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Hematology Reports 2016; volume 8:6295

Immunoglobulin D multiple Case Report Correspondence: Naveed Ali, Abington Memorial myeloma, Hospital/Abington-Jefferson Health, Department and chronic myelogenous An 88-year-old male urologist with a history of Internal Medicine, 1200 Old York Road, leukemia in a single patient of atrial fibrillation, iron deficiency anemia Abington, 19001 PA, USA. and unprovoked pulmonary thromboembolism, Tel.: +1.267.471.0165 - Fax: +1.215.481.4361. treated simultaneously with presented to our hospital in January 2014 after E-mail: [email protected] , bortezomib, a fall leading to rhabdomyolysis and quadri- Key words: Immunoglobulin D ; and imatinib ceps tendon rupture. Upon laboratory investi- plasma cell leukemia; chronic myelogenous gations, he was found to have normocytic nor- leukemia; bortezomib; imatinib. Naveed Ali,1 Peter V. Pickens,2 mochromic anemia with a hemoglobin level of Herbert E. Auerbach3 9.8 g/dL, mean corpuscular volume of 94.3 fl Contributions: the authors contributed equally. and reticulocyte count of 2.3%. White blood cell 1 Departments of Internal Medicine, count was 14.6×103 per µL (58% neutrophils, Conflict of interest: the authors declare no poten- 2 3 Hematology and Oncology, Pathology, 12% lymphocytes, 30% monocytes, 0% tial conflict of interest. Abington Memorial Hospital/Abington- basophils and 0% eosinophils) and platelet Jefferson Health, PA, USA count was 191×103 per µL. Absolute monocyte Received for publication: 4 November 2015. count was elevated at 4.4×103 per µL (normal Revision received: 19 January 2016. Accepted for publication: 19 January 2016. range 0.0-0.9×103 per µL). Iron deficiency ane- mia and megaloblastic anemia due to hypovit- This work is licensed under a Creative Commons Abstract aminosis B12 or folate were excluded. Attribution-NonCommercial 4.0 International Presence of anemia and persistent monocyto- License (CC BY-NC 4.0). Multiple myeloma (MM) is a neoplastic lym- sis suggested underlying bone marrow pathol- ogy such as myelodysplasia or chronic ©Copyright N. Ali et al., 2016 phoproliferative disorder characterized by Licensee PAGEPress, Italy uncontrolled monoclonal plasma cell prolifera- myelomonocytic leukemia, and warranted a bone marrow examination. onlyHematology Reports 2016; 8:6295 tion. Among different isotypes of MM, doi:10.4081/hr.2016.6295 immunoglobulin D (IgD) MM is very rare, rep- A bone marrow aspirate and biopsy showed resenting only 1 to 2% of all isotypes. Chronic mild trilineage hypercellularity with myeloid to erythroid cell ratio of 4.7:1; however monocytes myelogenous leukemia (CML) is a neoplastic kappa smoldering multiple myeloma (Durie- were not noted to be elevated (Figure 1A-C). myeloproliferative disorder of pluripotent use Salmon stage I and International Staging Immunohistochemical stains demonstrated 15 hematopoietic stem cell, which is character- System I) and chronic phase chronic myel- CD138 positive, CD20 positive, monoclonal ized by the uncontrolled proliferation of ogenous leukemia simultaneously. Therapy kappa plasma cells accounting for 10% cellular- myeloid cells. An 88-year-old male was diag- was not initiated and a watch and wait ity (Figure 1D,E). Flow cytometry demonstrat- nosed simultaneously with IgD kappa MM and approach was implemented with serial clinical ed plasma cells positive for kappa chain, CD38, CML. A distinctive feature in this patient was and laboratory assessments. CD138, CD20, partial CD45, dim CD27 and the progression to plasma cell leukemia with- In May 2014, after two months of initial CD200, and negative for CD19, CD56, CD117, out any symptomatic myeloma stage. He was diagnosis, he developed profound fatigue, CD28 and CD81. Cytogenetic analysis by FISH treated simultaneously with lenalidomide, severe nocturnal sweating and low grade (fluorescence in situ hybridization) demon- bortezomib and imatinib. Synchronous occur- fevers. On laboratory evaluation, he had a sud- strated translocation t(11;14) (Figure 1F) and den increase in white blood cell count to rence of these rare hematological malignan- deletion chromosome 17p13 (TP53) but did not 40×103 per µL, increase in serum kappa chain cies in a single patient is an exceedingly rare commercialdetect rearrangements of chromosome 1p or level and decrease in immunoglobulin levels event. Multiple hypotheses to explain co-occur- 1q, gain of chromosome 5q, deletion of chro- (Table 1). A peripheral blood smear examina- rence of CML and MM have been proposed; mosome 13 (or 13q), t(14;16) or t(4;14). tion showed presence of circulating plasma however, the exact etiological molecular patho- Unexpectedly, karyotype analysis detected cells, plasmacytoid lymphocytes and abnormal physiology remains elusive. Non Philadelphia chromosome [t(9;22)(q34;q11)] lymphocytes which were previously not pres- in 8 out of 20 metaphases analyzed (Figure ent (Figure 1H). He had rapidly progressed 1G). Serum protein electrophoresis and from an asymptomatic smoldering myeloma immunofixation showed immunoglobulin D stage to PCL. Introduction kappa monoclonality with M-spike of 1 g/dL. A Therapy for MM and PCL was instituted as skeletal survey was unremarkable for any char- RVD (lenalidomide, bortezomib and dexam- Multiple myeloma (MM) has an annual inci- acteristic myeloma bony lesions, as was mag- ethasone) regimen that resulted in disappear- dence of 5.6 cases per 100,000 individuals in netic resonance imaging of the spine. Serum ance of plasma cells from peripheral circula- the US.1 Chronic myelogenous leukemia calcium and renal function were normal. tion. Imatinib for treatment of CML was not (CML) has an annual incidence of 1-2 cases Serum free kappa chains were elevated with started along with RVD to avoid potentially per 100,000 individuals.2-4 Co-occurrence of an increased kappa:lambda chain ratio (Table dangerous adverse effects from combined pro- these two disorders in one patient is an 1). Immunoglobulin levels were depressed teasome inhibitor and tyrosine kinase extremely rare event, described in a handful of except for markedly elevated immunoglobulin inhibitor therapy given patient’s advanced age cases in the literature.4-14 We describe an D level (Table 1). At the same time, quantifica- and co-morbidities. However, he exhibited exceedingly rare case of simultaneous tion of chimeric BCR-ABL mRNA transcripts worsening leukocytosis and thrombocytosis immunoglobulin D kappa MM with plasma cell was done by reverse transcription polymerase with counts as high as 90×103 per µL and leukemia (PCL) and CML which, to our knowl- chain reaction (RT-PCR). There were no plas- 2069×103 per µL, respectively. BCR-ABL mRNA edge, has not been reported in the literature. ma cells detected on peripheral smear exami- transcripts were found elevated at 180.38%. He nation. He was therefore diagnosed with IgD was subsequently started on imatinib (400 mg

