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Table of Contents
LETTER TO EDITOR
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 832-835

Daratumumab and its efficacy in refractory myeloma with anemia


Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission02-Sep-2020
Date of Decision01-Nov-2020
Date of Acceptance04-Nov-2020
Date of Web Publication25-Dec-2020

Correspondence Address:
Bhausaheb Bagal
Department of Medical Oncology, Room No. 81, Main Building, Tata Memorial Hospital, Parel East, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_283_20

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How to cite this article:
Bondili SK, Nandhana R, Gokarn A, Bonda A, Sengar M, Bagal B. Daratumumab and its efficacy in refractory myeloma with anemia. Cancer Res Stat Treat 2020;3:832-5

How to cite this URL:
Bondili SK, Nandhana R, Gokarn A, Bonda A, Sengar M, Bagal B. Daratumumab and its efficacy in refractory myeloma with anemia. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Jan 18];3:832-5. Available from: https://www.crstonline.com/text.asp?2020/3/4/832/304964



Multiple myeloma commonly presents with anemia, bone lesions, renal failure, hypercalcemia, and infections. Anemia is seen in about 70% of the patients at diagnosis, and the incidence increases to about 97% during the course of the illness.[1] Causes of anemia in patients with myeloma include direct bone marrow infiltration by plasma cells, renal failure, anemia of inflammation, and autoimmunity, and it usually responds to antimyeloma therapy.[2] Daratumumab, a human monoclonal antibody against CD38, which is active in multiple myeloma, has been shown to be effective in some cases of refractory autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) post-allogeneic stem cell transplant.[3] Here, we report an unusual case of multiple myeloma presenting with isolated anemia and refractory to multiple lines of chemotherapy that finally responded to daratumumab-based chemotherapy with a rapid improvement of anemia, thereby suggesting specific benefits of daratumumab in anemia associated with multiple myeloma.

A 69-year-old male presented with a 2-week history of dyspnea on exertion and swelling of the legs. On evaluation, he was found to have severe anemia with hemoglobin of 4.0 g/dL and congestive cardiac failure. He was transfused three units of packed red cells. Further evaluation revealed normal serum iron indices, Vitamin B12 and folate levels as well as negative direct and indirect Coomb's tests. His renal function tests were normal with a serum creatinine of 1.1 mg/dL and a normal serum calcium of 9.2 mg/dL. He was noted to have high globulin levels and an erythrocyte sedimentation rate of 55 mm/h. Further investigations revealed an M protein level of 1.4 g/dL and serum immunofixation revealed the presence of IgG-lambda type M-protein; the serum beta-2 microglobulin was normal (2.7 mg/dL). The serum-free light chain (SFLC) assay revealed the amount of free kappa light chains (LCs) to be 31.6 mg/L and that of free lambda LCs to be 348 mg/L; the kappa-lambda ratio was 0.09. Bone marrow evaluation showed 26% clonal plasma cells with normal erythroid cellularity. Fluorescence in situ hybridization (FISH) using a myeloma panel was negative for high-risk cytogenetics. His baseline positron emission tomography scan showed no fluorodeoxyglucose-avid lesions in the body. Based on these reports, he was diagnosed with Stage I multiple myeloma according to the revised multiple myeloma International Staging System with isolated anemia. There was no evidence of dysplasia on the marrow, and a FISH panel for myelodysplastic syndrome (MDS) was negative as well.

