Occurrence Of Multiple Myeloma In A First Degree Relative Of A Previously Diagnosed Patient

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Obodo, Chukwudi S. Anigbo, Sunday Ocheni, Odichimma C. Obodo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5860773/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Multiple myeloma (MM) is a haematological malignancy characterized by neoplastic proliferation of terminally differentiated plasma cells. First degree relatives of patients who previously suffered from MM are believed to be at an increased risk of developing the disease. Though this is a very rare occurrence, it suggests that there are genetic factors that play key roles in the pathogenesis of the disease. Objectives To report a case of familial multiple myeloma and highlight the need for family screening. Methods This is the case report of a 65-year-old woman who presented to our clinic requesting to be screened for MM, as she was being worked up for a knee replacement surgery due to severe osteoarthritis of the right knee. She gave a history of MM occurring in her mother, who later passed following complications from the disease. She had no significant associating complaint, other than incidental findings of anaemia on complete blood count (CBC) during routine clinical visits. Results Results showed an ESR of 76mm/1hr, IgG was elevated at 3079 mg/dL (700–1600), elevated kappa FLC of 86.1mg/L (6.7–22.4), kappa/lambda FLC ratio of 7.688 (0.31–1.56), and bone marrow plasmacytosis of > 30%, with numerous abnormal forms (flaming cells, multinucleated cells) seen. Conclusion Cases of familial MM have been reported in the literature, with the majority occurring amongst siblings, and a few in the off-springs of previous MM patients. This case report highlights the need for routine screening and genetic counselling to be offered to first-degree of persons with multiple myeloma. Introduction Multiple myeloma (MM) is a haematological malignancy characterized by clonal, neoplastic proliferation of terminally differentiated plasma cells in the bone marrow. This aberrant process leads to the secretion of monoclonal, defective immunoglobulins 1 . Globally, it accounts for 13.4% of all haematological malignancies, but in Nigeria, it represents about 8.2% of all haematological malignancies, making it a commonly encountered haematological cancer. 2 , 3 Though the exact cause is unknown, several factors have been implicated including a possible familial association. 4 , 5 First degree relatives of patients who previously suffered from MM are believed to be at a 2- to 4- fold increased risk of also developing the disease. 6 , 7 Though this is a very rare occurrence, it suggests that there are genetic factors that play key roles in the pathogenesis of the disease. Cases of familial MM have been reported in the literature, with the majority occurring amongst siblings, and the minority occurring in the off-springs of previous sufferers of the disease. 5 , 8 – 12 Here we report a case of multiple myeloma occurring in a woman whose mother was previously managed for MM, similar to two cases of familial myeloma in one father and daughter, and another father and son reported in the literature. 13 , 14 Case Report Patient X, is a 65-year-old woman who presented to our clinic requesting that she be screened for multiple myeloma. She gave a history of multiple myeloma occurring in her mother, who later passed following complications from the disease. She had no significant complaints at initial evaluation other than complaints of progressively worsening right thigh and knee pain of about 15 years duration. She also gave a history of incidental findings of anaemia on complete blood count (CBC) during routine clinical visits dating back to when she was in her twenties, with no symptoms necessitating intervention. There were no other associating symptoms. Due to worsening severity of right thigh and knee pain, she was evaluated by an orthopaedic surgeon and a diagnosis of severe right knee osteoarthritis was made following review of radiological/imaging studies. She was been worked up for surgery when she requested for a referral to the haematologists for screening for multiple myeloma. She gave a history of a previous screen for multiple myeloma done fourteen years ago, where she was told that she had paraproteinaemia, but the values were not significant, requiring no further evaluation at the time. Following the initial evaluation, she was asked to do some preliminary investigations including a CBC, erythrocyte sedimentation rate (ESR), total protein, serum albumin and globulin, serum protein electrophoresis (SPEP), immunoglobulin quantitation, serum free light chains (FLC), beta-2 microglobulin, and lactate dehydrogenase (LDH). Bone marrow aspiration cytology was deferred till further evaluation with the results of the requested investigations. She was seen two weeks later at the haematology-oncology clinic with a few results of the requested investigations. The ESR was 76mm/1hr, while the CBC showed a haemoglobin of 8.6g/dL, total white blood cell count (TWBC) of 4.41 x 10 9 /L, with neutrophil, lymphocyte and monocyte differentials of 41.9%, 43.1% and 12.9% respectively, and a platelet count of 204 x 10 9 /L. There was no reversal of the albumin-globulin ratio, though