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`
`Familial Multiple Myeloma:
`a Family Study and Review
`of the Literature
`
`Henry T. Lynch, Warren G. Sanger,
`Samuel Pirruccello, Brigid Quinn-
`Laquer, Dennis D. Weisenburger
`
`Background: The etiology of multiple
`myeloma (MM) remains obscure, al-
`though reports of familial clustering
`have implicated both a host susceptibil-
`ity factor and environmental effects.
`Here we describe the medical histories
`of members of a family prone to MM.
`Methods: We developed a pedigree for
`an MM-prone family by using informa-
`tion obtained from a questionnaire.
`Protein immunoelectrophoresis of se-
`rum and urine from the proband and
`from 19 family members was per-
`formed to detect monoclonal immuno-
`proteins. Peripheral blood obtained
`from the proband and from five rela-
`tives was subjected to standard cytoge-
`netic studies to detect constitutional
`chromosomal abnormalities. Multi-
`fluor-fluorescence in situ hybridization
`(M-FISH) and standard FISH studies
`were performed on peripheral blood
`from the proband and from two other
`affected living relatives to determine
`their karyotypes and to detect clonal
`chromosomal abnormalities frequently
`seen in patients with MM. Results:
`Within this family, a sibship of seven
`included three individuals (including
`the proband) with histologically veri-
`fied MM and two individuals with a
`monoclonal gammopathy of unknown
`significance (MGUS), as determined by
`immunoelectrophoresis of serum and
`urine. This family also had members
`with acute lymphocytic leukemia, ma-
`lignant melanoma, and prostate cancer.
`In the family members tested, we de-
`tected no constitutional chromosomal
`abnormality. None of the three indi-
`viduals analyzed by FISH had a dele-
`tion of the retinoblastoma (Rb-1) locus,
`which is frequently deleted in patients
`with MM, and only one (the proband)
`had a translocation involving chromo-
`somes 11 and 14, a clonal abnormality
`commonly seen in MM. Conclusion:
`The study of familial MM may provide
`insights into the pathogenesis and, ulti-
`mately, the control and prevention of
`
`MM and related disorders. [J Natl
`Cancer Inst 2001;93:1479–83]
`
`Multiple myeloma (MM), regardless
`of its initial response to therapy, is usually
`fatal (1). MM has a projected incidence of
`13 600 new cases in the United States dur-
`ing the year 2000, which closely approxi-
`mates its projected mortality of 11 200
`(1). MM is a malignancy that involves
`both mature and immature plasma cells.
`The proliferation and accumulation of
`these cells, coupled with their overpro-
`duction of specific proteins, have an im-
`pact on the clinical manifestations of this
`disorder (2). Although the etiology of
`MM remains obscure, environmental fac-
`tors, particularly radiation exposure
`among radiologists (3), have been impli-
`cated. Compared with other racial groups,
`African-Americans, especially males,
`have an increased frequency of MM (4).
`MM among married couples (5,6) and
`community clusters of MM (7,8) have
`also been described, suggesting the poten-
`tial importance of environmental factors
`in the etiology of MM.
`Reports of substantial familial cluster-
`ing of MM (4,5,7,9–23) and one report of
`a pair of identical twins with MM (21)
`suggest that primary genetic factors may
`have a role in the etiology of MM. Here
`we describe an MM-prone family and dis-
`cuss the clinical pathology and genetic
`features of the affected family members.
`
`SUBJECTS AND METHODS
`
`Family Study
`
`This study was approved by the Institutional
`Review Board at Creighton University, Omaha, NE.
`It was initiated after the proband, the first family
`member identified, expressed concern to one of the
`authors (H. T. Lynch) about an excess of MM in her
`family and gave us permission to study the family.
`We sent a questionnaire to each of the proband’s
`first- and second-degree relatives requesting a de-
`tailed genealogy and medical history, which in-
`cluded their history of cancer at all anatomic sites.
