Case Sharing Hui Professor Lou Shifeng's Comments: Re-challenge after multi-drug refractory, the combination of Selinesol helps patients with plasma cell leukemia achieve complete remission

Multiple myeloma (MM) is a malignant disease with a highly heterogeneous abnormal proliferation of clonal plasma cells
.

Because the disease is incurable, most patients face the dilemma of disease relapse/refractory, multi-line therapy, multi-drug exposure and patients with high-risk cytogenetics or extramedullary lesions are difficult to treat and lack effective treatment options.
Drugs with novel mechanisms are urgently needed to bring deeper relief
.

Nuclear export of tumor suppressor proteins is an important mechanism for tumor cells to escape apoptosis.
Nuclear export protein 1 (XPO1) is highly expressed in MM and is closely related to poor prognosis of patients
.

Selinexor (trade name: Sivio®) is the world's first approved oral selective nuclear export inhibitor (SINE), which can reversibly bind to XPO1 and exert anti-tumor effects
.

Preclinical studies have confirmed that selinisol can exert a synergistic effect in combination with a variety of drugs
.

At present, the clinical study of multiple combination regimens with selinesol as the skeleton for the treatment of relapsed and refractory (R/R) MM is in progress.
Prof.
Jianchuan shared his experience in treating MM with Seliniso, and Prof.
Lou Shifeng from the Second Affiliated Hospital of Chongqing Medical University commented on the case! A 62-year-old male patient with MM progressed to plasma cell leukemia was admitted to the Department of Orthopedics in March 2020 due to the onset of recurrent low back pain.
MRI examination showed that the posterior mediastinum (T9-11 level) had anterior spinal tumor lesions.
Ultrasound biopsy was performed, and immunohistochemistry showed that it was consistent with plasmacytoma.
Out-of-hospital bone biopsy showed abnormal proliferation of plasma cells, accounting for 47%.
The diagnosis was MM (light chain type).
In April of the same year, he received bortezomib combined with dexamethasone (Vd) regimen chemotherapy, the effect was not good, transferred to the Department of Hematology in May
.

>>>>Patient baseline characteristics Blood routine and biochemistry: HGB 87g/L, PLT 66×109/L, WBC 7.
59×109/L, β2 microglobulin 8.
57mg/L, albumin 43g/L, LDH 736U/L
.

Immunoglobulin: IgG 7g/L, IgA 0.
77g/L, IgM 0.
25g/L, light chain κ 4.
57mg/L, light chain λ 5.
64g/L
.

Bone marrow examination: plasma cells accounted for 59%
.

Bone marrow flow cytometry: abnormal plasma cells accounted for 52.
29%, immunophenotype: CD138-, CD38+, CD56-, cKappa-, CD28 part, cLambda+, CD117-, CD19 positive accounted for 24.
81%, CD33+, CD20-, CD45-
.

Immunofixation electrophoresis: suggest IgD-λ monoclonal M protein
.

FISH: 1q21 partial polysomy, del(13)(q14), -16 or del(16)(q23), del(17)(p13)
.

>>>>Clinical diagnosis of multiple myeloma IgD-λ type, ISS stage III, with extramedullary plasmacytoma, type 2 diabetes
.

First-line treatment May 2020 Bortezomib combined with cyclophosphamide and dexamethasone (VCd) regimen, a total of 3 courses; the efficacy evaluation was complete remission (CR), bone marrow MRD was negative, immunofixation electrophoresis was negative, free light chain ratio Normal; extramedullary lesions shrink rapidly
.

In October 2020, autologous hematopoietic stem cell transplantation was performed as consolidation therapy, followed by maintenance therapy with lenalidomide
.

In December 2020, the bone marrow plasma cells were negative; immunofixation electrophoresis and extramedullary lesions were negative
.

In March 2021, the reexamination of bone marrow plasma cells was 20%, indicating disease recurrence
.

Second-line treatment: Daratumumab combined with ixazomib and dexamethasone (DId) regimen in March 2021; bone marrow reexamination in April 2021 showed that plasma cells were 28%, and bone marrow MRD: abnormal plasma cells accounted for 30.
93% of the total cells , suggesting disease progression and resistance to DId regimen
.

Third-line treatment April 2021 Ixazomib combined with pomalidomide and liposomal doxorubicin (IPD) regimen, a total of 2 courses
.