the serum globulin was at the upper limit of normal (36g/L, with a reference of 18–36). There was a monoclonal band detected on SPEP, though at a very low concentration of 0.99g/dL, suggesting a low risk (< 1.5g/dL). There was a monoclonal proliferation of kappa FLC in the serum with a value of 86.1mg/L (6.7–22.4), and an elevation of the kappa/lambda FLC ratio (7.688, reference range of 0.31–1.56). IgG was elevated at 3079 mg/dL (700–1600), while IgM and IgA were normal. Beta- 2 microglobulin was 2mg/dL (1–3), and LDH was 388U/L (230–460). Bone marrow aspiration showed circulating plasma cells comprising > 30% of the nucleated marrow elements, with abnormal forms (flaming cells, multinucleated cells) seen. Bone marrow biopsy histology showed significant interstitial infiltrate of plasma cells showing moderate cytological atypia and representing approximately 20–30% of all nucleated cells in the biopsy by immunohistochemistry for CD 38, 138 and Mum 1. The cells also showed aberrant expression of CD 56, but not cyclin D1. Immunophenotyping showed that the clonal/neoplastic cells were positive (0.8%) for CD 38 and 138, weak for CD 27, 56, and 117, and negative for CD 19, 45 and 81. No pathologic or likely pathogenic variants were seen within the regions analysed in the BRAF, KRAS, NRAS, TP53, DIS3, FAM46C, and IRF4. Whole body magnetic resonance imaging (MRI) did not reveal any overtly suspicious focal lesions. Skeletal survey revealed bilateral knee osteoarthritis, with no lytic lesions seen. With the available results, a diagnosis of IgG Kappa myeloma was made. Patient was adequately counselled about the diagnosis and offered the various treatment options, including bone marrow transplantation. In view of the absence of demonstrable end organ damage (anaemia is likely attributable to a cause other than myeloma), a watch and wait approach was adopted until there is evidence of myeloma defining events. We recommended monthly to 3-monthly monitoring of specific laboratory parameters, and annual whole body skeletal survey with MRI or low-dose computed tomography (CT) scan. Patient has remained stable so far, with a follow up on some requested laboratory investigations not showing any significant rise in their levels in comparison with those done at diagnosis. Discussion The frequency of familial MM seems to be approximately 3.2 per 1000 cases of MM, leading to an occurrence of familial MM in approximately 1 per 10 million persons per year, making it a very rare occurrence. 5 The reports of familial MM in the literature suggests that primary genetic factors may have a role to play in the development of MM. Though several explanations have been given for the occurrence of familial MM such as shared environmental factors, the pattern of inheritance observed in several family buttresses the claim of the involvement of underlying genetic factors. 5 Landgren et al 15 in their study investigated the risk of both plasma cell disorders and lymphoproliferative diseases occurring in the first-degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS), which is a precursor MM lesion. It was a population-based study involving 14,621 relatives of 4458 patients with MGUS. The found an increased risk of MGUS among relatives of the patients (relative risk [RR] = 2.8; 95% CI, 1.4–5.6), and an increased risk of MM in the relatives of the patients (RR = 2.9; 95% CI, 1.9–4.3). their findings suggest that genetic factors, environmental factors or a combination of both was responsible for the observation. In a similar population-based study to assess the risk of MGUS and MM in first-degree relatives of MGUS patients, Vachon et al 16 tested the serum samples of 911 first-degree relatives older than 40 years via electrophoresis and immunofixation. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3–9.8). Though both studies were carried out in a predominantly Caucasian dominated environment, findings from studies by Jain et al 9 and Lynch et al 17 which involved African Americans found evidence that was in agreement with the possibility of an underlying familial linkage, suggesting the involvement of underlying genetic factors. Their findings were similar to that of VanValkenburg et al 18 whose case-control study carried out to assess for the contribution of family history of any hematologic malignancy on the presence of defining clinical features and laboratory characteristics in MM patients, concluded that the risk of myeloma occurring in the presence of a family history of same was higher when compared with the risk associated with any other haematological malignancy (odds ratio [OR] 3.75, 95% CI 1.75–8.05). They also found that the risk effect was higher in blacks (OR 20.9, 95% CI 2.59–168) than in whites (OR 2.04, 95% 0.83–5.04). Landgren et al 19 were able to establish the prevalence of MGUS among Ghanaian men to be 2-fold increase when compared with white men. This is in keeping with the literature where it is observed that in sporadic MM, blacks were found to have a 2- to 3-fold increased risk of MGUS and MM when compared with Caucasians. 