Introduction
Multiple myeloma (MM) is a bone marrow (BM)-based malignancy characterized by the proliferation of clonal, long-lived plasma cells (PCs) and accounts for 10% of all hematologic malignancies. There have been marked advancements in treatments leading to improvements in these patients’ outcomes with the use of chemotherapeutic agents, immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), bispecific antibodies, and chimeric antigen receptor T-cell therapies. The mAbs target specific receptors on the surface of MM cells leading to their destruction. Current Food and Drug Administration-approved mAbs for MM target either CD38 including daratumumab and isatuximab or signaling lymphocytic activation molecule family 7, such as elotuzumab, and have been shown to be effective. Daratumumab has been approved as a single agent for relapsed/refractory (RR) MM for those patients who have been treated with at least three prior lines of therapy, including a PI and IMiD [ 1 ], although it is more often used in combination with other anti-MM drugs.
CD38 is a 46-kDa type II transmembrane glycoprotein with a 20-amino acid N-terminal cytoplasmic tail and a 256-aa extracellular domain [ 2 ]. While it is expressed at low levels on normal lymphoid, myeloid, and some nonhematopoietic cells, it is highly expressed on PCs, making it an excellent target for treating MM patients. Daratumumab induces malignant PC death via Fc-dependent mechanisms, including complement-dependent cytotoxicity, natural killer-cell-mediated antibody-dependent cellular cytotoxicity, macrophage-mediated phagocytosis, and apoptosis via Fcγ receptor cross-linking. It reduces immunosuppressive CD38-expressing cells which enhances T-cell killing of MM cells [ 3 ].
The combination of daratumumab and dexamethasone has demonstrated efficacy in RRMM, with an overall response rate (ORR) of 31% and overall survival of 20.1 months [ 4 ]. In another study, it achieved a 37% ORR with median progression-free survival (PFS) and overall survival of 7.2 and 7.8 months, respectively [ 1 ]. The CENTAURUS study showed this combination delayed progression in intermediate- or high-risk smoldering MM, with 24-month PFS rates of 89.9% and 82.0% in the intense (weekly dosing followed by biweekly and then monthly) and intermediate (weekly dosing followed by every 8 weeks) arms, respectively [ 5 ].
As part of frontline treatment, daratumumab is highly effective in combination with lenalidomide, bortezomib, and dexamethasone [ 6 , 7 ]. In transplant-eligible NDMM patients, adding daratumumab to bortezomib, thalidomide, and dexamethasone (VTd) improved response depth and PFS, with 29% achieving a stringent complete remission (CR) versus 20% with VTd alone and 64% achieving measurable residual disease negativity versus 44% in the control arm [ 6 ]. In transplant-ineligible patients, the addition of daratumumab to lenalidomide and dexamethasone significantly improved PFS [ 7 ]. However, the use of this mAb in the frontline setting with only dexamethasone remains limited with no reported CRs.
Neutropenia is a common hematologic adverse event that results from MM and its treatment [ 8 ]. It increases susceptibility to infections, which can lead to complications such as febrile neutropenia, prolonged hospitalizations, and life-threatening sepsis [ 8 ]. In MM, neutropenia is most commonly the result of therapy. It can also occur unrelated to treatment of the disease. In the SIRIUS trial with daratumumab as a single agent, 12% of patients had grade 3 or higher neutropenia [ 9 ]. In the POLLUX trial, a combination study of daratumumab and IMiDs, 52% of patients developed grade 3 or higher neutropenia with daratumumab, lenalidomide, and dexamethasone compared to the 37% with lenalidomide and dexamethasone [ 10 ]. In the CASTOR trial, a combination study of daratumumab and PIs, 13% of patients developed grade 3 or higher neutropenia [ 8 ]. The risk of neutropenia secondary to treatment was higher when daratumumab was combined with IMiDs or PIs, but relatively low with dexamethasone alone. While neutropenia is often an adverse event secondary to daratumumab, daratumumab may actually help resolve neutropenia if it is due to MM itself and not treatment [ 11 ].