[Hematology Reports 2016; 8:6295] [page 1] Case Report daily) for CML. Both RVD and imatinib were ment in free kappa chain, LDH, BCR-ABL ued to decline. In September 2014, he was continued which he tolerated well with diar- mRNA transcripts and immunoglobulin D lev- admitted to the hospital and succumbed to ful- rhea as the only which was well con- els. A trend of myeloma parameters longitudi- minant septic shock consequent to pneumo- trolled with antidiarrheal medication. nally over time is summarized in Table 1. A nia. Over the next few weeks, he demonstrated complete clinical remission, however, was not subjective improvement as well as improve- achieved. The immunoglobulin levels contin-

Table 1. Laboratory myeloma parameters. Smoldering MM MM/PCL (therapy initiated) Follow-up on treatment M-spike, g/dL 1 1 0 Free kappa chain level (normal range 3.3-19.4 mg/L) 99.5 107.2 21.5 Free lambda chain level (normal range 5.7-26.3 mg/L) 6.4 8.1 10.8 Free kappa/lambda ratio (normal range 0.26-1.65) 15.55 13.23 1.99 Beta 2 microglobulin (normal <2.51 mg/L) 2.56 3.53 4.61 LDH (normal range 120-250 U/L) 258 595 209 Immunoglobulin G (normal range 694-1618 mg/dL) 433 312 267 Immunoglobulin A (normal range 81-463 mg/dL) 65 34 31 Immunoglobulin M (normal range 48-271 mg/dL) 49 38 32 Immunoglobulin D (normal <179 mg/L) 4640 3570 152 MM, multiple myeloma; PCL, plasma cell leukemia; LDH, lactate dehydrogenase

Table 2. Characteristics of cases of coexisting multiple myeloma and chronic myelogenous leukemia. Light chain Case Age/ Sex Chronological Treatment only report order Immunoglobulin G

