a low level of monoclonal protein in serum or urine by electrophoresis and/or immunofixation, and (similar to our experience with SBP) we require normal levels of uninvolved immunoglobulins to confirm the absence of occult disease elsewhere^ref. Although current experience is minimal, free-light chain assays should also prove useful in monitoring such patients, particularly those classified with non-secretory features. In addition, patients should have no sign of underlying myeloma by bone survey and chemistries should reveal no abnormalities attributable to plasma cell dyscrasia.

Therapy : like SBP, EMP are highly sensitive to radiotherapy with nearly all patients successfully achieving local control (80%-100%) and approximately the 50-65% of patients remaining free of disease longer than 10 years^{ref1, ref2, ref3, ref4, ref5}. Due to small patient numbers and historical retrospective analyses over many decades, no firmly established criteria for treatment exist. Similar to SBP, Tsang et al reported successful local control for nearly all patients (13 of 14) treated with 35 Gy with only 1 failure in a patient with disease > 5 cm; others also confirmed less satisfactory control in sites with bulky disease.8 Median doses of radiation in most studies ranged from 35 to 45 Gy and in our own experience, there appears to be little value for doses beyond 50 Gy (myeloma developed in 1 of 5 patients who received 40-49 Gy versus 4 of 15 patients treated with 50-60 Gy)^ref. The utility of prophylactic irradiation of local lymph nodes is unclear as there have been excellent results with elective inclusion (but with increased morbidity), as well as similar results with inclusion of draining lymph nodes only when clinically involved (or for Waldeyer's ring involvement, which is considered at high risk for local recurrence)^{ref1, ref2, ref3, ref4}.

series	no. of patients	radiotherapy dose (Gy)	10-year DFS (%)	OS (yrs)	10-year OS (%)
Galieniref	46	40-75	78	-	80
Liebrossref	22	40-60	56	-	50
Brinchref	18	28-60	80	-	76
Chaoref	16	40-50.4	75	-	54
Tsangref	14	< 30-50	84	-	65
Hollandref	14	16.11-62	64	-	NA

A group reported 100% local regional control in 5 of 7 patients with tumors in the oral cavity, oral/nasopharynx, larynx, or parotid treated with elective nodal radiotherapy^ref. Because of these excellent results, we currently recommend elective radiation of nodal areas, but not for maxillary sinus or nasal cavity involvement. Current evidence-based recommendations by the United Kingdom Myeloma forum are otherwise similar to our own recommendations and those for SBP^ref. Their recommendations include a radiotherapy dose of 40 Gy in 20 fractions for tumors < 5 cm and up to 50 Gy in 25 fractions for tumors >= 5 cm with at least a 2 cm margin encompassing the primary tumor. If cervical nodes are involved (or in Waldeyer's ring tumors), these should be included in the radiotherapy field. Multiple myeloma-free survival for patients with extramedullary plasmacytoma (EMP) (A) and overall and cause specific survival for all patients (B).