`We asked living family members with a history
`of any cancer or the legal next of kin of deceased
`family members with a history of any cancer to sign
`permission forms that allowed us to obtain the origi-
`nal medical and pathology documents and any avail-
`able tissue specimens (slides or blocks) of the af-
`fected individuals. A hematopathologist (D. D.
`Weisenburger) reviewed the slides and tissue
`blocks.
`On the basis of the information that we obtained
`from the questionnaires, we developed a working
`pedigree of the proband’s family (Fig. 1). Twenty-
`five available family members (including spouses
`and offspring) were assembled for an information
`
`session (i.e., a family information service) (24) that
`covered the natural history of MM, current knowl-
`edge about familial factors in this disease, and the
`aims and objectives of our study. Each individual in
`attendance was then told that we were interested in
`identifying a possible genetic basis for MM through
`studies of DNA obtained from samples of their
`peripheral blood.
`The family members in attendance were told that
`they could decline participation in this study at any
`time without penalty. Those family members not in
`attendance were informed about our study by letter.
`They were advised that all findings would be held in
`strict medical confidence and that their identities
`would be protected if the results of the study were
`published in the future. Family members were also
`told that any findings with clinical translation to
`their benefit would be provided to them and, with
`their permission, to their family physicians. Genetic
`counseling was provided to each member of the
`family individually. The information provided by
`the genetic counselor was based on MM risk deter-
`mined by the individual’s position in the pedigree,
`with particular attention being paid to whether they
`had a first-degree relative with MM.
`
`Immunofixation Electrophoresis of
`Urine and Serum
`
`Urine was collected over a 24-hour period from
`19 first-degree relatives of the proband. We also
`obtained peripheral blood samples by venipuncture
`from the same individuals; a portion of each of those
`samples was used to obtain serum, which was stored
`frozen at −70 °C. We used the Paragon Electropho-
`resis System (Beckman Diagnostic Systems, Brea,
`CA) and the manufacturer’s recommended protocol
`to perform standard immunofixation electrophoresis
`to identify monoclonal immunoglobulins in the
`urine and serum samples.
`
`Cytogenetic Studies
`
`Peripheral blood cells were also used for standard
`cytogenetics studies. Phytohemagglutinin (PHA)-
`stimulated and unstimulated cell cultures were es-
`tablished from peripheral blood obtained from
`individuals III-1, III-4, III-5, III-8, III-9, and IV-3.
`High-resolution G-banding was performed on chro-
`mosome preparations from PHA-stimulated cultures
`to determine if there were any constitutional chro-
`mosomal abnormalities or rearrangements segregat-
`ing with myeloma in this family. Unstimulated
`peripheral blood cultures were used to determine if
`there was an acquired clonal chromosomal abnor-
`
`Affiliations of authors: H. T. Lynch, B. Quinn-
`Laquer, Department of Preventive Medicine,
`Creighton University School of Medicine, Omaha,
`NE; W. G. Sanger (Human Genetics Laboratory),
`S. Pirruccello, D. D. Weisenburger (Department
`of Pathology and Microbiology), University of
`Nebraska Medical Center, Omaha.
`Correspondence to: Henry T. Lynch, M.D., De-
`partment of Preventive Medicine, Creighton Univer-
`sity School of Medicine, 2500 California Plaza,
`Omaha, NE 68178 (e-mail: htlynch@creighton.edu).
`See “Notes” following “References.”
`
`© Oxford University Press
`
`Journal of the National Cancer Institute, Vol. 93, No. 19, October 3, 2001
`
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`Fig. 1. Pedigree of an extended
`multiple myeloma family. The
`source of documentation for
`cancer in individuals I-2, II-1
`(for both skin and prostate car-
`cinomas), and II-6 was family
`reports. The source of docu-
`mentation for monoclonal gam-
`mopathy of unknown signifi-
`cance (MGUS) in individuals
`III-1 and III-8 was our findings
`as reported in this study. The
`source of documentation for
`prostate carcinoma in individual
`III-2 was medical records that
`discussed the cancer. The source
`of documentation for cancer in
`individuals III-2 (multiple my-
`eloma), III-5, III-6, and IV-3
`was diagnostic pathology re-
`ports. d. ⳱ dead at age (in
`years).