5 κ Pessach et al. 63/F CML → MM CML: Imatinib, MM: bortezomib,use lenalidomide, dexamethasone 5 λ Pessach et al. 68/M MM → CML MM: , , dexamethasone, radiation, zoledronic acid, CML: imatinib 6 κ Alsidawi et al. 60/M MM → CML MM: Radiation, lenalidomide, bortezomib, dexamethasone, CML/ AML – hydroxyurea, dasatinib 7 κ Ragupathi et al. 62/F MM → CML MM: Radiation, dexamethasone, bortezomib, , doxorubicin, lenalidomide, CML: dasatinib 8 κ Offiah et al. 71/F MM + CML CML: Imatinib, MM: , prednisolone, bortezomib, dexamethasone, lenalidomide, cyclophosphamide 9 κ Ide et al. 72/F CML → MM CML: Imatinib, MM: no treatment 12 λ Garipidou et al. 68/M CML → MM CML: INF-alpha, imatinib, MM: malphalan and prednisolone 5 λ Wakayama et al. 85/F MM + CML 13 κ Shwarzmeier et al. 66/M CML +commercial MM CML: Hydroxyurea, IFN-alpha, , MM: melphalan and prednisolone 5,7 κ Nitta et al. 70/M MM → CML CML: , MM: Not reported 5,7 κ Tanaka et al. 72/F CML + MM CML: INF-alpha, hydroxycarbamide, MM: INF-alpha, sulfate, prednisolone 5,7 κ Klenn et al. 71/M MM → CML MM: Radiation, malphalan, , CML: Hydroxyurea 5,7 κ Boots et al. 58/MNon CML + MM MM: Radiation, malphalan, prednisone, CML: hydroxyurea, busulfan, thioguanine 5,7 κ Derghazarian et al. 65/F CML → MM MM and CML: busulphan, Radiation, mustard Immunoglobulin A

4 λ Maerki et al. 77/M CML + MM MM: radiation, bortezomib, CML: anti CML treatment (not specified) 5 κ Romanenko et al. 64/F CML + MM MM: bortezomib, dexamethasone, CML: Imatinib 10 κ Michael et al. 57/F CML → MM CML: Imatinib, MM: thalidomide, dexamethasone, vincristine, liposomal doxorubicin, bortezomib 11 κ Galanopoulos et al. 76/M CML → MM CML: INF-alpha, imatinib, MM: malphalan and prednisolone 14 κ Alvarez-Larran et al. 81/M CML + MM MM: Malphalan and prednisone, CML: not reported Bence Jones protein

5 λ Yokota et al. 71/ M CML → MM CML: Imatinib 5 κ Nakagawa et al. 47/ M MM → CML 5 MacSween et al. 77/ M MM → CML CML: 6-, MM: None Immunoglobulin D

κ Present Case 88/M MM + CML MM: RVD, CML: Imatinib MM, multiple myeloma; CML, chronic myelogenous leukemia; INF-alpha, interferon alpha.

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Figure 1. A) Myeloid and erythroid cells in bone marrow aspirate; B) bone marrow core biopsy showing mild hypercellularity; C) trilineage hematopoiesis; D) CD 138 positive plasma cells; E) kappa chain positive plasma cells; F) fluorescence in situ hybridization analysis showing 1 red signal (CCND1 or Cyclin D1), 1 green signal (IgH) and 2 yellow fusion signals [t(11;14)]; G) karyotype analysis showing translocation between chromosome 9 and 22 (arrows); H) peripheral smear showing plasma cells with eccentric nucleus and perinuclear halo.

