The first published case of multiple myeloma involving osteosclerosis appeared in 1933 (10). A case series of 5 cases by Langley et al. was published in 1966 (11). Kelly et al reviewed osteosclerotic myeloma cases at the Mayo Clinic over a decade and reported their results in 1983 (12). Since then, there has only been one review publication by Lacy et al. that summarizes all 15 published cases of diffuse osteosclerosis with multiple myeloma until 1997 (13). These three publications together represent the sum of all comprehensive publications on osteosclerotic myeloma; the remaining literature comprises mostly of case reports. Approximately 50 cases have been published prior to 1997 (10). This paper’s greatest strength is that it provides the most comprehensive current review of osteosclerotic multiple myeloma, diffuse or otherwise, distinct from POEMS syndrome since 1997. We identified 17 patients in the literature as well as our own case, the features of whom are summarized in Table 2. Given the extreme rarity of OMM, we chose to present the unique data of each case rather than in a summary table so that providers might more easily identify similarities that may inform treatment and prognosis between past cases and future.
[Insert Table 2. here during production for final manuscript.]
History and Demographics
Previous literature prior to 1997 reported that patients with osteosclerotic myeloma are younger, present commonly with neuropathy, and less commonly with bone pain than those with classical multiple myeloma (CMM) (13). Of the 17 cases since 1997, age at time of diagnosis ranged from 32 to 82 years, with a mean and median of 60 years compared to the median of 66 to 70 years in CMM (14). OMM does appear to present at a younger age, however, neuropathy is in fact a rare presentation. Of the 17 patients reviewed, only 1 presented with neuropathy, 1 with skin changes, 1 with organomegaly, and 2 with lymphadenopathy. These cases were diagnosed as osteosclerotic MM despite the presence of 1 or 2 POEMS syndrome features because they lacked sufficient criteria to be categorized as POEMS in addition to fulfilling criteria for diagnosis of MM. The most common presenting symptoms in OMM include back pain (35%), dyspnea (35%), weakness/fatigue (35%), weight loss (29%), and chest pain (24%). In CMM, bone pain is the most common reported symptom at diagnosis in 58% of patients, followed by fatigue in 32% and weight loss in 24%. Only 2 patients reported bone pain, although patients may have chosen to describe bone pain by location as back pain, lowering subjective reports of bone pain. Distribution between the sexes was almost equal, with 9 (56.25%) men and 7 (43.75%) women, reflective of the established equal sex distribution in multiple myeloma. This contrasts with previous literature, which reported that osteosclerotic myeloma more commonly presents in men than women at a 4:1 ratio (10). CMM is reported to be twice as common in African-Americans compared to Caucasians and less common in Asians (1). In OMM, 29% of patients were South Asian. The reasons for this are unclear. Prior literature reviews of OMM by Lacy et al. also surveyed English-language literature, and while they did not report race, none of the cases they reviewed were authored in India. Incidence of CMM in India remains low at 1.0 per 100,00 compared to 4.1 per 100,000 individuals in the West (15). Further research is needed to determine if this population has genetic factors that would classify them as a higher risk group or change treatment or prognosis.
Laboratory Tests
Of the 47% of cases reporting serum calcium values, none were hypercalcemic ( >12 mg/dL). Of the 64.7% reporting serum creatinine, 45.5% were elevated (>2 mg/dL). Of the 82.4% of cases reporting hemoglobin, 57.1% were anemic (<10 g/dL). Reference values were taken from the IMWG criteria (2). Table 3 compares presentation of laboratory evidence of end-organ damage at initial presentation between OMM and CMM. The lack of hypercalcemia among OMM can be attributed to the comparative lack of lytic bone processes releasing calcium into the bloodstream. Our study supports the previously reported findings that hypercalcemia is rare in OMM, but renal insufficiency, rather than being rare per prior literature, actually appears more common than in CMM (13). These observations are limited due to sample size which preclude tests of statistical significance.
Table 3. Laboratory Evidence of End-Organ Damage at Initial Presentation in Osteosclerotic versus Classical Multiple Myeloma
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Osteosclerotic Multiple Myeloma
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Classical Multiple Myeloma
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No. of patients
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% of patients
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No. of patients
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% of patients
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Hypercalcemia (Serum Calcium >12 mg/dL)
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8
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0
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1018
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13*
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Renal Insufficiency (Serum Creatinine > 2 mg/dL)
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11
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45
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1020
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19
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Anemia (Hemoglobin < 10g/dL)
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14
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57
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1025
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35
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Data for classical multiple myeloma taken from Kyle et al. and are not original to this paper (16). *Kyle et al. reported serum calcium only above 11 mg/dL not the 12 mg/dL criteria described by the International Myeloma Working Group, so the real percentage of CMM with serum calcium >12 mg/dL is likely lower than 13%
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Our review revealed a wide range of abnormal plasma cells on bone marrow biopsies, ranging from 0.8% to 86%, with a mean of 49% and median of 45% for the 12 cases reporting percent infiltration. OMM has comparable plasma cell infiltration to CMM, which has a median infiltrate of 50% (16). Prior review reported plasma infiltrates mostly <5% plasma cells (13). Of the 17 patients reviewed, including our own, 10 (59%) had specified monoclonal gammopathy type, evenly split with 5 cases of kappa and 5 cases of lambda chain monoclonal gammopathy. Kappa chain monoclonal gammopathy cases were mostly associated with immunoglobulin G heavy chain, while lambda chain monoclonal gammopathy cases were mostly associated with immunoglobulin A heavy chain. The frequency with which IgG and IgA were represented were reflective of how commonly these immunoglobulins are produced in CMM. Four cases, including our own, reported non-secretory MM (7, 9, 17).