`
`mality associated with the affected family members
`(25).
`Fluorescence in situ hybridization (FISH) studies
`were also performed on interphase lymphocyte nu-
`clei prepared from the unstimulated peripheral blood
`cultures obtained from individuals III-5, III-8, and
`IV-3. Hybridization probes (Vysis, Inc., Downers
`Grove, IL) utilized included the LSI D135319 probe,
`which detects the presence or absence of the 13q14
`locus, and the immunoglobulin H (IgH)/CCND1
`probe, which detects the presence or absence of a
`translocation involving bcl-1 on chromosome 11 at
`q13 and the IgH locus on chromosome 14 at q32. In
`addition, we used the SpectraVysion® probe set
`(Vysis, Inc.) according to the manufacturer’s in-
`structions and the protocol described by Dave et
`al. (26) to perform multifluor-FISH (M-FISH) on
`slides of peripheral blood cells from individuals
`III-5, III-8, and IV-3 to determine their constitu-
`tional karyotypes. For both the FISH and M-FISH
`studies, freshly prepared blood slides were incu-
`bated for approximately 30 minutes at 60 °C. The
`slides were incubated in 0.1% pepsin at 37 °C for
`30 minutes, followed by a 5-minute incubation in
`phosphate-buffered saline (PBS) containing 4%
`paraformaldehyde and 50 mM MgCl2, and then
`rinsed with PBS and dehydrated by washing in suc-
`cessively increasing concentrations of ethanol. Co-
`denaturation of individual target DNA with probe
`DNA was performed at 75 °C for 5 minutes in a
`HYBrite® instrument (Vysis, Inc.) according to the
`
`manufacturer’s protocol and was followed by an
`overnight incubation at 37 °C to allow hybridization
`of the probes. The slides were then washed once
`with 0.4× standard saline citrate/0.3% Nonidet P-40
`at 72 °C for 2 minutes. The cells were then counter-
`stained with DAPI II (Vysis, Inc.) as described by
`Dave et al. (26) and viewed on an Olympus BX60
`microscope equipped with appropriate filters. Image
`capture and analysis were performed with Applied
`M-FISH capture software (Applied Imaging, Phila-
`delphia, PA).
`
`RESULTS
`
`Pedigree
`
`Fig. 1 shows the pedigree (over four
`generations) of the family that we studied.
`It also summarizes the specific cancers
`and the age of cancer onset for the af-
`fected individuals in this kindred. The
`proband (III-5) and two of her siblings
`(III-2 and III-6) developed MM. The pro-
`band’s maternal grandfather (I-2) was di-
`agnosed with leukemia (type unknown) at
`age 80 years, and he died at age 84 years.
`The proband’s mother (II-2) died of an
`unknown cause at age 66 years. The pro-
`band’s aunt (II-6) had malignant mela-
`
`noma and died at age 35 years. One of the
`proband’s siblings with MM (III-2) was
`diagnosed with prostate cancer at age 54
`years, 4 years before he was diagnosed
`with MM, and one of that sibling’s daugh-
`ters (IV-3) had acute lymphocytic leuke-
`mia when she was 3 years old. She is now
`29 years old and is in good health.