To date, there have been no reports of successfully using mAbs with steroids to reverse neutropenia associated with MM. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000549657 ).
Case Report
A 32-year-old Filipino female presented with an elevated total protein in March 2019 without other symptoms. Further workup showed her to have a normal physical examination. Her laboratories showed white blood cell count of 3.2 with an absolute neutrophil count (ANC) of 1,418 cells/μL ( Fig. 1 ). Her serum albumin was 4.1 g/dL, creatinine 0.53, calcium 8.9, hemoglobin 12.4 g/dL, platelet count 292 × 10 3 /μL, and serum monoclonal protein (sMP) 2.6 g/dL. Her immunoglobulin G (IgG), IgA, and IgM levels were 3,756, 59, and 36 mg/dL, respectively, and immunofixation showed an IgG kappa monoclonal gammopathy. Her BM biopsy showed 30% monoclonal PCs. Fluorescent in situ hybridization showed a t(4;14) and a deletion of the long arm of chromosome 13. Total body MRI did not show lytic bone disease. Her bone density showed evidence of osteopenia with a t-score in her spine of −2. As a result, she was diagnosed with smoldering MM and started on zoledronic acid monthly for her bone loss without other therapy.
In January 2022, her ANC decreased to 420 cells/μL ( Fig. 1 ). Her serum β2 microglobulin was 1.47 mg/L, serum albumin 4.1 g/dL, hemoglobin 11.8 g/dL, sMP 3.65 g/dL, and serum-free light chain (sFLC) kappa and lambda were 20.3 and 7.8 mg/L, respectively ( Fig. 1 ). Her M-protein and IgG increased to 3.65 g/dL and 5,002 mg/dL, respectively, and IgA and IgM levels were 44 and 28 mg/dL, respectively. Because of her neutropenia, she was started in February 2022 only on treatment with dexamethasone 40 mg intravenously (IV) administered on days 1, 8, 15, and 22 of a 28-day cycle and daratumumab 16 mg/kg IV once weekly for the first 8 weeks, then once every other week for 16 weeks, and then once monthly thereafter. Her ANC levels increased to 2,600/μL after 2.5 cycles, increasing further to 5,490/μL after 6.5 cycles, and have remained in the normal range since with her last ANC 6,020/μL in February 2025 ( Fig. 1 ). After 3 cycles, the patient decreased her IV dexamethasone dose to 20 mg due to dry eyes and thirst; she started oral methylprednisolone at 12 mg every other day but not within 48 h before or after her dexamethasone infusion. The patient’s sMP decreased to 0.17 g/dL after 10 cycles and was unable to be identified after 11 cycles ( Fig. 1 ). The patient’s sFLC kappa and lambda were 4.3 and 3.4 mg/L, respectively, and her IgG was 647 mg/dL ( Fig. 1 ). A BM biopsy in July of 2023 confirmed CR after 18 cycles. She remains in CR as of February 2025; her laboratories showed an IgG of 527 mg/dL, sFLC kappa of 4.8 mg/dL, sFLC lambda of 3.7 mg/dL, and hemoglobin 11.4 g/dL. The treatment was well tolerated, and she experienced no side effects from this treatment.
Discussion
Recent studies highlight the enhanced efficacy of therapies for NDMM when the anti-CD38 antibody daratumumab is added to lenalidomide, bortezomib, and dexamethasone [ 6 , 7 ]. This combination including IMiDs/PIs is often associated with significant side effects including cytopenias, peripheral neuropathy, and a reduced quality of life from its adverse impact on cognitive function and energy levels. Patients receiving this mAb with other drugs often experience grade 3 or 4 neutropenia [ 7 , 8 ].
Some patients gain clinical benefit from daratumumab and steroids alone. The phase 2 DARE study demonstrated the efficacy of this combination for RRMM patients with severe renal impairment requiring dialysis [ 12 ].
