Case Sharing Professor Luqun Comments: Targeted therapy has shown its skills, and the frontline use of the Celineso combination regimen has brought relief to MM patients involved in CNS!

Multiple myeloma (MM) is a malignant proliferative disease of plasma cells in which clonal plasma cells grow abnormally and secrete monoclonal immunoglobulins or fragments thereof (M proteins), causing damage

Nuclear output protein 1 (XPO1) is a key nuclear transporter in cells, and its overexpression plays an important role

• Neurological examination: mild dysarthria; Right limb muscle strength level 2, right side of the face and limb sensory loss, right heel knee shin test is not stable.

  
  

• Bone marrow examination: morphology: 40% of naïve plasma cells; FCM: Plasma cells occupy 21.

  
  

• Cerebrospinal fluid (CSF) test: positive for globulin; Leukocytes 88.

  
  

• Blood M protein test: immunostaxy: IgG-κ positive 35.

  
  

• Other hematological tests: blood calcium 2.

  
  

• PET-CT: the bone density of multiple bones is uneven, and the homogeneity of FDG metabolism is increased, which is in line with MM image performance; Bilateral ischemic degenerative foci in the white matter area of the

  
  

Figure 1.
Baseline PET-CT examination

• CRR and enhancement: multiple positions of the right sphenoid wing and skull, combined with medical history, multiple myeloma is more likely; Multiple ischemic degenerative foci and softening foci in the brain; Bilateral thalamus regions of old hemorrhagic foci may be; Brain atrophy
  .
  
  

Figure 2.
April 9, 2022 Cranial MR and enhancement test

Clinical diagnosis:

MM (IgG-κ type, D-S staging III.
ISS stage III.
, R-ISS stage III.
), extramedullary plasma cell tumor (CNS involvement), ECOG 3 points; Lung infections; Hypertensive disease grade 2 (very high risk); Type 2 diabetes; Old cerebral infarction; Coronary atherosclerotic heart disease; Recovery period of ST-segment elevation myocardial infarction; Osteosamangioma; Liver cysts
.

• On April 28, 2022, the patient was given 1 course
  of treatment with dalytoliumab plus bendamustine and dexamethasone.
  
  

• The patient's right muscle strength improves and he can stand
  on the ground.
  
  

• M protein test: M protein content is reduced (as shown in Figure 3
  ).
  
  

Figure 3.
Comparison of M protein content at baseline and chemotherapy after 1 course

Summary of the efficacy of the previous regimen: After the patient received 1 course of chemotherapy in the past, the muscle strength symptoms improved and the M protein decreased
.

• 19 May 2022 Celinenisol (60 mg po qw) combined with darrituliumab (16 mg/^m2 qw) and dexamethasone (20 mg qw) regimens
  were given.
  
  

• The patient's right muscle strength is improved, he can stand on the ground, walk 200 meters, and live partially self-care
  .
  
  

• M protein test: M protein content decreased (as shown in Figure 4
  ).
  
  

Figure 4.
Comparison of M protein content at baseline, after chemotherapy course 1, and after celineso combination regimen

• CSF examination: negative cytology, leukocyte 0/ul, M protein negative; CSF flow cytology was negative and no abnormal plasma cell metamorphosis
  was found.
  
  

• Craniocerebral MR and enhancement: lesions are smaller than in the previous film (April 9, 2022) (as shown in Figure 5
  ).
  
  

Figure 5.
Left: April 9, 2022 Right: July 19, 2022 Craniocerebral MR and enhancement test results

• Evaluation of hematologic efficacy: very good partial response (VGPR
  ).
  
  

• Evaluation of extramedullary efficacy: partial response (PR
  ).
  
  

The patient was an elderly MM patient with CNS, with multiple underlying diseases, and after receiving 1 course of chemotherapy, celineso combination therapy was given, and the optimal efficacy evaluation reached VGPR, the lesions were narrowed earlier, and the muscle function was relieved
.

In this case, a patient with advanced MM, plasma cell tumors involving the CNS have led to a series of clinical symptoms related to the nervous system, such as right muscle weakness, which seriously affect the patient's quality of life
.

In addition, patients with a combination of multiple underlying diseases, poor physical fitness status, poor tolerance to chemotherapy, and severe cardiovascular adverse events
occurred during the use of bortezomib prior to this admission.

Considering the above factors, from the perspective of improving the patient's physical function and improving the patient's drug tolerance, it is considered to give them highly effective and low-toxic small molecule targeted drugs
.

First, the patient was given 1 course of anti-CD38 monoclonal antibody combined chemotherapy regimen, and the patient's right muscle strength was improved, and the M protein content was reduced
to a certain extent.

In order to enable patients to obtain more targeted treatment, the results of this basic study combined with Celineso can significantly prolong the survival time of mice with primary central nervous system lymphoma (PCNSL)², and in subsequent treatment, celineso plus darrituliumab and dexamethasone regimens
were provided to patients in this case.