`We reviewed the medical records and
`pathology reports for the three individuals
`with MM (III-2, III-5, and III-6). Indi-
`vidual III-2 underwent magnetic reso-
`nance imaging (MRI) at age 58 years. The
`MRI results suggested that he had a tumor
`in his spine. A subsequent work-up deter-
`mined that the tumor was MM that had
`completely replaced the fifth lumbar ver-
`tebra and suggested that there was a ques-
`tionable lesion in the second sacral verte-
`bra. A bone marrow specimen from the
`iliac crest of III-2 contained atypical
`plasma cells, and immunoelectrophoresis
`of this individual’s serum revealed a
`monoclonal increase in the immunoglob-
`ulin G (IgG)-lambda immunoprotein. In-
`dividual III-5, the proband, had an MRI at
`age 62 years that showed pathologic frac-
`
`1480 REPORTS
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`tures of the twelfth thoracic and the sec-
`ond lumbar vertebrae and diffuse, abnor-
`mal signals in the bone marrow that were
`consistent with MM. A bone marrow
`specimen from the sacrum of III-5
`showed marked plasmacytosis. A final
`diagnosis of plasma cell myeloma with
`hypogammaglobulinemia was made when
`the urine immunoelectrophoresis revealed
`monoclonal kappa light chains. Individual
`III-6 sustained a pathologic fracture of
`the fourth lumbar vertebra at the age of
`53 years. Smears of his bone marrow re-
`vealed that approximately 30% of the
`cells were plasma cells. Serum protein
`immunoelectrophoresis of this individu-
`al’s serum detected an IgG-lambda
`monoclonal protein, which was consistent
`with MM.
`We performed immunofixation elec-
`trophoresis on urine and serum samples
`obtained from 19 other members of this
`family; the results of these analyses are
`summarized in Table 1. With the excep-
`tion of individuals III-1 and III-8, all fam-
`ily members tested had normal test re-
`sults; i.e., we detected no monoclonal
`proteins in their urine or serum. Indi-
`vidual III-1 had small amounts of kappa
`proteins in his serum, whereas individual
`III-8 had small amounts of monoclonal
`IgG-lambda proteins in his serum. Neither
`III-1 nor III-8 displayed any evidence of
`MM during a thorough clinical and labo-
`ratory work-up by their personal physi-
`cians. On the basis of these results, we
`conclude that the appropriate diagnosis
`for these two individuals is monoclonal
`gammopathy of unknown significance
`(MGUS). In addition, we suggest that in-
`
`dividuals III-1 and III-8, who are the
`brothers of the three siblings diagnosed
`with MM, may have an increased lifetime
`risk of developing MM and should be fol-
`lowed carefully in the future. Unfortu-
`nately, we cannot determine their absolute
`risk for MM.
`
`Cytogenetics
`
`Standard cytogenetic and FISH studies
`were performed. We observed no mitotic
`cells in unstimulated cell cultures estab-
`lished from peripheral blood samples ob-
`tained from individuals III-1, III-4, III-5,
`III-8, III-9, and IV-3. High-resolution
`chromosome analysis of the PHA-stimu-
`lated cell cultures established from the
`peripheral blood samples revealed that all
`but two of these individuals had the nor-
`mal complement of chromosomes (i.e.,
`46,XX for females and 46,XY for males).
`The two exceptions were individual III-5,
`who had a very unusual polymorphism
`(variant) involving a very large satellite
`stalk on the short arm of chromosome 14,
`and individual III-8, who had the same
`polymorphism on both copies of chromo-
`some 14. G-banding analysis at the 750-
`band level and M-FISH studies on indi-
`viduals III-5, III-8, and IV-3 revealed no
`consistent constitutional chromosomal
`abnormality or polymorphism that might
`serve as a cytogenetic marker to follow
`the segregation of the MM phenotype in
`this family.