He was treated with the bortezomib, cyclophosphamide, and dexamethasone (VCd) protocol[4] but remainedtransfusion-dependent, requiring two to three packed red blood cell transfusions every month. In view of the suboptimal response, his therapy was changed to second-line bortezomib, thalidomide, and dexamethasone (VTd) along with danazol and darbepoetin for anemia. Desferrioxamine was started in view of the repeated transfusions and elevated level of ferritin (1970 ng/mL). Post 10 weeks of VTd, he had a persistent requirement for transfusion, and response evaluation revealed progressive disease. His therapy was then changed to pomalidomide, bortezomib, and dexamethasone (VPd), but the disease progressed biochemically after six cycles with worsening anemia and an increase in the free lambda LCs not accompanied by a concomitant rise in the M band, suggesting LC escape. Due to the refractory anemia, a repeat bone marrow examination was performed, which ruled out MDS and revealed 25% plasma cells. As a desperate measure, he was started on daratumumab, lenalidomide, and dexamethasone (DRd). During the first cycle, he developed bronchospasm which was managed with steroids, antihistamines, and bronchodilators. There was a dramatic improvement in his anemia after the initiation of daratumumab, his transfusion requirements decreased, and he became transfusion independent after four cycles [Figure 1]. Post 12 cycles of daratumumab, his response evaluation showed very good partial response (VGPR) with a hemoglobin level of 12.5 g/dL and an SFLC ratio of 0.373. He was continued on daratumumab for a total of 20 cycles after which he was kept under observation. Sixteen months post the cessation of chemotherapy, he still showed VGPR with normal hemoglobin level [Table 1].
Figure 1: Improvement in hemoglobin and urine Bence-Jones proteins and the difference between involved and uninvolved light chains after starting daratumumab. *VCd: Bortezomib, cyclophosphamide and dexamethasone, VTd: Bortezomib, thalidomide, dexamethasone, VPd: Bortezomib, pomalidomide, dexamethasone, DRd: Daratumumab, lenalidomide and dexamethasone

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Table 1: Laboratory parameters at various time points

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This was an unusual case of myeloma presenting with anemia without any other myeloma-defining events, with minimal plasma cell burden in the marrow, and which was refractory to multiple lines of therapy but later had an unusually rapid and lasting response to daratumumab-based therapy.

Our patient had refractory myeloma with a low tumor burden in the bone marrow. He required extensive workup to rule out other causes of anemia given the low burden of plasma cells and an isolated presentation with anemia. The extensive workup delayed the initiation of therapy by almost four months due to the uncertainty in diagnosis. However, despite the delay, there was no significant increase in the number of marrow plasma cells. He remained transfusion-dependent while on three lines of chemotherapy, to which he had no biochemical response. Later, he showed a dramatic response to daratumumab and became transfusion-independent, which went hand in hand with his biochemical response, suggesting a link between the number of plasma cells and anemia, thus justifying our decision to treat him for myeloma despite the absence of other myeloma-defining events. Notably, there was an exceptional response of anemia to daratumumab. He is progression free at 16 months from stopping the therapy, which is unusual in refractory myeloma.

A review of randomized controlled studies of daratumumab -based regimens shows a high incidence of Grade 3 or more neutropenia and thrombocytopenia with this regimen, but Grade 3 or more anemia was found to be less common in the daratumumab arm [Table 2]. This is suggestive of specific benefits of daratumumab in anemia and warrants a closer look in the subsequent studies involving daratumumab.[5],[6],[7]
Table 2: Prevalence of anemia in various studies of daratumumab

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Anemia in myeloma is multifactorial. Infiltration of the bone marrow by plasma cells may disrupt erythroblastic islands, the functional unit of erythropoiesis, by direct physical disruption or by impairing its function by producing various cytokines. Transforming growth factor-beta produced by myeloma cells causes a decrease in the colony-forming unit-Erythroid. Elevated levels of interleukin-6, bone morphogenetic protein-4, and other cytokines cause activation of the downstream signaling pathways such as the JAK/STAT pathway which increases hepcidin production as a part of the acute phase reaction, thereby restricting iron availability for erythropoiesis.[8] Other mechanisms include direct inhibition of erythropoiesis by disruption of erythroblastic islands, decreased adhesion of the erythroid precursors to the stromal elements,[9] renal failure with subsequently decreased erythropoietin,[1] AIHA caused by immune dysregulation (which occurs in 4% of the myeloma cases), and bone marrow suppression by chemotherapeutic drugs.[10]