Because EMP is a highly radiosensitive tumor, surgical procedures of the head and neck are not recommended, but surgery may be considered for other sites of disease, such as the gastrointestinal tract. This approach is supported by a literature review by Alexiou et al, in which patients with sites other than the head and neck received either surgery, radiation, or a combined-modality treatment^ref. There was no difference between the 3 arms, suggesting that either surgery or radiotherapy is reasonable for such patients. Considering the high cure rate of EMP with radio-therapy and the lack of published data regarding the use of adjuvant chemotherapy, use of adjuvant chemotherapy is not justified outside a clinical trial.
Prognosis : in most series, < 10% of patients have local recurrence of disease and the 10-year disease free and overall survival ranges from 50-80%, for the 30-50% of patients who develop disease progression to myeloma. This occurs after a median of 1.5-2.5 years and their clinical course at progression is similar to those of patients diagnosed with de novo symptomatic myeloma. Because of the small number of patients in most series, any statistically significant risk factors for development of myeloma are not clear and are further complicated by the inclusion of patients over many decades during which treatment and diagnostic modalities have become more refined and are likely to impact prognosis. In some series, bulky disease > 5 cm may have prognostic significance^ref. In contrast to SBP, because < 25% of patients have a monoclonal protein, any statistically significant analysis of disappearance of paraprotein is precluded for patients with EMP
• indolent myeloma : a variant of MM in which the tumor cells are hypoproliferative; an M component and bone marrow plasmacytosis are present, but significant bone marrow destruction, hypercalcemia, and Bence Jones proteinuria are absent. It is defined as asymptomatic MM with < 4 osteolytic lesions and normal renal function. MRI can detect involvement of the vertebral marrow in 50% of patients^{ref1, ref2}
• plasma cell or plasmacytic leukemia (PCL) (2-4% of all myelomas^{ref1, ref2, ref3}) : a rare form of plasma cell dyscrasia characterized by Kyle's criteria : the presence of > 20% plasma cells in peripheral blood and an absolute plasma cell count > 2,000/ml (Grogan TM, Muller-Hermelink HK, Van CB, Harris NL, Kyle RA. World Health Organization Classification Tumours of Haematopoietic and Lymphoid Tissues. France: IARC Press Lyon; 2001.pp. 142-56)

Epidemiology : in almost all the series median age ranged between 53-57 years (about 10 years younger than median age in MM series). The youngest age reported was 30 years^ref
PCL can be of 2 types :
• primary PCL (PPCL) (60-80%) presents de novo in patients with no previous history of MM and usually features a rapid clinical progression and a short survival. PPCL is a distinct clinicopathological entity, because its clinical features, response to chemotherapy and prognosis are different from those of typical multiple myeloma. PPCL shows higher expression of CD20 as compared to MM^ref.

Epidemiology : incidence < 1 case in 1 million
Symptoms & signs : less lytic bone lesions (60%), hepatosplenomegaly and lymphadenopathy are more common; PPCL has a more aggressive course high frequency of extramedullary involvement (liver, spleen, lymph nodes, extra osseous plasmacytomas etc), thrombocytopenia, anemia, hypercalcemia and impaired renal function
Laboratory examinations : in certain PCL cases, the leukemic cells are more immature than usual and a definitive diagnosis is difficult to obtain (small lymphoid or lymphoplasmacytoid cells with numerous cytoplasmic hairy projections; CD19^-20^-38⁺49e^-79a^-; cytoplasmic and urinary l-type Bence–Jones protein; germinal center B-cells^ref) without electron microscopic^ref or immunohistochemical studies.
Therapy : single alkylating agent with prednisolone is not appropriate for patients with primary PCL. VAD and EDAP with rituximab^ref. Survival is significantly better in PCL patients treated with polychemotherapy as compared to melphalan and prednisolone. Drugs used are vincristine, doxorubicin, dexamethasone and/or cyclophosphamide and etoposide^ref. Alternatively VCMP/VBAP^ref or DMVM^ref is also used. Since the prognosis is so poor, intensification of high dose chemotherapy followed by allogenic/autologous hematopoietic stem cell transplantation should be tried^{ref1, ref2, ref3, ref4, ref5}
Prognosis : median survival is 6 months^ref. The longest survival reported was 28 months^ref. The failure to achieve 50% clearance of blood plasma cells within 10 days after the initiation of treatment is a predictor of no response^ref. Garcia-Sanz et al.^ref identified 10 variables which have unfavorable prognostic value on the survival of PPCL cases, of which serum b₂ microglobulin level > 6 mg/L and S phase bone marrow plasma cells >4.5% retained an independent value on multivariate analysis. Response to treatment of PCL is poor.
• secondary PCL (40%)^ref evolves as a terminal event in 1-2% of MM^ref; it is mostly considered as a complication of the alkylating agents or radiation therapy^{ref1, ref2}