`The retinoblastoma (Rb-1) locus at
`13q14 is frequently deleted in individuals
`with MM (27). Therefore, we performed
`interphase FISH studies on unstimulated
`
`Table 1. Serum and urine protein immunofixation electrophoresis test results for this kindred*
`
`Test (monoclonal proteins detected)
`
`Individual†
`
`III-1
`
`III-4
`III-5
`III-8
`
`III-9
`IV-2, 2 individuals§
`IV-3
`IV-5, 5 individuals§
`IV-6, 6 individuals§
`
`SIFE-1
`
`A
`(IgA-kappa)
`N
`N
`A
`(IgG-lambda)
`N
`N
`N
`N
`N
`
`SIFE-2
`
`A
`(IgA-kappa)
`ND
`ND
`A
`(IgG-lambda)
`N
`ND
`N
`ND
`ND
`
`UIFE
`
`N
`
`N
`NS‡
`N
`
`N
`N
`N
`N
`N
`
`*SIFE ⳱ serum immunofixation electrophoresis; UIFE ⳱ urine immunofixation electrophoresis;
`N ⳱ normal protein pattern; A ⳱ abnormal protein pattern; NS ⳱ no urine sample was received from that
`individual; ND ⳱ the test was not repeated; IgA ⳱ immunoglobulin A; IgG ⳱ immunoglobulin G.
`†The number designation for each individual corresponds to the individual number designations on the
`pedigree in Fig. 1.
`‡UIFE results were obtained from this individual’s medical records.
`§All siblings tested had identical test results on both tests.
`
`cultures of peripheral blood from indi-
`viduals III-5, III-8, and IV-3 by using the
`LSI D135319 probe, which detects
`13q14. All three individuals had two cop-
`ies of the 13q14 locus, thereby indicating
`that they did not have a deletion of the
`Rb-1 region. We also performed inter-
`phase FISH on these same individuals
`by using the LSI IgH/CCND1 probe,
`which detects t(11:14)(q13:q32), a trans-
`location involving bands 11q13 and
`14q32 that is also found frequently in in-
`dividuals with MM (28,29). Individual
`III-5 had a translocation involving bands
`11q13 and 14q32, but individuals III-8
`and IV-3 did not.
`
`Genetic Counseling
`
`We advised individuals III-1 and III-8
`of the abnormal electrophoretic findings
`and their long-term cancer risk implica-
`tions. These individuals were made fully
`aware of their increased risk for MM.
`They were also advised that these find-
`ings, particularly in concert with the fact
`that three of their siblings had MM, war-
`ranted long-term follow-up. Specifically,
`we recommended that each of them have
`annual protein immunoelectrophoresis of
`their serum and a 24-hour urine sample to
`screen for myeloma protein as well as a
`bone marrow examination when clinically
`indicated, because of their perceived in-
`creased risk of developing MM.
`
`DISCUSSION
`
`This family contains a remarkable sib-
`ship, wherein three siblings developed
`MM and two others, III-1 and III-8, cur-
`rently have MGUS. However, our genea-
`logic investigations do not allow us to as-
`cribe a mode of genetic transmission for
`MM in this family. The proband’s father,
`who had skin carcinoma (type unknown)
`at age 42 years and prostate cancer at age
`61 years and who died at age 84 years, did
`not have any type of hematologic cancer
`that we can determine. The proband’s
`mother, who died at age 66 years, could
`conceivably have transmitted MM to her
`children but may not have lived long
`enough to develop the disease. This find-
`ing may be due to decreased penetrance
`of a deleterious gene. According to family
`history, the proband’s maternal grandfa-
`ther (I-2) had leukemia, but whether or
`not he had MM is unclear. His wife (I-1)
`died at age 35 years of an unknown cause.
`The proband’s maternal aunt (II-6) died
`of malignant melanoma at age 35 years.
`
`Journal of the National Cancer Institute, Vol. 93, No. 19, October 3, 2001
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`Using both high-resolution chromo-
`some analysis and M-FISH, we found no
`apparent constitutional chromosomal ab-
`normalities or rearrangements that segre-
`gated with MM or with MGUS in this
`family. However, our observation that in-
`dividual III-8 had two identical copies of
`a very unusual polymorphism on the short
`arm of chromosome 14 suggests that this
`individual’s biologic parents may have
`had a common ancestor. Our inquiries
`into the possibility of consanguinity have
`produced no evidence of this to date. Al-
`ternatively, it is also possible that the ho-
`mozygous appearance of the chromosome
`14 polymorphism in individual III-8 rep-
`resents uniparental disomy. Finally, we
`found that individual III-5 had a translo-
`cation involving bands 11q13 and 14q32,
`which is an acquired chromosomal abnor-
`mality commonly linked to MM. Al-
`though t(11:14)(q13:q32) is a recurrent
`clonal abnormality in MM, the prognostic
`significance is not yet clear.
