Case sharing M protein continues to be negative, but patients with multiple myeloma have relapsed

Author: Zhou Qinghe This article is authorized by the author to publish by Yimaitong, please do not reprint without authorization
.

Case data: The patient, female, 48 years old, was admitted to our department on December 14, 2019 for "lower back pain for half a year, worsening for 1 week".
After admission, the relevant laboratory tests were perfected: hemoglobin 75g/L, lactate dehydrogenase 433U/L , Creatinine and blood calcium are normal, β-microglobulin is 6.
71ug/mL, and albumin is 45.
3g/L
.

Serum immunofixation electrophoresis prompts: M protein 38.
9%, total protein 111.
1g/L, free κ light chain 4800mg/L, free λ-light chain (blood) 15.
2mg/L, Fκ/Fλ-light chain ratio (blood) 315.
789
.

Bone marrow phenomenon: bone marrow hyperplasia is active, the plasma cell system is obviously proliferated, the proportion of plasma cells is 56.
5%, primitive plasma cells account for 2.
5%, immature plasma cells account for 50%, and mature plasma cells account for 4%
.

Immunophenotyping: combined gating analysis on CD45/SSC and FSC/SSC dot plots.
Abnormal cell populations can be seen in areas where CD45 is negative and FSC/SSC are larger than lymph nodes, accounting for about 39.
5% of nuclear cells, expressing CD33, The karyotypes of CD38, CD56, CD117, and cKappa are normal
.

The patient was clearly diagnosed as: multiple myeloma (IgG-κ, ISS stage III, DS stage III), received 9 cycles of "PCD (bortezomib 2.
7 mg + dexamethasone 20 mg + cyclophosphamide 600 mg)", and rechecked the M protein Negative, minor residual lesions were negative, and after taking lenalidomide 25mg maintenance treatment for half a year, low back pain occurred again, and the M protein was still negative on reexamination.
Imaging examination revealed soft tissue masses around the left ribs.
Fine needle aspiration indicated a large number of patients.
Immature lymphoid hematopoietic system tumor cells, some cells have plasmacytoid differentiation, which is consistent with multiple myeloma changes
.

Although the M protein was negative, the patient developed extramedullary recurrence.
The diagnosis was multiple myeloma (IgG-κ type, recurrence), and received “VRD (bortezomib + lenalidomide + dexamethasone)” chemotherapy and then combined After local radiotherapy, the patient's back pain symptoms have improved slightly, and the tumor has been slightly reduced.
What will the patient do next? Discussion Multiple myeloma (MM) is a mature B-cell tumor that accounts for 13% of all hematological malignancies.
MM is mainly seen in the elderly.
In the past ten years, the median survival of myeloma patients The period has almost doubled, extending from 4 years to 8 years
.

The significant improvement in the survival time of MM patients is mainly due to the high-dose treatment followed by autologous hematopoietic stem cell transplantation.
In addition, it also includes the extensive use of immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) Including new drugs
.

And the library of effective new drugs for patients with recurrent diseases is increasing, such as second-generation immunomodulators (pomalidomide), next-generation proteasome inhibitors (carfilzomib, ixazomib, etc.
), histone deacetylation Enzyme inhibitors (pabisstat) and monoclonal antibodies (CD38 monoclonal antibody, etc.
)
.

However, some patients may have extramedullary lesions.
Although it is relatively rare, the prognosis is poor.
Extramedullary lesions can occur at the first diagnosis or during the diagnosis and treatment of patients with MM.
The latter are more common and usually related to the drug resistance of tumor cells.
Sex is closely related
.

The bone marrow microenvironment is closely related to tumor proliferation, survival and drug resistance.
As the disease progresses, the dependence of the tumor on the bone marrow microenvironment decreases.
When it is separated from the bone marrow, it will appear as extramedullary myeloma (EMM) or extramedullary Plasma cell leukemia [1]
.

According to reports, the incidence of soft tissue EMM in newly diagnosed MM patients is 6% [2], and the incidence in relapsed MM patients is 7.
5%-14% [3,4]
.

EMM is a more aggressive subtype of MM, with an overall survival period of no more than 3 years, especially for those patients who have undergone standard therapies or autologous hematopoietic stem cell transplantation.
If the median survival period of EMM is less than 1 year, the current study believes There are three main forms of EMM [5]: ① Local growth of MM cells directly invades adjacent soft tissues, forming bony extramedullary soft tissue plasmacytoma; ② MM cells spread through the blood source to distant organs of the bone marrow to form single or multiple masses; ③Extramedullary involvement caused by invasive surgical operations such as surgery on the bones of the lesion is rare
.

The specific mechanism of EMM is unclear.
The current study believes that extramedullary recurrence is related to hypoxia and abnormal adhesion molecules [6].
The characteristics of EMM are shown in the following table [7]: This patient is a young and middle-aged female, with lack of medical history data at the first visit and no MM Related prognostic genes, but the patient is accompanied by high lactate dehydrogenase at the onset of the disease.
The stage is late and the prognosis is relatively poor.
Although the M protein has been monitored continuously during the period, the patient has an extramedullary lesion and relapses quickly.
The patient relapses and the patient was first diagnosed Poor prognosis may be related, and it may also be related to bridging treatment among patients who did not choose autologous hematopoietic stem cell transplantation
.

Combined with recent retrospective studies, the incidence of EMM did not increase in patients receiving new drug treatments including lenalidomide and bortezomib
.

However, it has been reported that patients receiving allogeneic hematopoietic stem cell transplantation have a higher incidence of extramedullary recurrence
.