Epidemiology : older than PPCL
Symptoms & signs : hepatosplenomegaly and lymphadenopathy are less common; more lytic bone lesions (100%), lower platelet count, larger M-protein in the serum than did patients with primary plasma cell leukemia
Prognosis : mean survival is 1.3^ref-2.0 months^ref
Therapy : bortezomib^ref
Pathogenesis : deletions of 13q14 were detected in 11 (78%) cases and deletions of 17p13.1(TP53) in 6 (43%) cases. Translocations (11;14), (4;14), and (14;16) were found in 5 (35%), 2 (14%), and 1(7%) cases, respectively. Except for an association between t(4;14) and 13q14 deletions, no association was identified among the genetic abnormalities^ref. Phenotypically they originate from proliferation of plasma cells expressing CD38^ref. Minority of cells expresses CD10, HLA-DR and CD20. The presence of multiple haemopoietic surface antigens on malignant plasma cells suggests its origin from a pluripotent stem cell. Also, plasma cells from both primary and secondary PCL lacks CD56, which is important in anchoring plasma cells to bone marrow stroma. > 80% have a diploid/hypodiploid DNA content^ref. Cytogenetic study shows complex karyotype with multiple numerical and structural abnormalities^ref. Up to 90% may show chromosome 13 monosomy^ref. Among immunoglobulins, IgG is most often increased.
• non-secretory PCL^ref
Laboratory examinations : anaemia with a haemoglobin < 9 g/dl occurs in 80% of cases of PCL versus 35% of cases of MM. Rouleaux formation is usually evident on the peripheral blood smear. Thrombocytopenia with platelets < 100 x 10⁹/L occurs in 50% of patients with PCL versus only 10% of those with MM. Leucocytosis ranges from 20 to > 100 x 10⁹/L with 20% to 100% of plasma cells. An elevated BUN and/or creatinine occur in 75% of cases of PCL versus only 40% cases MM. Most patients with PCL have a monoclonal IgG heavy chain or light chain in the serum and Bence Jones proteinuria occurs in about 80% of cases^ref
Therapy : infection and haemorrhage contribute significantly to morbidity and mortality. DIC has also been reported^ref. SPCL rarely responds to chemotherapy.
Differential diagnosis : acalculous cholecystitis^ref
• ‘hairy-cell’ variant of plasma cell myeloma (Crogan TM, Spier CM. B-cell Immunoproliferative disorders, including multiple myeloma and amyloidosis. In: Knowles DM, editor. Neoplastic hematopathology, 2nd ed. Philadelphia: Lippincot Williams and Wilkins 2001;1564–5)
• lymphoplasmacytoid leukemia producing biclonal IgA but not Bence–Jones protein^ref

• I (approx. cell mass : 0.6 x 10¹²/m²; < 500 cells / mL; low) : all of the following
• hemoglobin > 10 g/dl
• serum calcium < 12 mg/dl (normal)
• on roentgenogram, normal bone structure (scale 0) or solitary bone plasmacytoma only
• low M component production rates
• IgG value < 5 g/dl
• IgA value < 3 g/dl
• urine light chain M-component on electrophoresis < 4 g/24h
• II (approx.cell mass : 0.6-1.2 x 10¹²/m²; 500÷1200 cells / mL; intermediate) : overall data not as minimally abnormal as shown for stage I and no single value as abnormal as defined for stage III
• III (approx.cell mass > 1.2 x 10¹²/m²; > 1200 cells/mL; high) : one or more of the following
• hemoglobin value < 8.5 g/dl
• serum calcium value > 12 mg/dl
• advanced lytic bone lesions (scale 3)
• high M-component production rates
• IgG value > 7 g/dl
• IgA value > 5 g/dl
• urine light chain M-component on electrophoresis > 12 g/24 h

• A : relatively normal renal function (serum creatinine < 2.0 mg/dl)
• B : abnormal renal function (serum creatinine > 2.0 mg/dl)