[Hematology Reports 2016; 8:6295] [page 3] Case Report

CD56. Lack of CD56, a cell adhesion molecule, background of immunoparesis rendered by Discussion is a characteristic finding in PCL that causes multiple myeloma. In addition, chronic anti- egression of plasma cells from bone marrow genic stimulation due to multiple etiological Based on National Cancer Institute microenvironment to the peripheral circula- factors may be involved in the development of Surveillance, Epidemiology and End Results tion.19,20 The presence of CD20/CD27 and simultaneous myeloid and lymphoid neo- Program (SEER) data, there is an increased absence of CD117/CD56 are more common in plasms.17 Other factors such as genotypic poyl- risk of secondary hematological malignancies primary PCL than in MM (or secondary PCL). morphism may also be involved. after MM and CML.4,5,16,17 However, co-occur- IgH gene rearrangements, in particular rence of these two disorders in one patient is translocation t(11;14), are also more common exceedingly rare, described very infrequently in primary PCL than secondary PCL.19,20 Based in the literature (Table 2).4-14 Most of these on lack of intermediary symptomatic myeloma Conclusions cases were diagnosed sequentially with one stage, presence of t(11;14) and immunopheno- disease preceding the other with varying time typic observations described above, we may In conclusion, the association between MM intervals between the two diagnoses. MM hypothesize that our patient developed pri- (or plasma cell leukemia) and CML may be developed first in 7 cases,5-7 while CML was mary PCL rather than secondary PCL. multifactorial. Survival has improved in diagnosed first in 7 cases.5,9-12 Eight cases Investigators have proposed several poten- patients with MM and CML, due to the advent were diagnosed with MM and CML simultane- tial pathophysiologies to explain the synchro- of novel therapies. With improving survival, ously.4,5,8,13,14 Our case is different from the nous or metachronous presence of MM and increased incidence of secondary malignan- prior-reported ones in several perspectives. CML. Firstly, a common malignant progenitor cies is emerging. Therefore, secondary malig- First, to our knowledge, our patient is the only stem cell capable of differentiating into both nancies in patients with MM and CML should case of CML coexisting with immunoglobulin myeloid and lymphoplasmacytic cell lineages be vigilantly investigated if there is a high D MM. Among previously reported cases, 14 could potentially transform into either MM or index of suspicion. Based on our and others patients had immunoglobulin G myeloma, 5 CML, which can explain the present case. experiences,4-6 we can conclude that simulta- patients had immunoglobulin A myeloma and 3 Schwarzmeier et al. studied this hypothesis in neous treatment with inhibitors patients demonstrated light chain disease a patient with simultaneous MM and CML. In and tyrosineonly kinase inhibitors may be compat- (Bence Jones protein) (Table 2). Although vitro analysis of the isolated myeloma cells did ible. In any case, further investigation on this rare, IgD MM is prognostically unfavorable as not demonstrate BCR-ABL fusion gene, there- aspect is required and encouraged. the disease is usually advanced at diagnosis by concluding that MM and CML did not arise (Durie-Salmon stage III), has higher risk of from a common malignant clone.13 extramedullary spread, poor prognosis and Tanaka et al., on the other hand, reporteduse a increased risk of transforming into plasma cell case where 97% of the marrow nucleated cells References leukemia which is a rare and aggressive plas- exhibited BCR-ABL fusion gene. Plasma cells ma cell disorder seen in only 1 to 4% of end constituted 19% of the bone marrow cellularity 1. Palumbo A, Anderson K. Multiple myelo- stage myeloma patients.18-20 Secondly, M-spike suggesting that some of these cells harbored ma. N Engl J Med 2011;364:1046-60. was noted to be only 1 g/dL in our patient. IgD BCR-ABL fusion gene.4 2. Sawyers CL. Chronic myeloid leukemia. N myeloma tends to have low M-spike as com- Secondly, tumorigenesis after exposure to Engl J Med 1999;340:1330-40. pared to other myeloma types.18 In addition, environmental carcinogens such as ionizing 3. Goldman JM, Melo JV. Chronic myeloid IgD myeloma tends to express lambda light radiation and chlorinated solvents is a well- leukemia. Advances in biology and new chains more commonly which is different in known phenomenon.17 A common insult to the approaches to treatment. N Engl J Med our case as the plasma cell clones were kappa bone marrow can cause irreparable DNA dam- 2003;349:1451-64. chain restricted.18 Thirdly, the present patient agecommercial potentially leading to neoplasms of 4. Maerki J, Katava G, Siegel D, et al. received lenalidomide, bortezomib and ima- myeloid and lymphoid origin. We postulate that Unusual case of simultaneous presenta- tinib simultaneously with minimal side out patient, being a urologist, may have had tion of plasma cell myeloma, chronic myel- effects. Only 3 cases were reported to have exposure to ionizing radiation during his pro- ogenous leukemia, and a jak2 positive received proteasome inhibitors and tyrosine fessional life that manifested in the form of myeloproliferative disorder. Case Rep kinase inhibitors together with favorableNonsimultaneous occurrence of MM and CML. Hematol 2014;2014:738428. adverse effect profile.5,6,8 Fourthly, our patient Thirdly, treatment of first malignancy with 5. Pessach I, Bartzis V, Tzenou T, et al. rapidly progressed to aggressive plasma cell cytotoxic drugs or radiation can potentially Multiple myeloma and chronic myeloge- leukemia. PCL superimposed on CML has been lead to secondary malignant transforma- nous leukemia; an uncommon coexistence reported on very rare occasions.4,14 It is worth tion.4,17 In this regard, the role of melphalan in 2 patients, with literature review. Ann mentioning that our case progressed from and cylophosphamide in developing secondary Hematol Oncol 2015;2:1030. smoldering MM to PLC without a transitional malignancies is well documented. Various sec- 6. Alsidawi S, Ghose A, Qualtieri J, symptomatic myeloma stage. ondary malignancies in lenalidomide-treated Radhakrishnan N. A case of multiple Primary PCL (arising de novo) and second- patients have also been described.17 myeloma with metachronous chronic ary PCL (leukemic transformation of terminal Nevertheless, this hypothesis cannot be myeloid leukemia treated successfully stage relapsed or refractory MM) represent two extrapolated to our patient because he did not with bortezomib, dexamethasone, and distinct entities with different cytogenetic and receive any of such prior treatments. dasatinib. Case Rep Oncol Med molecular findings.19 Immunophenotype Fourthly, epigenetic upregulation or down- 2014;2014:962526. analysis showed CD20 positive plasma cells in regulation of molecular pathways as a result of 7. Ragupathi L, Najfeld V, Chari A, et al. A our patient which is highly expressed in cases progression or treatment of multiple myeloma case report of chronic myelogenous of PCL. Furthermore, CD27 was expressed could potentially pave ways for malignant leukemia in a patient with multiple myelo- which confers plasma cells an antiapoptotic myeloid clones to emerge. These malignant ma and a review of the literature. Clin capability, another observation in PCL.20 Our cells acquire antiapoptotic ability and mecha- Lymphoma Myeloma Leuk 2013;13:175-9. patient lacked expressions of CD117 and nisms to escape immune surveillance in the 8. Offiah C, Quinn JP, Thornton P, Murphy