18 Gerkes et al 5 in their study not only proposed that the risk was higher in persons with a family member who has had/who has MM, but that the risk was higher for individuals with more than one family member who has suffered from the disease. Findings from the study by Ogmundsdottir et al 20 were also similar to those earlier mentioned, however they also proposed that in addition to a significantly increased risk of developing MM for first-degree relatives (RR 2.33), the risk was largest for female relatives (RR 3.23) Familial MM is said to occur at an earlier age when compared to sporadic cases, 18 however this was not the case, as the diagnosis was made at the 6th decade of life, though her mother was over 70 years of age at diagnosis. Other reported cases of familial MM in siblings and twins also did not follow the suggested pattern of occurring at an earlier age. 11 , 12 Some other studies reported that the mean age of diagnosis of familial MM decreased with successive generations and was found to be lower for children than for parents. 8 , 21 Chance alone might have caused the observation of clustering within families, however, several families have shown a pattern of inheritance pattern that points to the involvement of some underlying genetic factor(s). Findings from the study by Lynch et al 22 that three of five siblings had a diagnosis 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. Though no genetic factor or exact mode of inheritance has been determined for familial MM, there are variations by several authors on the pattern of inheritance. While some authors propose an autosomal dominant mode of inheritance, with reduced penetrance, to explain the occurrence of multiple cases of MM within a family, 5 , 23 others suggest that an autosomal recessive inheritance with low penetrance was responsible for the occurrence of familial MM. 24 In summary, following an extensive review of the literature, there is a strong association of familial MM, and this association is found to be greater in blacks than whites. Even though the possibility that some of the proposed relationships and inheritance patterns might be due to chance, there is no doubt that there are underlying genetic aberrations and environmental factors that play significant roles in the patho-biology of familial MM, either singly or in combination. Conclusion Though not a commonly encountered scenario, this case report highlights the need to screen family members, especially first-degree relatives of individuals who have previously been diagnosed with multiple myeloma. Generally, the goal of cancer screening is to detect a pre-malignant, treatable lesion or to detect a cancer in an early, treatable stage. Even though most cases of MM are incurable, and preventing the benign precursor MGUS from progressing is practically impossible, screening might nevertheless be beneficial because detection of MGUS or early-state MM is advantageous for morbidity and delays mortality from the disease. The disadvantages of screening for MM are the possible distress for relatives in whom MGUS or MM is detected, hence proper counselling should be offered to those who might have low serum and/or urine paraproteins as seen in monoclonal gammopathy of undetermined significance (MGUS) such as the index patient, so they present for routine evaluation to monitor the progression of the disease. Routine screening with genetic counselling should be offered to first-degree and even second-degree relatives of persons with multiple myeloma. Since MM is rarely diagnosed before age 40, we propose that relatives should be screened from this age using basic laboratory investigations such as annual total serum protein quantification, serum protein electrophoresis, beta-2 microglobulin, lactate dehydrogenase, etc. Declarations Author Contribution OIO conceptualized and designed the manuscript. OIO, CSA, SO, OCO, AGO and HCO wrote the introduction and summarized the relevant clinical, laboratory and radiological information. OIO, CSA, SO, AND and HC wrote the discussion and conclusion. All authors were involved in revising the manuscript for intellectual content. All authors have read and approved the final manuscript and agreed to be accountable for all aspects of the work. All authors accept responsibility for the entire content of this manuscript and consent to its submission to this journal. Acknowledgment The authors are grateful to the patient for her cooperation and consent to publish this case. Declaration of patient consent The authors certify that they have obtained all relevant and appropriate patient consent forms. In the form, the patient has given her consent for her clinical and other relevant information to be reported in this journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, however anonymity cannot be guaranteed. Financial support and sponsorship No financial support or sponsorship was received for this manuscript. Conflict of Interest The authors declare no conflict of interest, both financial and non-financial that are directly or indirectly related to this manuscript. References Nwabuko OC, Igbigbi EE, Chukwuonye II, Nnoli MA (2017) Multiple myeloma in Niger Delta, Nigeria: complications and the outcome of palliative interventions. Cancer Manag Res 2017(9):189–196 Mahindra A, Hideshima T, Anderson KC (2010) Multiple myeloma: Biology of the disease. Blood Rev 24(Suppl 1):S5–11 Madu AJ, Ocheni S, Nwagha TU, Ibegbulam OG, Anike US (2014) Multiple myeloma in Nigeria: An insight to the clinical, laboratory features, and