• multiple bone marrow tumor foci and secretion of an M component, associated with widespread osteolytic lesions resulting in bone pain, pathologic fractures, height decrease (=> spinal cord compression => paralysis)
• hypercalcemia
• normochromic normocytic anemia
• spread to extraosseous sites occurs frequently in advanced disease
• depression of immunoglobulin levels results in increased susceptibility to opportunistic bacterial infections
• renal failure may also occur from .... :
• calcium nephropathy
• extensive cast formation
• hyperuricemia
• renal amyloidosis (l> k  chains)
• light chain nephropathy (k > l chains)
These features have strong diagnostic value if accompanied by > 10% atypical plasma cells in the bone marrow and either a monoclonal immunoglobulin in the serum or light chains in the urine (Durie BGM, Salmon SE. Multiple myeloma, macroglobulinaemia and monoclonal gammopathies. In: Hoffbrand AV, Brain MC, Hirsh J, eds. Recent advances in haematology. No. 2. Edinburgh, Scotland: Churchill Livingstone, 1977:243-61). Light chains appear in the serum only if the patient has severe renal failure. Bone lesions, hypercalcemia, and anemia correlate directly with the presence of the total mass of myeloma cells^ref and have prognostic value^{ref1, ref2, ref3, ref4}. All these complications, especially infection and renal insufficiency, are also major causes of death^ref. The pathogenesis of these clinical features depends on interactions between myeloma cells and the microenvironment of the bone marrow by means of cell-to-cell contact, adhesion molecules, and cytokines^ref or on the direct effects of circulating monoclonal immunoglobulins or light chains^ref.
• Crow-Fukase syndrome / polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy and skin changes (POEMS) syndrome
• sclerosing myeloma : myeloma associated with osteosclerosis, most often manifested by peripheral neuropathy; the myeloma involved may be localized or a part of multiple myeloma; POEMS syndrome may be present

• serum protein electrophoresis (SPE) and immunofixation with % of eventual monoclonal component(s) in g-globulins


• IgG MM (60%)
• IgA MM (20%)^ref
• IgE MM^ref (0.01% in all plasmocytomas^ref) : < 40 cases of IgE myeloma have been described^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14}; more malignant clinical course; a case in which a monoclonal chain was detected in the urine of the patient several years prior to diagnosis^ref; associated with plasma cell leukaemia^ref; in a case an unusual picture was found in the urine where two IgE fragments, namely an incomplete Fc fragment and an IgE specific Fab fragment were excreted^ref
• IgD MM (1-2% of all myelomas) : a small band or no evident M-spike on serum electrophoresis and heavy light-chain proteinuria. Thus, IgD myeloma can be considered a variant of Bence Jones myeloma; the presence of the IgD M-protein and the predominance of the l light chain are the only distinctive features. Predominant occurrence in males and young patients. The median survival of patients with IgD MM is almost 2 years, with 20% of them surviving for > 5 years, frequent renal impairment, hypercalcemia and amyloidosis.
• nonsecretory IgD MM^ref
Outcome remains poor with chemotherapy and appears to be superior with ASCT^ref. Bence Jones myeloma should not be diagnosed without excluding the presence of an IgD paraprotein^ref.
• IgM MM
• biclonal MM (0.1%)
• urine protein immunofixation to detect Bence-Jones proteinuria (70% of MM and 100% of micromolecular myeloma)
• dosage of serum IgA, IgG, IgM
• IgA (n.v : 70-400 mg/dl)
• IgG (n.v. : 700-1600 mg/dl)
• IgM (n.v. : 40-280 mg/dl)
• IgD (n.v. 0.3-14 mg/dl)
• IgE (n.v. : < 0.025 mg/dl or < 150 E/l)
• dosage of l and k L chains in :
• serum :
• k (n.v. 1.7-3.7 g/l)
• l (n.v. 0.9-2.1 g/l)
• k/l ratio (n.v. 1.35-2.65)
• urine :
• k (n.v. : 0.0-7.1 mg/l)
• l (n.v. : 0.0-3.9 mg/l)
• hypogammaglobulinemia (93%) (Kyle RA, Greipp PR, Witzig TE, et al. An analysis of 1027 newly diagnosed cases of multiple myeloma. Blood 1999;94:Suppl 1:537a-537a.abstract)
• hypercalcemia (30%) is uncommon at diagnosis
• hypeuricemia (40%)
• increased plasma viscosity (80%)
• increase in T_reg
• increased [bone marrow AlkP isozyme]_plasma
• increased [b₂m]_plasma
• CBC
• increased ESR (95%), sideremia, transferrin, ferritin, bilirubin, SGOT, SGPT, g-GT, alkaline phosphatase, LDH, fibrinogen, total serum proteins; IL-6, IL-6R, TDK
• at diagnosis : mosaic HAV, HBV, HCV antigens/serology
• skull X-rays : rounded "punched out" lesions