Few anecdotal case reports have suggested daratumumab activity in other types of anemia (AIHA, PRCA, etc.).[11],[12],[13] Persistence of plasma cells that continue to secrete iso-hemagglutinins has been proposed as a mechanism for refractory immune-mediated anemia. Daratumumab, by causing elimination of these pathogenic residual plasma cells, may be responsible for its remarkable efficacy in such conditions.[11]

Cooling and Hugan reported a case of refractory AIHA in a child with Langerhans cell histiocytosis. Anemia was refractory to more than two lines of therapy but responded dramatically to daratumumab.[13] Similarly, a case report of refractory Evans syndrome postallogenic transplant for aplastic anemia, which was resistant to multiple lines of therapy, showed a marked response to daratumumab with the patient becoming transfusion independent.[12] Another case of PRCA secondary to an ABO mismatched allogenic transplant for aplastic anemia was reported, which eventually responded to daratumumab.[11]

Daratumumab has diverse mechanisms of action and exerts both direct and indirect antimyeloma action through antibody-mediated cytotoxicity, antibody-mediated cellular phagocytosis, and complement-mediated cytotoxicity by activating the membrane attack complex and inhibiting the regulatory T-cells. Daratumumab by inhibiting the synthesis of adenosine leads to increased T-cell response against myeloma cells and improved disease control.[14] In view of the unusual response of anemia to daratumumab in our case and the trials with daratumumab showing the lower prevalence of anemia, it appears that daratumumab may have a specific benefit in anemia, and the mechanism for this needs to be elucidated.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his names and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Acknowledgment

We acknowledge the support from the head of the department of medical oncology and the head of adult hematolymphoid disease management group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mittelman M. The implications of anemia in multiple myeloma. Clin Lymphoma 2003;4 Suppl 1:S23-9.  Back to cited text no. 1
    
2.
VanderWall K, Daniels-Wells TR, Penichet M, Lichtenstein A. Iron in multiple myeloma. Crit Rev Oncog 2013;18:449-61.  Back to cited text no. 2
    
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Raedler LA. Darzalex (Daratumumab): First anti-CD38 monoclonal antibody approved for patients with relapsed multiple myeloma. Am Health Drug Benefits 2016;9:70-3.  Back to cited text no. 3
    
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Bagal B, Bonda A. Induction therapy in newly diagnosed multiple myeloma: Current research scenario and questions for the future. Cancer Res Stat Treat 2019;2:76-82.  Back to cited text no. 4
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5.
Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 2019;380:2104-15.  Back to cited text no. 5
    
6.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016;375:754-66.  Back to cited text no. 6
    
7.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016;375:1319-31.  Back to cited text no. 7
    
8.
Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 2010;116:3635-44.  Back to cited text no. 8
    
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Bouchnita A, Eymard N, Moyo TK, Koury MJ, Volpert V. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. Am J Hematol 2016;91:371-8.  Back to cited text no. 9
    
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Shimanovsky A, Alvarez Argote J, Murali S, Dasanu CA. Autoimmune manifestations in patients with multiple myeloma and monoclonal gammopathy of undetermined significance. BBA Clin 2016;6:12-8.  Back to cited text no. 10
    
11.
Salas MQ, Alahmari A, Lipton JH. Successful treatment of refractory red cell aplasia after allogeneic hematopoietic cell transplantation with daratumumab. Eur J Haematol 2020;104:145-7.  Back to cited text no. 11
    
12.
Blennerhassett R, Sudini L, Gottlieb D, Bhattacharyya A. Post-allogeneic transplant Evans syndrome successfully treated with daratumumab. Br J Haematol 2019;187:e48-51.  Back to cited text no. 12
    
13.
Cooling L, Hugan S. Daratumumab in combination with standard treatment for autoimmune hemolytic anemia in a pediatric patient. Transfusion 2019;59:3801-2.  Back to cited text no. 13
    
14.
Plesner T, Krejcik J. Daratumumab for the treatment of multiple myeloma. Front Immunol 2018;9:1228.  Back to cited text no. 14
    


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