Efficacy assessment showed disease progression (4% plasma cells in peripheral blood)
.

The efficacy of previous regimens was summarized.
The patient achieved complete remission after first-line treatment.
Although he underwent autologous hematopoietic stem cell transplantation and lenalidomide maintenance treatment, the disease relapsed within 6 months, and the subsequent DId and IPD regimens failed to achieve remission.
Progressive and multidrug resistant
.

Fourth-line treatment May 2021 The regimen of selinisol combined with pomalidomide and dexamethasone (XPd)
.

During the treatment period, the patient's peripheral plasma cells turned negative, and the remission lasted for one month
.

The bone marrow reexamination in July 2021 showed 72% plasma cells, 37% peripheral plasma cells, hepatosplenomegaly, multiple serous cavities, and the disease progressed to plasma cell leukemia
.

Fifth-line treatment In July 2021, considering the patient's medical history, tumor burden and drug resistance, selenisole 60mg qw, carfilzomib 20mg/m2 (d1, 2, 8, 9, 15, 16), pomalidomide 2mg d1-21 and dexamethasone 20mg d1-2 (XKPd) combination regimen
.

After one course of treatment, the efficacy evaluation reached CR; peripheral blood and bone marrow plasma cells were negative; immunofixation electrophoresis showed negative IgD; free light chain κ/λ ratio returned to normal, spleen size returned to normal, and pleural effusion was significantly reduced
.


The patient's medication compliance is high, and the adverse reactions are controllable.
Mild fatigue and transient heart failure have occurred during treatment
.

To sum up, this patient belongs to relapsed and refractory multiple myeloma with extramedullary lesions.
He has undergone multiple lines of therapy in the past and has not been effectively relieved in the treatment after the first relapse, and eventually progressed to plasma cell leukemia (PCL).
drug resistance and difficult to treat
.

Complete remission was achieved after treatment with a four-drug regimen containing serinesole, and the adverse reactions were controllable
.

Professor Deng Jianchuan's diagnosis and treatment experience in this patient was MM with extramedullary lesions.
After first-line treatment, he achieved complete remission.
Despite subsequent autologous hematopoietic stem cell transplantation and lenalidomide maintenance therapy, the patient still experienced early relapse, indicating a poor prognosis
.

Subsequent treatment also confirmed that the patient was resistant to CD38 monoclonal antibodies, proteasome inhibitors and third-generation immunomodulators, and the options for subsequent treatment were limited
.

In the fifth-line treatment, combined with the 2021 NCCN guidelines (V4 version) and the 2021 CSCO guidelines, the XPO1 inhibitor with a new mechanism of action, selenisol combined with pomalidomide and dexamethasone, was selected.
Negative, after short-term remission, re-examination showed that the disease progressed to plasma cell leukemia
.

Due to the high tumor burden, multidrug resistance, and poor prognosis of the patient, the patient's condition was considered comprehensively in the final-line treatment, and the "strong and strong combination" XKPd regimen was selected.
More than 4 months, and the adverse reactions are controllable
.

For such MM patients with multi-line relapse, multi-drug resistance and combined plasma cell leukemia, clinical treatment options are limited.
Selinexor is an oral selective nuclear export inhibitor with a new mechanism, which plays an anti-tumor effect mediated by multiple pathways.
It has brought new hope to patients with R/R MM and plasma cell leukemia with extramedullary lesions
.

Professor Lou Shifeng commented that MM is a common hematological malignancy, which is more common in the elderly
.

With the emergence of new drug combination regimens and the development of autologous hematopoietic stem cell transplantation technology, the overall treatment level of MM has been improved, but currently MM is still incurable, and patients are faced with the dilemma of disease relapse/refractory.
As the number of relapses increases, the remission rate of patients increases.
and the depth of remission gradually decreases, and drug resistance after relapse makes the treatment of the disease "worse", and effective treatment options are limited
.

XPO1 is an important nuclear export protein, and its high expression in MM cells is closely related to tumor cell apoptosis and cell drug resistance
.

As the world's first innovative oral targeted XPO1 inhibitor, selinesol can promote the accumulation of various MM-related tumor suppressor proteins in the nucleus and exert a tumor suppressor effect
.