• bone marrow trephine biopsy (BMTB) :
• myeloma cell : found in bone marrow and occasionally in peripheral blood
• in the more anaplastic forms, the cell is large, has abundant blue-staining cytoplasm with no perinuclear pallor, and has one or more moderately large and vesicular nuclei that may be centrally or eccentrically placed and may contain nucleoli
• in better differentiated tumors, the cell is smaller and, except for the finer chromatic structure, greatly resembles a plasmacyte

• Mott cell / berry, grape, or morular cell (an abnormal plasma cell that contains Mott bodies or Russell bodies)
• immunophenotype : CD19^+/-20^9%28⁺33^+/-38⁺⁺43^+/-45^9%52^5%54 / ICAM-1⁺56^72%117^+(18%)138 / syndecan 1⁺227 / EMA^+/-, HM1.24⁺, SP17⁺, MUC1⁺, sIg^-, cIg^hi

• major criteria :
• histological diagnosis of plasmacytoma at bone or soft tissue biopsy
• bone marrow plasma cells > 20%
• M component
• IgG > 3.5 g/dl
• IgA > 2 g/dl
• Bence-Jones proteinuria > 1g/24h
• urinary k or l chain > 1 g/24hr
• minor criteria
• bone marrow plasma cell 10-20%
• M component
• IgG < 3.5 g/dl
• IgA < 2 g/dl
• Bence-Jones proteinuria < 1 g/24h
• osteolytic lesions
• suppression of normal IgG (IgG < 600 mg/dl, IgA < 100 mg/dl, IgM < 50 mg/dl)