outcomes. Niger J Clin Pract 17(2):212–217 Alexandra J, Greenberg S, Vincent Rajkumar, Celine MV (2012) Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics. Blood 119(23):5359–5366 Gerkes EH, de Jong MM, Sijmons RH, Vellenga E (2007) Familial Multiple Myeloma: Report on Two Families and Discussion of Screening Options. Hered Cancer Clin Pract 5(2):72–78 Catalano C, Paramasivam N, Blocka J, Giangiobbe S, Huhn Stefanie et al (2021) Characterization of rare germline variants in familial multiple myeloma. Blood Cancer J 11(33):1–4 Frank C, Fallah M, Chen T, Mai EK, Sundquist J et al (2016) Search for familial clustering of multiple myeloma with any cancer. Leukemia. ; 30(2016):627–632 Grosbois B, Jego P, Attal M, Payen C, Rapp MJ et al (1999) Familial multiple myeloma: report of fifteen families. Br J Haematol 105(3):768–770 Jain M, Ascensao J, Schechter GP (2009) Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 84(1):34–38 Várkonyi J, Farkas P, Tamáska J, Masszi T, Gopcsa L et al (2009) Familial multiple myeloma. Two more families. cent eur j med 4(4):501–505 Olujohungbe AB, Gledhill T, Satchithananathan G (2006) Temporal development of myeloma in a syngeneic twin pair. Br J Haematol 133(2):211–212 Cutting RJ, Snowden JA (2006) Myeloma in monozygotic twin. Br J Haematol 134(6):646–646 Crozes-Bony P, Palazzo E, Meyer O, De Bandt M, Kahn MF (1995) Familial multiple myeloma. Report of a case in a father and daughter. Review of the literature. Rev Rhum Engl Ed 62(6):439–445 McCrea AP, Morris TC (1986) Concurrent familial myeloma in Northern Ireland. Cancer 58(2):394–396 Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C et al (2009) Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 114(4):791–795 Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR et al (2009) Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 114(4):785–790 Lynch H, Ferrara K, Barlogie B, Coleman EA, Lynch JF et al (2008) Familial myeloma. N Engl J Med 359(2):152–157 VanValkenburg ME, Pruitt GI, Brill IK, Costa L, Ehtsham M et al (2016) Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features. Cancer Causes Control. ;27(2016):81–91 Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA et al (2007) Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. In Mayo Clinic Proceedings. ;82(12):1468-73 Ogmundsdottir HM, Haraldsdottirm V, Johannesson GM, Olafsdottir G, Bjarnadottir K, Sigvaldason H, Tulinius H (2005) Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families. Haematologica 90(1):66–71 Deshpande HA, Hu XP, Marino P, Jan NA, Wiernik PH (1998) Anticipation in familial plasma cell dyscrasias. Br J Haematol 103(3):696–703 Lynch HT, Sanger WG, Pirruccello S, Quinn-Laquer B, Weisenburger DD (2001) Familial Multiple Myeloma: A Family Study and Review of the Literature. J Natl Cancer Inst 93(19):1479–1483 Landgren O, Linet MS, McMaster ML, Gridley G, Hemminki K, Goldin LR (2006) Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study. Int J Cancer 118(12):3095–3098 Engelhardt M, Ihorst G, Behringer D, Finke J, Roth B (2006) Incidence of monoclonal B-cell disease in siblings of patients with multiple myeloma. Haematologica 91(2):274–276 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5860773","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":406197321,"identity":"7a9f5946-58be-4fa9-a7aa-44b074db7fc7","order_by":0,"name":"Onochie I. 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This aberrant process leads to the secretion of monoclonal, defective immunoglobulins\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Globally, it accounts for 13.4% of all haematological malignancies, but in Nigeria, it represents about 8.2% of all haematological malignancies, making it a commonly encountered haematological cancer.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Though the exact cause is unknown, several factors have been implicated including a possible familial association.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e First degree relatives of patients who previously suffered from MM are believed to be at a 2- to 4- fold increased risk of also developing the disease.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Though this is a very rare occurrence, it suggests that there are genetic factors that play key roles in the pathogenesis of the disease.\u003c/p\u003e \u003cp\u003eCases of familial MM have been reported in the literature, with the majority occurring amongst siblings, and the minority occurring in the off-springs of previous sufferers of the disease.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Here we report a case of multiple myeloma occurring in a woman whose mother was previously managed for MM, similar to two cases of familial myeloma in one father and daughter, and another father and son reported in the literature.