`The literature contains some reports of
`families with multiple cases of MM. In a
`review of 53 published families with MM
`in more than one family member, Roddie
`et al. (11) identified only three families
`with three affected siblings. In one of
`those three families, MM occurred in the
`three siblings over a 6-year period. Gros-
`bois et al. (10) identified 15 families with
`multiple cases of MM; three of those
`families had members with MGUS. The
`cases of MM in 10 of those 15 families
`occurred in siblings whose mean age at
`diagnosis was similar to the mean age at
`which sporadic MM is diagnosed in the
`general population. It is interesting that
`the mean age at diagnosis in those 10
`families decreased in successive genera-
`tions, suggesting the genetic phenomenon
`of anticipation, which is the increase in
`the severity of symptoms of a genetic dis-
`ease with an earlier age of onset in suc-
`cessive generations. Deshpande et al. (12)
`also found that the mean age at which
`MM is diagnosed in successive genera-
`tions was lower for children than for par-
`ents, which also raises the possibility of
`anticipation in familial MM.
`Family studies reveal that a subset of
`MM shows substantial familial clustering
`consonant with a hereditary etiology of
`MM. In their review of the pertinent lit-
`erature, Shoenfeld et al. (19) analyzed 37
`families with MM. It is interesting that the
`family members with MM showed no ma-
`jor differences with regard to sex, age,
`distribution of monoclonal proteins, clini-
`
`cal and laboratory data, or prognosis com-
`pared with individuals with nonfamilial
`myeloma in the general population. The
`authors did observe an increased inci-
`dence of immunoglobulin abnormalities
`in healthy relatives of the patients mani-
`festing MM, suggesting possible genetic
`susceptibility to MM. Meijers et al. (18)
`also identified a family with an increased
`incidence of immunoglobulin abnormali-
`ties in healthy members; in that family,
`three individuals died of MM and three
`manifested asymptomatic paraprotein-
`emia.
`Studies have also found MGUS occur-
`ring in families that also manifested MM.
`Horwitz et al. (20) described a family in
`which MM was present in three siblings,
`two of whom had a history of a monoclo-
`nal gammopathy. Their review of the lit-
`erature suggested that some cases of MM
`may have a hereditary basis and that other
`family members may be at increased risk
`for developing the disease. They con-
`cluded that, while families exhibiting sev-
`eral individuals with benign (monoclonal)
`gammopathies may not be unusual, frank
`myeloma in three siblings appeared very
`rarely. Bizzaro and Pasini (16) studied a
`family in which five siblings had a mono-
`clonal gammopathy. Two of the five sib-
`lings were diagnosed with MGUS, and
`one sister died of MM. There was, how-
`ever, no association between the human
`leukocyte antigen haplotypes of these af-
`fected individuals and the presence of a
`monoclonal protein.
`Individuals with familial MM, like
`those with the majority of hereditary can-
`cer syndromes (30), appear to show sus-
`ceptibility to other hematologic cancers as
`well as solid tumors. Eriksson and Hall-
`berg (14) studied hematologic malignan-
`cies and different types of cancer in re-
`lated individuals in Sweden. They found
`that, among 239 case subjects with my-
`eloma and 220 control subjects, individu-
`als who had first-degree relatives with
`hematologic malignancies, specifically
`MM, had an increased risk of MM them-
`selves. They also observed an increased
`risk of MM for individuals whose first-
`degree relatives had had other types of
`tumors, especially if they occurred in the
`prostate or brain.