Dexamethasone is an effective therapeutic agent for treating MM through its ability to induce apoptosis in MM cells. Dexamethasone alone shows efficacy for treating MM patients and increases the clinical activity of other drugs including anti-CD38 antibodies [ 13 ]. Specifically, dexamethasone and daratumumab treatment for RRMM patients showed an ORR of 36% with a median PFS of 5.6 months [ 14 ]. Similarly, in the phase 2 SIRIUS study this combination achieved an ORR of 29.2% and median PFS of 3.7 months for RRMM patients [ 9 ].
The underlying cause of autoimmune neutropenia in MM remains unclear, but there is an association between immune dysregulation and MM. Case studies of M-protein binding endogenous proteins have been reported in the literature, leading to complications due to the deleterious impacts of these antibody-mediated immune effects. It is possible that this patient’s M-protein targeted neutrophils, leading to antibody-mediated killing of these cells and the observed neutropenia. This would then be resolved with the effective management of the patient’s myeloma and, as a result, elimination of the neutropenia-inducing M-protein. It has also been postulated that autoimmune neutropenia in MM may result from crosstalk between B-cell and T-cell lineages, as MM has been associated with clonal expansion of CD4+ and CD8+ T cells [ 15 ], as well as clonal T-cell receptor gene rearrangements [ 16 ]. These abnormalities can lead to dysregulated T-cell signaling, potentially contributing to immune-mediated neutrophil destruction. It is also possible that steroids contributed to the resolution of the autoimmune neutropenia which has been previously reported [ 17 ]. Dexamethasone may also have counteracted any neutrophil-lowering effects of daratumumab, thereby supporting the observed normalization of neutrophil counts. In addition, other antibodies besides the paraprotein may have contributed to this patient’s autoimmune neutropenia; the PCs producing these antibodies may have been eliminated with the use of the combination of the PC-targeting mAb daratumumab and dexamethasone.
In our patient, the BM biopsy demonstrated 30% clonal PCs but no significant hypoplasia of the myeloid lineage, suggesting that direct hematopoietic suppression was unlikely to be the primary cause of neutropenia. Another possibility is that the patient’s M-protein exerted anti-neutrophil antibody activity, leading to immune-mediated neutrophil destruction. This mechanism has been described in myeloma and other paraproteinemias, where monoclonal proteins can bind endogenous proteins and alter immune function [ 15 – 17 ]. The rapid normalization of the ANC in parallel with suppression of the patient’s M-protein further supports the interpretation of autoimmune neutropenia rather than BM failure. Thus, in this case, the diagnosis of autoimmune neutropenia was primarily clinical, with resolution following effective treatment of the underlying myeloma. Regardless, the use of this combination was effective to treat both this patient’s myeloma and severe neutropenia without significant side effects.
Here, we describe a case of a 32-year-old patient with MM and neutropenia prior to treatment who achieved CR with daratumumab and glucocorticosteroids as a frontline treatment. This patient’s remission has been maintained for more than 3 years and has not required the addition of other drugs. This patient experienced no adverse effects, and her neutropenia resolved after starting the treatment. Thus, this treatment approach effectively treated her MM and neutropenia.
Conclusion
This case report demonstrated that daratumumab combined with glucocorticosteroids achieved a CR as a frontline treatment while resolving neutropenia for a patient with NDMM. Further investigation into daratumumab’s mechanism of action is crucial for optimizing its use in novel drug combinations for MM. Ongoing efforts aim to identify response predictors, mechanisms of resistance, and patient subgroups who may benefit from daratumumab and steroids without other drugs. Additionally, understanding the pathophysiology of autoimmune neutropenia may provide valuable insights into immune alterations in MM, which may guide the development of improved therapies for these patients.
Statement of Ethics
This study protocol was reviewed and approved by WCG IRB, Approval No. 1053702. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder. J.R.B. receives speaker fees and clinical research support from Janssen.
Author Contributions
James R. Berenson, Sarah Mettias, and Jamie Cheung reviewed the records. Sarah Mettias, Jamie Cheung, Jonathan Moore, and James R. Berenson wrote the manuscript. Sarah Mettias created the figures.
Data Availability Statement
All data generated or analyzed during this study are comprehensively documented within this article. Further inquiries can be directed to the corresponding author.
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