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003ePatient X, is a 65-year-old woman who presented to our clinic requesting that she be screened for multiple myeloma. She gave a history of multiple myeloma occurring in her mother, who later passed following complications from the disease. She had no significant complaints at initial evaluation other than complaints of progressively worsening right thigh and knee pain of about 15 years duration. She also gave a history of incidental findings of anaemia on complete blood count (CBC) during routine clinical visits dating back to when she was in her twenties, with no symptoms necessitating intervention. There were no other associating symptoms. Due to worsening severity of right thigh and knee pain, she was evaluated by an orthopaedic surgeon and a diagnosis of severe right knee osteoarthritis was made following review of radiological/imaging studies. She was been worked up for surgery when she requested for a referral to the haematologists for screening for multiple myeloma. She gave a history of a previous screen for multiple myeloma done fourteen years ago, where she was told that she had paraproteinaemia, but the values were not significant, requiring no further evaluation at the time. Following the initial evaluation, she was asked to do some preliminary investigations including a CBC, erythrocyte sedimentation rate (ESR), total protein, serum albumin and globulin, serum protein electrophoresis (SPEP), immunoglobulin quantitation, serum free light chains (FLC), beta-2 microglobulin, and lactate dehydrogenase (LDH). Bone marrow aspiration cytology was deferred till further evaluation with the results of the requested investigations.\u003c/p\u003e \u003cp\u003eShe was seen two weeks later at the haematology-oncology clinic with a few results of the requested investigations. The ESR was 76mm/1hr, while the CBC showed a haemoglobin of 8.6g/dL, total white blood cell count (TWBC) of 4.41 x 10\u003csup\u003e9\u003c/sup\u003e/L, with neutrophil, lymphocyte and monocyte differentials of 41.9%, 43.1% and 12.9% respectively, and a platelet count of 204 x 10\u003csup\u003e9\u003c/sup\u003e/L. There was no reversal of the albumin-globulin ratio, though the serum globulin was at the upper limit of normal (36g/L, with a reference of 18\u0026ndash;36). There was a monoclonal band detected on SPEP, though at a very low concentration of 0.99g/dL, suggesting a low risk (\u0026lt;\u0026thinsp;1.5g/dL). There was a monoclonal proliferation of kappa FLC in the serum with a value of 86.1mg/L (6.7\u0026ndash;22.4), and an elevation of the kappa/lambda FLC ratio (7.688, reference range of 0.31\u0026ndash;1.56). IgG was elevated at 3079 mg/dL (700\u0026ndash;1600), while IgM and IgA were normal. Beta- 2 microglobulin was 2mg/dL (1\u0026ndash;3), and LDH was 388U/L (230\u0026ndash;460). Bone marrow aspiration showed circulating plasma cells comprising\u0026thinsp;\u0026gt;\u0026thinsp;30% of the nucleated marrow elements, with abnormal forms (flaming cells, multinucleated cells) seen. Bone marrow biopsy histology showed significant interstitial infiltrate of plasma cells showing moderate cytological atypia and representing approximately 20\u0026ndash;30% of all nucleated cells in the biopsy by immunohistochemistry for CD 38, 138 and Mum 1. The cells also showed aberrant expression of CD 56, but not cyclin D1. Immunophenotyping showed that the clonal/neoplastic cells were positive (0.8%) for CD 38 and 138, weak for CD 27, 56, and 117, and negative for CD 19, 45 and 81. No pathologic or likely pathogenic variants were seen within the regions analysed in the BRAF, KRAS, NRAS, TP53, DIS3, FAM46C, and IRF4. Whole body magnetic resonance imaging (MRI) did not reveal any overtly suspicious focal lesions. Skeletal survey revealed bilateral knee osteoarthritis, with no lytic lesions seen.\u003c/p\u003e \u003cp\u003eWith the available results, a diagnosis of IgG Kappa myeloma was made. Patient was adequately counselled about the diagnosis and offered the various treatment options, including bone marrow transplantation. In view of the absence of demonstrable end organ damage (anaemia is likely attributable to a cause other than myeloma), a watch and wait approach was adopted until there is evidence of myeloma defining events. We recommended monthly to 3-monthly monitoring of specific laboratory parameters, and annual whole body skeletal survey with MRI or low-dose computed tomography (CT) scan. Patient has remained stable so far, with a follow up on some requested laboratory investigations not showing any significant rise in their levels in comparison with those done at diagnosis.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe frequency of familial MM seems to be approximately 3.2 per 1000 cases of MM, leading to an occurrence of familial MM in approximately 1 per 10\u0026nbsp;million persons per year, making it a very rare occurrence.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e The reports of familial MM in the literature suggests that primary genetic factors may have a role to play in the development of MM. Though several explanations have been given for the occurrence of familial MM such as shared environmental factors, the pattern of inheritance observed in several family buttresses the claim of the involvement of underlying genetic factors.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eLandgren et al\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e in their study investigated the risk of both plasma cell disorders and lymphoproliferative diseases occurring in the first-degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS), which is a precursor MM lesion. It was a population-based study involving 14,621 relatives of 4458 patients with MGUS. The found an increased risk of MGUS among relatives of the patients (relative risk [RR]\u0026thinsp;=\u0026thinsp;2.8; 95% CI, 1.4\u0026ndash;5.6), and an increased risk of MM in the relatives of the patients (RR\u0026thinsp;=\u0026thinsp;2.9; 95% CI, 1.9\u0026ndash;4.3). their findings suggest that genetic factors, environmental factors or a combination of both was responsible for the observation.