`In the pedigree of the family we have
`described (Fig. 1), note that the proband’s
`maternal aunt (II-6) had early-onset ma-
`lignant melanoma, a disorder often asso-
`ciated with a mutation in the CDKN2A
`tumor suppressor gene (31,32). Dilworth
`
`et al. (15) have described a family in
`which a germline mutation of CDKN2A
`was present in four melanoma-affected
`individuals as well as in a fifth family
`member who had MM. Loss-of-heterozy-
`gosity studies performed on sorted bone
`marrow from the MM patient showed loss
`of the wild-type CDKN2A allele in the
`malignant plasma cells. Dilworth et al.
`(15) have suggested “. . . that germline
`mutations of CDKN2A may predispose
`individuals to a wider variety of malig-
`nancy than has been hitherto reported, but
`that the expression of these cancers may
`depend heavily on the genetic background
`of the patient.” Whether this CDKN2A
`mutation is present in our family has not
`yet been established; this issue will be ad-
`dressed in our future studies of this fam-
`ily. However, the significance of mela-
`noma and other cancers in our MM family
`must be viewed cautiously, given the fact
`that this is a single family and of limited
`size.
`Racial differences in the incidence of
`MM could indicate cultural and/or inher-
`ited susceptibilities to MM. Brown et al.
`(33) conducted a population-based, case–
`control interview study of 361 white and
`204 black individuals with MM to deter-
`mine whether family history of cancer
`contributed to MM and what, if any, fac-
`tors might explain the racial disparity of
`risk. For both racial groups, the risk of
`MM was statistically significantly higher
`among individuals who had a first-degree
`relative with MM than among those lack-
`ing a first-degree relative with MM. The
`risk of MM was also increased among
`those who had a family history of any
`hematolymphoproliferative cancer, par-
`ticularly if the affected individual was a
`sibling of the person whose risk was be-
`ing assessed. Brown et al. concluded that
`their study provided no evidence for dif-
`ferences in MM incidence rates according
`to race.
`There are many limitations to our un-
`derstanding of familial clustering of MM,
`in which a chance association must al-
`ways be considered. For example, any
`estimate of the frequency of familial clus-
`tering of cancers such as MM could be
`substantially distorted by ascertainment
`bias. Additional biases that could lower
`the frequency estimates include the re-
`duced penetrance of genes that cosegre-
`gate with the MM phenotype and the pos-
`sible association of MM with a hereditary
`predisposition to other cancers, such as
`malignant melanoma (15). Finally, strik-
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`1482 REPORTS
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`Journal of the National Cancer Institute, Vol. 93, No. 19, October 3, 2001
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`Celgene Ex. 2006, Page 4
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`ing familial clustering of MM is more
`likely to be observed in large families, in
`which genetic susceptibility to MM is
`present, than in small families with a
`similar genetic susceptibility, given a
`larger number of genetically informative
`individuals in the larger families. Such
`findings of strong familial clustering of
`MM are also more likely to be published
`than are occurrences in patients from
`small families, skewing the information in
`the literature.
`The etiology of MM remains elusive.
`However, several studies (14,15,30) have
`suggested that individuals with familial
`MM may be susceptible to various other
`hematologic cancers as well as solid tu-
`mors. Although we identified cases of
`leukemia, prostate cancer, and malignant
`melanoma in the MM-prone family pre-
`sented in this report, we believe that cau-
`tion in the genetic interpretation of these
`cancer cases must be invoked, given the
`fact that this is a single family. Our find-
`ings that three of five siblings had a diag-
`nosis of MM and two had MGUS appear
`to defy chance and suggest that an as-yet-
`unknown host susceptibility factor and/or
`interaction with common environmental
`exposures may be associated with these
`conditions. Although familial MM is rare,
`our experience indicates that the study of
`families that have a preponderance of any
`type of cancer, including those with MM,
`could be rewarded by insights into the
`pathogenesis and, ultimately, the control
`and prevention of the disease.
`
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`NOTE