Radiologic Studies
Rousseau was the first to further classify osteosclerosis with multiple myeloma in 1978 into four groups: diffuse (37%), focal areas of osteocondensation (30%), bony spiculation on the surface of the bone (20%), and sclerotic reaction at the rim of the lytic lesion (13%) (18, 19). Given that these radiologic classifications were created several decades ago, we reviewed these groups. In doing so, we identified a case that did not fit the previously hypothesized categories for radiological features. Sufficient information to determine the osteosclerosis subgroups was provided for 16/17 cases. One case described two focal mixed lesions that were primarily osteosclerotic at the center, with peripheral lytic activity (7). Two cases had findings in two categories. The first patient had diffuse sclerotic lesions and one primarily lytic lesion with peripheral sclerosis at the rim (20). The second had focal areas of condensation as well as bony spiculation on the surface of the bone (21). Otherwise, diffuse sclerosis was most common at 73% (12/16), followed by focal areas of osteocondensation at 19% (3/16), bony spiculation on bone surface at 6% (1/16), and sclerotic reaction at the rim of lytic lesion at 6% (1/16). The distribution of CMM parallels red marrow distribution and thus mostly occurs in the axial skeleton and proximal appendicular skeleton. Most common sites of lytic lesions in CMM include the vertebrae (66%), ribs (45%), skull (40%), pelvis (30%), and long bones (25%) (22). Other less common sites include the jaw in 20-30% of cases (23, 24), sternum, and phalanges. No literature was found reporting rate of sternal or distal extremity, or phalangeal, involvement. Table 4 compares the common sites for OMM against CMM. OMM most commonly involves the vertebrae like CMM but has greater involvement in the pelvis and long bones than CMM. 59% of OMM cases were purely sclerotic without any lytic lesions.
Table 4. Frequency of involvement of different anatomical regions in 16 osteosclerotic multiple myeloma and multiple myeloma
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Osteosclerotic Multiple Myeloma n = 16*
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Multiple Myeloma
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Number of patients with sclerotic lesions
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Number of patients with lytic lesions
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Number of patients with sclerotic or lytic lesions
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Lytic Lesions Only
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Vertebrae
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12/16 (75%)
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1/16 (6%)
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13/16 (81%)
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66%
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Ribs
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4/16 (25%)
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2/16 (13%)
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6/16 (38%)
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45%
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Skull
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5/16 (31%)
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3/16 (19%)
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8/16 (50%)
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40%
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Pelvis
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7/16 (44%)
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3/16 (19%)
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10/16 (63%)
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30%
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Long Bones
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7/16 (44%)
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2/16 (13%)
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9/16 (56%)
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25%
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Jaw
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1/16 (6%)
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(-)
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1/16 (6%)
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30%
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Sternum
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2/16 (13%)
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(-)
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2/16 (13%)
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N/A
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Phalanges
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1/16 (6%)
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1/16 (6%)
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2/16 (13%)
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N/A
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Percentages for lytic lesions in MM were retrieved from prior research and are not generated by this review (22). No counts (n) were reported for classic MM and small sample size of OMM precluded any comparison using statistical tests for significance.
*One patient was excluded because no lesions were reported on imaging and site of bone marrow biopsy demonstrating osteosclerosis was not specified.
(-) Indicates no patients had lesions of the indicated type.
N/A Indicates that the literature does not report frequency of the specified site for lesions in multiple myeloma
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Prognosis and Treatment
Although MM remains incurable, recent advancements in therapeutic options and increased use of stem cell transplants have increased median survival for CMM from 33 months at the turn of the century to 6 years (1, 16). OMM is more indolent than MM, but given its rarity, it is difficult to determine survival. Most case reports report treatment response at 1 year. Only 1 patient demise was reported, which occurred prior to biopsy due to rapid deterioration from GI bleed and DIC. 24% received either bone, hematopoietic, or stem cell transplant. OMM had no significant differences in treatment to MM, but patients were more likely to receive a transplant (16).
Pathophysiology of Osteosclerosis
The pathophysiology behind osteosclerosis in multiple myeloma remains unclear. Although previous reports have theorized alkaline phosphatase might contribute to this process, only 3 cases reported elevated alkaline phosphatase levels (25, 26, 27). More likely, sclerosis results from an imbalance between osteoblasts and osteoclasts in favor of greater bone building and/or lesser resorptive activity. The same mediators thought to be involved in the production of lytic lesions via the uncoupling between blastic and lytic activity should be studied. These include Rank-L, MIP-1α, IL-1β, IL-3 , IL-6, IL-7, and TNF-α (28). There may also be parallels between the pathophysiology of sclerotic lesions in MM and prostate cancer given that prostate cancer is typically blastic. This would benefit from the study of PDGF and other mediators of prostatic sclerotic lesions, as suggested by Lacy (13).