\u003c/p\u003e \u003cp\u003eIn a similar population-based study to assess the risk of MGUS and MM in first-degree relatives of MGUS patients, Vachon et al\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e tested the serum samples of 911 first-degree relatives older than 40 years via electrophoresis and immunofixation. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3\u0026ndash;9.8).\u003c/p\u003e \u003cp\u003eThough both studies were carried out in a predominantly Caucasian dominated environment, findings from studies by Jain et al\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and Lynch et al\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e which involved African Americans found evidence that was in agreement with the possibility of an underlying familial linkage, suggesting the involvement of underlying genetic factors. Their findings were similar to that of VanValkenburg et al\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e whose case-control study carried out to assess for the contribution of family history of any hematologic malignancy on the presence of defining clinical features and laboratory characteristics in MM patients, concluded that the risk of myeloma occurring in the presence of a family history of same was higher when compared with the risk associated with any other haematological malignancy (odds ratio [OR] 3.75, 95% CI 1.75\u0026ndash;8.05). They also found that the risk effect was higher in blacks (OR 20.9, 95% CI 2.59\u0026ndash;168) than in whites (OR 2.04, 95% 0.83\u0026ndash;5.04). Landgren et al\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e were able to establish the prevalence of MGUS among Ghanaian men to be 2-fold increase when compared with white men. This is in keeping with the literature where it is observed that in sporadic MM, blacks were found to have a 2- to 3-fold increased risk of MGUS and MM when compared with Caucasians.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGerkes et al\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e in their study not only proposed that the risk was higher in persons with a family member who has had/who has MM, but that the risk was higher for individuals with more than one family member who has suffered from the disease.\u003c/p\u003e \u003cp\u003eFindings from the study by Ogmundsdottir et al\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e were also similar to those earlier mentioned, however they also proposed that in addition to a significantly increased risk of developing MM for first-degree relatives (RR 2.33), the risk was largest for female relatives (RR 3.23)\u003c/p\u003e \u003cp\u003eFamilial MM is said to occur at an earlier age when compared to sporadic cases,\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e however this was not the case, as the diagnosis was made at the 6th decade of life, though her mother was over 70 years of age at diagnosis. Other reported cases of familial MM in siblings and twins also did not follow the suggested pattern of occurring at an earlier age.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Some other studies reported that the mean age of diagnosis of familial MM decreased with successive generations and was found to be lower for children than for parents.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eChance alone might have caused the observation of clustering within families, however, several families have shown a pattern of inheritance pattern that points to the involvement of some underlying genetic factor(s). Findings from the study by Lynch et al\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e that three of five siblings had a diagnosis 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.\u003c/p\u003e \u003cp\u003eThough no genetic factor or exact mode of inheritance has been determined for familial MM, there are variations by several authors on the pattern of inheritance. While some authors propose an autosomal dominant mode of inheritance, with reduced penetrance, to explain the occurrence of multiple cases of MM within a family,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e others suggest that an autosomal recessive inheritance with low penetrance was responsible for the occurrence of familial MM.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn summary, following an extensive review of the literature, there is a strong association of familial MM, and this association is found to be greater in blacks than whites. Even though the possibility that some of the proposed relationships and inheritance patterns might be due to chance, there is no doubt that there are underlying genetic aberrations and environmental factors that play significant roles in the patho-biology of familial MM, either singly or in combination.