• induction therapy :
• first line :
• IFN-a_2b has been shown to be effective in about 20% of patients
• chemotherapy : in most patients, the fraction of proliferating cells is < 1% until late in the disease^ref.
• melphalan + prednisone (MP) was the standard first-line treatment for elderly MM patients ineligible for stem cell transplant since 1960. However, complete responses (CRs) are rare
• cyclophosphamide + prednisone
• thalidomide
• alone or thalidomide + dexamethasone : 28 patients with previously untreated asymptomatic MM were treated with thalidomide 100 to 200 mg orally (PO) at bedtime (qhs) with serial increments of 50 to 100 mg at weekly intervals, as tolerated to a maximum of 600 mg PO qhs. 40 consecutive previously untreated patients with symptomatic MM were also treated as above (maximum dose 400 mg) and received dexamethasone 20 mg/m² for 4 days beginning on days 1, 9, and 17; the second and third cycles of repeated dexamethasone were begun on day 30. Both groups of patients were treated for at least 3 months. The response rate was 36% for patients treated with thalidomide alone and 72% for patients treated with Thal-Dex, the latter including complete remission in 16% of patients. The median time to remission was 4.2 months with thalidomide alone and 0.7 months with thalidomide-dexamethasone. Grade 3 toxicity included infections (9 patients) and thrombotic/embolic events (7 patients). 5 deaths have occurred as a result of MM (2 patients), infection (1 patient), unknown cause (1 patient), and a possible thromboembolic event (1 patient)^ref
• thalidomide + dexamethasone (Thal-Dex) : administered for 75 days (200 mg/day) and 3 months, respectively. The monthly dose of dexamethasone was 20 mg/m²/day for 4 days, with cycles repeated on days 9 to 12 and 17 to 20 on the first and the third month of therapy.
• is better than dexamethasone alone : the response rate with thalidomide 200 mg per day + dexamethasone 40 mg was significantly higher than with dexamethasone 40 mg alone (63% v 41%, respectively) in patients with newly diagnosed myeloma for 4 cycles (28 days per cycle), followed by stem cell collection in patients eligible for high-dose chemotherapy (ECOG-EA100). A recent interim analysis of 109 patients showed an overall response rate of 80% ( 50% reduction in serum and urine M-protein) in the Thal/Dex arm, significantly higher than 53% for patients on Dex alone (P = .0023; one-sided Fisher's exact test). The most important side effect reported was deep vein thrombosis (including pulmonary embolus), occurring in 16% of patients receiving the Dex/Thal combination, compared with 3% receiving Dex alone (Rajkumar SV, Blood E, Vesole DH, Shepard R, Greipp PR. A randomised phase III trial of thalidomide plus dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): a trial coordinated by the Eastern Cooperative Oncology Group. Proc Am Soc Clin Oncol; 2004:558). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively)^ref
• is better than VAD, Thal-Dex resulted in a significantly higher response rate (52% versus 76%, respectively; P < .001) and effected more profound reduction in myeloma cell mass of both IgG and IgA type. More frequent toxicities included nonfatal deep vein thrombosis with Thal-Dex (15%) and granulocytopenia with VAD (12%). In each of the 2 treatment groups, 91% of patients proceeded to PBSC mobilization. The median number of collected CD34⁺ cells was 7.85 x 10⁶/kg in the Thal-Dex group and 10.5 x 10⁶/kg in the control group. Thal-Dex may be considered an effective and relatively well-tolerated oral alternative to the more complex VAD regimen as front-line therapy for MM patients who are candidates for subsequent autologous transplantation^ref
• in young patients (< 61 years) with symptomatic MM, on an ITT basis, the overall response (> or = PR) rate was 74%, including 24% of patients who obtained a complete remission. Grade 3-4 toxicities consisted of infections (12%), deep-vein thrombosis (3%), constipation (5%), and neuropathy (5%). A total of 58 patients (96%) proceeded to PBSC mobilisation and yielded a median number of 8 x 10⁶ CD34⁺ cells/kg.^ref.
• In the Mayo Clinic Phase II trial, patients received Thal 200 mg per day and Dex 40 mg on days 1-4, 9-12, and 17-20 (odd cycles) and 40 mg/d on days 1-4 (even cycles); a 64% rate of major response, defined as  50% reduction in serum and urine M-protein, was reported. The most common grade 3/4 toxicities were deep vein thrombosis (12%), constipation (8%), rash (6%), and dyspnea (4%)^ref.