As a nuclear export protein inhibitor with a new mechanism of action, selinisol has a significant synergistic effect in combination with a variety of drugs.
The STOMP study using the Xd regimen as a backbone in combination with other drugs shows that it is effective for pomalidomide-unexposed or non-refractory 44 27 MM patients received XPd regimen, the overall response rate (ORR) was 57%, and the median progression-free survival (mPFS) was 12.
2 months3; 27 MM patients who were refractory to carfilzomib received XKd treatment, and the ORR reached 12.
2 months.
78%, mPFS reached 23.
7 months4
.

For patients who failed the CD38-containing regimen, the ORR of the XPd and XKd regimens were 52% and 65%, respectively, and the mPFS was 8.
7 months and 15 months, respectively 5
.

Based on its favorable efficacy, selinisol has been approved by the National Medical Products Administration (NMPA) of China for use in combination with dexamethasone for the treatment of previously treated patients with at least one proteasome inhibitor, an immunomodulatory agent and an R/R MM refractory to an anti-CD38 mAb
.

The MM patient with extramedullary plasmacytoma relapsed within 6 months after remission from the previous initial treatment.
After multiple lines of treatment, the curative effect was poor
.

In the fifth-line treatment, combined with the new mechanism of action of selinisol and the clinical research data of the combination drug, the drug resistance was overcome from different mechanisms, and the patients were given the XKPd regimen, and the efficacy evaluation reached CR
.

Based on the good efficacy and controllable safety of the Selinexol combination regimen in the treatment of this patient with MM progressive plasma cell leukemia, we also gave this drug to a patient with primary plasma cell leukemia with extramedullary lesions.
The patient was a 52-year-old man who had previously been treated with conventional chemotherapy but had multiple recurrences of the disease.
After receiving selinisol, bortezomib, and dexamethasone (XVd) in combination with lenalidomide, his extramedullary plasmacytoma significantly shrank
.

Based on the unique anti-tumor mechanism of Selinesol, it will bring more clinical benefits to patients with multidrug-resistant R/R MM and plasma cell leukemia! The above opinions are based on the clinical diagnosis experience of experts.
The cases involved in the article are teaching cases and have been anonymized
.

Professor Deng Jianchuan, Chief Physician, Master Supervisor Vice-chairman of the Precision Medicine and Molecular Diagnosis Special Committee of the Chongqing Association of Integrative Medicine and Molecular Diagnosis Member of the Lymphohematopoiesis Group of the Pathology Branch of the Chongqing Medical Association Member of the Occupational Disease Branch of the Chongqing Medical Association Research direction: molecular mechanism of leukemia and hematopoietic stem cell transplantation, presided over a number of The subject, published a number of SCI papers
.

Professor Lou Shifeng Chief Physician Doctoral Supervisor Director of Hematology Department of the Second Affiliated Hospital of Chongqing Medical University Chongqing Academic and Technical Leader Chairman, Deputy Chairman of the Chongqing Blood Professional Committee, Honorary Chairman of the Chongqing Municipal Committee on Integrative Medicine and Oncology, Expert Editor of the Physical Evidence Identification Center of Chongqing Public Security Bureau: Irena Typesetting: Wenting Execution: XY References: [1] NCCN Guidelines 2021.
Version 4.
B-CellLymphomas.
[2] Guidelines Working Committee of the Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Hematological Malignancies 2021[M].
Beijing: People's Health Publishing House, 2021.
319-326.
[3] Darrell White, et al.
Oral selinexor, pomalidomide, and dexamethasone (XPd) at recommended phase 2 dose in relapsedrefractory multiple myeloma (MM).
EHA Library.
White D.
06/09/21; 324731; EP1008.
[4] Gasparetto C , et al.
Once weeklyselinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiplemyeloma patients.
Br J Cancer.
2022 Mar;126(5):718-725.
doi:10.
1038/s41416-021-01608-2.
Epub 2021 Nov 20 .
PMID: 34802051; PMCID: PMC8605887.
[5] Suzanne Lentzsch, et al.
Efficacy and Safety of Selinexor-Containing Regimens in Patients with Multiple MyelomaPreviously Treated with Anti-CD38 Monoclonal Antibodies (αCD38 mAb).
ASHAbstract 1651, 2021.
Click "Read the original text", we will progress together