After this treatment, the patient's optimal efficacy was evaluated up to VGPR, and PET-CT showed that the patient's intracranial lesions were narrowed compared with before; Both blood and cerebrospinal fluid M protein tests are negative; And the patient's muscle function has been significantly improved, and part of his life can be self-care
.

For MM patients involved in CNS, the selection of a small molecule-targeted drug with a completely new mechanism of action during treatment may bring clinical benefits
to patients by directly targeting the antitumor effect.

MM is a common malignancy of the blood system with abnormal proliferation of clonal plasma cells, and patients usually have neurological complications, including peripheral neuropathy, radiculopathy, spinal cord compression, etc.
, and the causes mainly include fractures with vertebral compression, involvement of the base of the skull and other bone areas, metabolic changes (hypercalcemia, uremia and hyperamoniaemia), etc.
, and are also related to treatment-related drug ^toxicity3
.

However, CNS infiltration in MM patients is relatively rare, the prevalence is 1%, and the incidence of false positive and false negative results is high, which has an impact on
subsequent targeted treatment.

In addition, patients with MM involved with CNS had a poor prognosis, with a 2-year mortality rate of 75% after ^diagnosis4
.

For such patients, the current commonly used treatment strategies include intrathecal injection, local radiotherapy, systemic chemotherapy, etc.
, but the effect is limited
.

For patients with advanced age and poor physical fitness, compliance and quality of life are often reduced due to the inability to tolerate chemotherapy toxicity
.

Therefore, in the clinic, in addition to the need for early and clear diagnosis, there is an urgent need for new, efficient, low-toxicity, small molecule targeted drugs that can cross the blood-brain barrier to improve the treatment status of
patients.

As the first oral XPO1 inhibitor, Selinisole can selectively bind to XPO1, thereby inhibiting its activity, through multiple pathways mediated to induce tumor cell apoptosis, inhibit the development of MM disease, and Celineso as a small molecule targeted drug with a molecular weight of 443.
3 kd, can effectively cross the blood-brain barrier, is a new drug
that can be considered in the treatment process of MM patients involving CNS.

Both the previous STORM study ⁵ and the BOSTON study ⁶ validated the treatment of R/R MM with multiple drugs with selinisole with multiple drugs, with significant clinical efficacy and good safety.

In this case, patients with MM involved in CNS were given a chemotherapy-free regimen
of celinesso with celinesole during frontline treatment because they had more underlying diseases and were less tolerant to chemotherapy.

The evaluation of efficacy after administration showed that not only the neurologic symptoms of the patients improved significantly, but also the M protein was significantly reduced, and the MRI showed a reduction of intracranial lesions, and the optimal efficacy evaluation reached VGPR
.

It can be seen that the frontline use of the Celineso joint program can bring benefits to the efficacy of MM patients involved in CNS, and it is expected that more clinical studies will be further demonstrated in the future to provide new treatment options for this part of the patients!

Professor Wang Luqun

• Professor of Department of Internal Medicine/Qilu Hospital, Shandong University, Doctor of Medicine

• Member of the Asian Myeloma Network (AMN).
  

• Member of the Plasma Cell Disease Group of the Hematology Branch of the Chinese Medical Association

• Member of the Professional Committee of Multiple Myeloma of the Chinese Medical Doctor Association

• Member of the Myeloma and Plasma Cytology Group of the Hematology and Tumor Committee of the Chinese Anti-Cancer Association

• Member of the China Anti-Lymphoma Alliance

• Member of the Standing Committee of the Blood Professional Committee of the China Medical Education Association

• Member of the Standing Committee of the Expert Committee on Hematology of the Chinese Gerontological Society

• Member of the Blood Committee of the Chinese Geriatrics Association

• Member of the Hematology Committee of Shandong Medical Association

• Member of the Hematology and Tumor Professional Committee of Shandong Anti-Cancer Association

• Leader of the Working Group of Multiple Myeloma in Shandong Province

Professor Liu Na

• Deputy Chief Physician, Department of Hematology, Qilu Hospital, Shandong University

• MD, PhD, Shandong University

• He has presided over 1 national natural youth science fund project and 1 provincial project

• Research interests: Pathogenesis of malignant hematological diseases and the mechanism of drug resistance

• Published 6 SCI papers as the first author

References:

1.
Chen Lijuan, et al.
A case of central nervous system infiltrating multiple myeloma and literature review.
Leukemia & Lymphoma,2018,27(8): 489-492.

2.
Jiménez I, et al.
J Neurooncol.
2020 Aug; 149(1):13-25.

3.
Dias ALMS, et al.
Multiple myeloma and central nervous system involvement: experience of a Brazilian center.
Rev Bras Hematol Hemoter.
2018 Jan-Mar; 40(1):30-36.

4.
Jurczyszyn A, et al.
Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice.
Am J Hematol.
2016 Jun; 91(6):575-80.

5.
Ajai Chari, et al.
Oral Selinexor–Dexamethasone for Triple-Class Refractory Multiple Myeloma.
N Engl J Med .
2019 Aug 22; 381(8):727-738.

6.
Sebastian Grosicki, et al.
Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.
Lancet .
2020 Nov 14; 396(10262):1563-1573.

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