• The MD Anderson Cancer Center (MDACC) Phase II trial enrolled patients with previously untreated symptomatic disease to receive Thal 100 mg per day, escalated to 400 mg per day, plus Dex 20 mg. Partial and complete responses were observed in 63% of patients, and grade 3 toxicities included infection (23%), thrombotic/embolic events (15%), constipation (3%), and fatigue (3%)^ref.
• thalidomide was given at the fixed dose of 200 mg/day; dexamethasone was administered at the dose of 40 mg/day on days 1-4, 9-12 and 17- 20 in odd cycles and 40 mg/day on days 1-4 in even cycles, repeated monthly for 4 months. 71 patients with symptomatic MM were evaluated for response and toxicity. On an ITT basis, the overall response (>or= partial remission) rate was 66%, including 17% of patients who attained a complete remission or a very good partial remission. In addition to common toxicity of thalidomide, deep-vein thrombosis was a troublesome adverse event (16%). 9 patients (13%) required thalidomide discontinuation because of toxicity, including 3 patients who died during the study treatment. 59 patients proceeded to PBSC mobilization and yielded a median number of 7.1x10⁶ CD 34⁺ cells/kg^ref.
• pegylated liposomal doxorubicin (Caelyx) 40 mg/m² on day 1 every 28 days, dexamethasone 40 mg p.o. on days 1-4 and 9-12 and thalidomide 100 mg daily (TAD / ThaDD)
• in advanced MM achieved CR in 26%, nCR in 6%, VGPR in 6%, PR in 38%, minor response in 16% and PD in 8% (ORR = 92%). The median EFS was 17 months and the median OS was not reached. Grade 3 non-hematologic toxicity occurred in 12% of patients, thromboembolic disease in 12% and severe infection in 16%^ref
• phase II study in the treatment of 50 newly diagnosed MM patients > 65 years. Thalidomide was administered orally 100 mg at bedtime continuously, dexamethasone orally 40 mg days 1-4 and 9-12 and pegylated liposomal doxorubicin intravenously 40 mg/m² on day 1 over the 28-days cycle. Response was assessed according to the EBMT criteria. Seventeen (34%) patients achieved CR, 7 (14%) nCR, 5 (10%) VGPR, 15 (30%) PR and 5 (10%) MR resulting in an ORR of 98%. Only one patient (2%) presented progressive disease. TTP, EFS and OS projected at 3 years were 60%, 57% and 74% respectively, and these parameters were significantly higher in those patients achieving a response VGPR versus those who did not. Grade 3-4 nonhematologic adverse events were constipation (10%), fatigue (6%), tremors (4%), mucositis (4%) and palmar-plantar erythro-dysesthesia (2%). Grade 3-4 neutropenia occurred in 12% of patients. Grade 3-4 infections and thrombo-embolic accidents were observed in 22% and 14% of patients, respectively^ref.
• doxorubicin and dexamethasone were given for 2 or 3 months followed by thalidomide and dexamethasone for 2 months (AD-TD regimen) with prophylactic antibiotics and daily aspirin (81 mg/d). Among the 42 patients whose response could be assessed, 38 responded to therapy (90.5%). The ITT response rate was 84.4% with 7 complete responses (CR 15.5%), 9 near complete responses (nCR 20.0%), and 22 partial responses (PR 48.9%). 2 patients had stable disease (4.4%), and 2 progression of disease (4.4%). Normalization of the free light chain ratio after 1 or 2 cycles of treatment was highly predictive of achievement of CR or nCR. Patients tolerated the treatment well although 5 patients developed thromboembolic complications (11%)^ref
• melphalan + prednisone + thalidomide (MPT) : a multicentre randomised trial compared MP for 6 4-week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) with MP alone in patients aged 60–85 years with newly diagnosed MM. Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined CR or PR rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%), and the nCR or CR rates were 27.9% and 7.2%, respectively. 2-year EFS rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51). 3-year OS rates were 80% for MPT and 64% for MP (HR for MPT 0.68). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0·.002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0·005)^ref
The impact of thalidomide given in addition to chemotherapy throughout the whole program is currently being tested in the Arkansas Total Therapy II. When incorporated into high-dose, melphalan-based therapy for MM during primary remission-induction therapy, between the 2 autologous HSCT, with consolidation therapy, and as maintenance treatment, patients who received thalidomide had a significantly higher rate of both complete response (62% vs. 43%) and 5-year event-free survival (56% vs. 44%). Nevertheless, overall survival curves in the 2 groups were nearly identical, owing in part to the poorer outcome after relapse in the thalidomide group. In particular, thalidomide-treated patients had a lower rate of response to salvage therapy and