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PT. Co-existing chronic myeloid leukaemia patient with chronic myeloid leukemia National Cancer Institute. NIH Publ. No. and multiple myeloma: rapid response to after treatment with imatinib mesylate. 05-5302. Bethesda, MD, 2006. lenalidomide during imatinib treatment. Oncologist 2005;10:457-8. 17. Thomas A, Mailankody S, Korde N, et al. Int J Hematol 2012; 95:451-2. 13. Schwarzmeier JD, Shehata M, Ackermann Second malignancies after multiple myelo- 9. Ide M, Kuwahara N, Matsuishi E, et al. J, et al. Simultaneous occurrence of chron- ma: from 1960s to 2010s. Blood 2012;119: Uncommon case of chronic myeloid ic myeloid leukemia and multiple myelo- 2731-7. leukemia with multiple myeloma. Int J ma: evaluation by FISH analysis and in 18. Pandey S, Kyle RA. Unusual myelomas: a Hematol 2010;91:699-704. vitro expansion of bone marrow cells. review of IgD and IgE variants. Oncology Leukemia 2003;17:1426-8. 10. Michael M, Antoniades M, Lemesiou E, et (Williston Park) 2013;27:798-803. al. Development of multiple myeloma in a 14. Alvarez-Larrán A, Rozman M, Cervantes F. 19. Van de Donk NWCJ, Lokhorst HM, patient with chronic myeloid leukemia Simultaneous occurrence of multiple Anderson KC, Richardson PG. How I treat while on treatment with imatinib mesylate myeloma and chronic myeloid leukemia. plasma cell leukemia. Blood 2012;120: for 65 months. Oncologist 2009;14:1198- Haematologica 2001;86:894. 200. 15. Rajkumar SV, Dimopoulos MA, Palumbo A, 2376-89. 11. Galanopoulos A, Papadhimitriou SI, et al. International Myeloma Working 20. De Larrea CF, Kyle RA, Durie BG, et al. Kritikou-Griva E, et al. Multiple myeloma Group updated criteria for the diagnosis of Plasma cell leukemia: consensus state- developing after imatinib mesylate thera- multiple myeloma. Lancet Oncol ment on diagnostic requirements, py for chronic myeloid leukemia. Ann 2014;15:e538-48 response criteria, and treatment recom- Hematol 2009;88:281-2. 16. Curtis RE, Freedman DM, Ron E, et al. New mendations by the International Myeloma 12. Garipidou V, Vakalopoulou S, Tziomalos K. malignancies among cancer survivors: Working Group (IMWG). Leukemia Development of multiple myeloma in a SEER Cancer Registries, 1973-2000. 2013;27:780-91.

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