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThough not a commonly encountered scenario, this case report highlights the need to screen family members, especially first-degree relatives of individuals who have previously been diagnosed with multiple myeloma. Generally, the goal of cancer screening is to detect a pre-malignant, treatable lesion or to detect a cancer in an early, treatable stage. Even though most cases of MM are incurable, and preventing the benign precursor MGUS from progressing is practically impossible, screening might nevertheless be beneficial because detection of MGUS or early-state MM is advantageous for morbidity and delays mortality from the disease. The disadvantages of screening for MM are the possible distress for relatives in whom MGUS or MM is detected, hence proper counselling should be offered to those who might have low serum and/or urine paraproteins as seen in monoclonal gammopathy of undetermined significance (MGUS) such as the index patient, so they present for routine evaluation to monitor the progression of the disease. Routine screening with genetic counselling should be offered to first-degree and even second-degree relatives of persons with multiple myeloma. Since MM is rarely diagnosed before age 40, we propose that relatives should be screened from this age using basic laboratory investigations such as annual total serum protein quantification, serum protein electrophoresis, beta-2 microglobulin, lactate dehydrogenase, etc.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003eAuthor Contribution\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOIO conceptualized and designed the manuscript. OIO, CSA, SO, OCO, AGO and HCO wrote the introduction and summarized the relevant clinical, laboratory and radiological information. OIO, CSA, SO, AND and HC wrote the discussion and conclusion. All authors were involved in revising the manuscript for intellectual content. All authors have read and approved the final manuscript and agreed to be accountable for all aspects of the work. All authors accept responsibility for the entire content of this manuscript and consent to its submission to this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the patient for her cooperation and consent to publish this case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of patient consent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors certify that they have obtained all relevant and appropriate patient consent forms. In the form, the patient has given her consent for her clinical and other relevant information to be reported in this journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, however anonymity cannot be guaranteed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support and sponsorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support or sponsorship was received for this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest, both financial and non-financial that are directly or indirectly related to this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNwabuko OC, Igbigbi EE, Chukwuonye II, Nnoli MA (2017) Multiple myeloma in Niger Delta, Nigeria: complications and the outcome of palliative interventions. Cancer Manag Res 2017(9):189\u0026ndash;196\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahindra A, Hideshima T, Anderson KC (2010) Multiple myeloma: Biology of the disease. Blood Rev 24(Suppl 1):S5\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMadu AJ, Ocheni S, Nwagha TU, Ibegbulam OG, Anike US (2014) Multiple myeloma in Nigeria: An insight to the clinical, laboratory features, and outcomes. Niger J Clin Pract 17(2):212\u0026ndash;217\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexandra J, Greenberg S, Vincent Rajkumar, Celine MV (2012) Familial monoclonal gammopathy of undetermined significance and multiple myeloma: epidemiology, risk factors, and biological characteristics. Blood 119(23):5359\u0026ndash;5366\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerkes EH, de Jong MM, Sijmons RH, Vellenga E (2007) Familial Multiple Myeloma: Report on Two Families and Discussion of Screening Options. Hered Cancer Clin Pract 5(2):72\u0026ndash;78\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCatalano C, Paramasivam N, Blocka J, Giangiobbe S, Huhn Stefanie et al (2021) Characterization of rare germline variants in familial multiple myeloma. Blood Cancer J 11(33):1\u0026ndash;4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrank C, Fallah M, Chen T, Mai EK, Sundquist J et al (2016) Search for familial clustering of multiple myeloma with any cancer. Leukemia. ; 30(2016):627\u0026ndash;632\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrosbois B, Jego P, Attal M, Payen C, Rapp MJ et al (1999) Familial multiple myeloma: report of fifteen families. Br J Haematol 105(3):768\u0026ndash;770\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain M, Ascensao J, Schechter GP (2009) Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 84(1):34\u0026ndash;38\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eV\u0026aacute;rkonyi J, Farkas P, Tam\u0026aacute;ska J, Masszi T, Gopcsa L et al (2009) Familial multiple myeloma. Two more families. cent eur j med 4(4):501\u0026ndash;505\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlujohungbe AB, Gledhill T, Satchithananathan G (2006) Temporal development of myeloma in a syngeneic twin pair. Br J Haematol 133(2):211\u0026ndash;212\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCutting RJ, Snowden JA (2006) Myeloma in monozygotic twin. Br J Haematol 134(6):646\u0026ndash;646\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrozes-Bony P, Palazzo E, Meyer O, De Bandt M, Kahn MF (1995) Familial multiple myeloma. Report of a case in a father and daughter. Review of the literature. Rev Rhum Engl Ed 62(6):439\u0026ndash;445\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCrea AP, Morris TC (1986) Concurrent familial myeloma in Northern Ireland. Cancer 58(2):394\u0026ndash;396\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLandgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C et al (2009) Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood 114(4):791\u0026ndash;795\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR et al (2009) Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 114(4):785\u0026ndash;790\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLynch H, Ferrara K, Barlogie B, Coleman EA, Lynch JF et al (2008) Familial myeloma. N Engl J Med 359(2):152\u0026ndash;157\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanValkenburg ME, Pruitt GI, Brill IK, Costa L, Ehtsham M et al (2016) Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features. Cancer Causes Control. ;27(2016):81\u0026ndash;91\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLandgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA et al (2007) Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. In Mayo Clinic Proceedings. ;82(12):1468-73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgmundsdottir HM, Haraldsdottirm V, Johannesson GM, Olafsdottir G, Bjarnadottir K, Sigvaldason H, Tulinius H (2005) Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families. Haematologica 90(1):66\u0026ndash;71\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeshpande HA, Hu XP, Marino P, Jan NA, Wiernik PH (1998) Anticipation in familial plasma cell dyscrasias. Br J Haematol 103(3):696\u0026ndash;703\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLynch HT, Sanger WG, Pirruccello S, Quinn-Laquer B, Weisenburger DD (2001) Familial Multiple Myeloma: A Family Study and Review of the Literature. J Natl Cancer Inst 93(19):1479\u0026ndash;1483\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLandgren O, Linet MS, McMaster ML, Gridley G, Hemminki K, Goldin LR (2006) Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study. Int J Cancer 118(12):3095\u0026ndash;3098\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEngelhardt M, Ihorst G, Behringer D, Finke J, Roth B (2006) Incidence of monoclonal B-cell disease in siblings of patients with multiple myeloma. Haematologica 91(2):274\u0026ndash;276\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5860773/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5860773/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMultiple myeloma (MM) is a haematological malignancy characterized by neoplastic proliferation of terminally differentiated plasma cells. First degree relatives of patients who previously suffered from MM are believed to be at an increased risk of developing the disease. Though this is a very rare occurrence, it suggests that there are genetic factors that play key roles in the pathogenesis of the disease.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo report a case of familial multiple myeloma and highlight the need for family screening.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is the case report of a 65-year-old woman who presented to our clinic requesting to be screened for MM, as she was being worked up for a knee replacement surgery due to severe osteoarthritis of the right knee. She gave a history of MM occurring in her mother, who later passed following complications from the disease. She had no significant associating complaint, other than incidental findings of anaemia on complete blood count (CBC) during routine clinical visits.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eResults showed an ESR of 76mm/1hr, IgG was elevated at 3079 mg/dL (700\u0026ndash;1600), elevated kappa FLC of 86.1mg/L (6.7\u0026ndash;22.4), kappa/lambda FLC ratio of 7.688 (0.31\u0026ndash;1.56), and bone marrow plasmacytosis of \u0026gt;\u0026thinsp;30%, with numerous abnormal forms (flaming cells, multinucleated cells) seen.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCases of familial MM have been reported in the literature, with the majority occurring amongst siblings, and a few in the off-springs of previous MM patients. This case report highlights the need for routine screening and genetic counselling to be offered to first-degree of persons with multiple myeloma.\u003c/p\u003e","manuscriptTitle":"Occurrence Of Multiple Myeloma In A First Degree Relative Of A Previously Diagnosed Patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-28 04:02:53","doi":"10.21203/rs.3.rs-5860773/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9d4ff712-9419-4469-bfb9-9c3daa95a7c2","owner":[],"postedDate":"January 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-28T04:02:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-28 04:02:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5860773","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5860773","identity":"rs-5860773","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}