A recent retrospective study showed that the number of previous treatments and age are associated with a higher risk of extramedullary recurrence, and the use of lenalidomide before allogeneic hematopoietic stem cell transplantation was found to be a protective factor
.

EMM is more common in people with high levels of LDH, anemia, thrombocytopenia, non-secretory MM, and high-risk cytogenetics
.

Patients with recurrent EMM may have light chain escape (that is, switch from intact immunoglobulin to only secrete free light chains), and extramedullary disease plasma cells show high frequency of p53 and Ras mutations and FAK upregulation
.

EMM plasma cells are characterized by decreased expression of CD56 adhesion molecules and increased expression of CD44, which is related to cell proliferation and migration
.

Increased expression of CXCR4 and its ligand CXCL12 has also been suggested to contribute to the spread of plasma cells, especially by activating the epithelial-mesenchymal transition mode
.

Hypoxia has been shown to be an important factor affecting the spread of plasma cells [7]
.

The clinical situation of EMM is extremely diverse, and its management is particularly challenging.
PET-CT is an effective tool for detecting extramedullary diseases.
There is no effective method for detecting extramedullary diseases.
EMM is regarded as a high-risk disease and it is recommended to treat it as actively as possible
.

For newly diagnosed EMM patients who are eligible for stem cell transplantation, most experts recommend triple induction therapy first, followed by high-dose melphalan therapy followed by autologous hematopoietic stem cell transplantation, triple consolidation therapy and maintenance therapy.
Among them, at least Composed of lenalidomide; for elderly patients with EMM who cannot undergo autologous hematopoietic stem cell transplantation, bortezomib-melphalan-prednisone (VMP) or continuous lenalidomide-dexamethasone (RD) are currently the two most important Effective pre-treatment standards
.

For relapsed EMM, the previous treatment and duration of response should be clearly considered.
It is strongly recommended to confirm the diagnosis of EMM by biopsy.
This may provide biological principles for targeted therapy in some cases.
For CNS EMM, combined CNS radiotherapy is recommended , Intrathecal injection of chemotherapy drugs and systemic therapy based on immunomodulators
.

The use of molecular targeted therapy or immunotherapy (chimeric antigen receptor T cells) may benefit patients with recurrence of EMM [7]
.

Although the patient’s symptoms have improved from “VRD” chemotherapy combined with radiotherapy, it seems that there is a certain degree of curative effect, but the patient’s condition progresses rapidly, lactate dehydrogenase is progressively elevated, and the overall prognosis is very poor
.

From this case, we can get some experience and reflection.
For newly diagnosed patients, genetic testing should be strictly improved to assess the prognosis of patients.
Patients who are eligible for autologous hematopoietic stem cell transplantation should be treated with hematopoietic stem cell transplantation bridging treatment as much as possible, and then maintenance treatment, and the condition is stable.
Patients should not only detect M protein, but also need to pay close attention to the clinical symptoms of the patient, choose appropriate evaluation and examination methods according to the clinical symptoms, extend the plateau period of the patient as much as possible, and reduce the recurrence rate.
For patients with EMM, choose a stronger one.
Triple chemotherapy, in which lenalidomide is indispensable in combination chemotherapy, and some molecular targeted drugs and immunotherapy may have certain curative effects for such patients, and more exploration and more data may be needed.
Perhaps in the near future, EMM patients using new drugs may also be excluded from the high-risk group
.

References: 1.
Huang Hai-Fan,Xu Jian,Xu Ao-Shuang et al.
Disturbed MAPK pathway in early bilateral testicular extramedullary relapse of multiple myeloma.
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Zamagni, F.
Patriarca, C.
Nanni, B.
Zannetti, E.
Englaro, A.
Pezzi, et al.
, Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation, Blood 118 (2011) 5989–5995.
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KD Short, SV Rajkumar, D.
Larson, F.
Buadi, S.
Hayman, A.
Dispenzieri, et al.
, Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy , and the activity of pomalidomide on extramedullary myeloma, Leukemia 25 (2011) 906–908.
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Pour, S.
Sevcikova, H.
Greslikova, R.
Kupska, P.
Majkova, L.
Zahradova, et al.
,Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse, Haematologica 99 (2014) 360–364.
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Touzeau C, Moreau P.
How International myeloma [J].
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6 .
Qian Ying,Qian Zijun,Zhao Xiujie et al.
Successful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature.
[ J] .
Front Med (Lausanne), 2021, 8: 649824.
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Touzeau C, Moreau P.
How I treat extramedullary myeloma[J].
Blood, 2015, 127(8):971.
Stamp "read the original text" and we will make progress togetherQian Ying,Qian Zijun,Zhao Xiujie et al.
Successful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature.
[J ] .
Front Med (Lausanne), 2021, 8: 649824.
7.
Touzeau C, Moreau P.
How I treat extramedullary myeloma[J].
Blood, 2015, 127(8):971.
Stamp "read the original text" and we will make progress togetherQian Ying,Qian Zijun,Zhao Xiujie et al.
Successful Treatment of Relapsed/Refractory Extramedullary Multiple Myeloma With Anti-BCMA CAR-T Cell Therapy Followed by Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report and a Review of the Contemporary Literature.
[J ] .
Front Med (Lausanne), 2021, 8: 649824.
7.
Touzeau C, Moreau P.
How I treat extramedullary myeloma[J].
Blood, 2015, 127(8):971.
Stamp "read the original text" and we will make progress togetherPoke "read the original text", we make progress togetherPoke "read the original text", we make progress together