Selinexor combined bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma with extramedullary disease: a multicenter study

doi:10.21203/rs.3.rs-4702232/v1

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Selinexor combined bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma with extramedullary disease: a multicenter study

https://doi.org/10.21203/rs.3.rs-4702232/v1

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Objective: We aimed to explored the efficacy and safety of XVRD protocol in newly diagnosed multiple myeloma with extramedullary disease.

Methods: This is a single-arm, open, observational clinical study. For induction/consolidation(21-day cycles), patients (pts) received 8 cycles of XVRd (Selinexor 60 mg PO weekly, Bortezomib 1.3 mg/m² SC days1, 4, 8, 11, Lenalidomide 25 mg PO days 1-14, and Dexamethasone 40 mg PO weekly). In maintenance (28-day cycles), pts received XR (Selinexor+Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoint was overall response rates and minimal residual disease negative rates.

Results: The median age of the 10 pts was 62 (range 55-81) years. R-ISS stage 3 was present in 2 (20%) pts. 3 pts had high risk cytogenetic and 1 patient with plasma cell leukocyte. According to IMWG criteria, the ORR of 10 pts with NDMM was 100%, including 2 stringent complete response (sCR), 2 complete remission (CR), 4 very good partial response (VGPR) and 2 partial response (PR). Median progression-free survival and overall survival were not achieved. The most common grade 3-4 treatment-emergent adverse events (occurring in 10% of pts) were thrombocytopenia. The most common non-hematological adverse events were grade 1 or 2, including nausea (30%), fatigue (40%), and anorexia (20%). Overall, the severe toxicities are manageable.

Conclusion: The XVRd regimen has good efficacy and tolerance in newly diagnosed multiple myeloma with extramedullary disease.

Multiple myeloma

Selinexor

Extramedullary disease

In most patients with multiple myeloma (MM), plasma cell proliferation is confined to the bone marrow cavity, but a subset of patients may grow outside the bone marrow, called multiple myeloma extramedullary infiltration (EMM). EMM can arise from skeletal focal lesions, which disrupt the cortical bone and grow as extra-bone masses, and is referred to as extramedullary bone related (EMB), or derive from hematogenous spread as manifestation in soft tissues, and is called Extramedullary extraosseous(EME)¹. Incidence of EMM at diagnosis ranges between 7% and 18%, while later in the course of the disease this increases to 30%-50%². In recent years, with the prolongation of the survival of MM patients, the updating of examination methods and the attention of clinicians, the incidence of EMM has gradually increased. EMM is an independent poor prognostic factor of MM. High-risk (HR) cytogenetics are significantly enriched in MM with EMM. To date, the treatment of EMM remains very challenging and prospective clinical studies are urgently needed to explore optimal options.

Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates exportin-1(XPO1). In the STORM study (NCT02343042), 122 patients(pts) with penta-exposed, triple-class refractory multiple myeloma were enrolled to receive Selinexor combined with low-dose dexamethasone. 27 pts were diagnosed with EMM at baseline. Follow-up evaluation of plasma cell tumor was performed in 16 cases, and complete disappearance or shrinkage of extramedullary lesions was observed in 9 cases³. However, there are no studies on the combination regimen of Selinexor for the treatment of newly diagnosed multiple myeloma (NDMM) with EMM. In this study, we aimed to explored the efficacy and safety of Selinexor combined with lenalidomide, bortezomib, and dexamethasone (XVRd) protocol in NDMM with EMM.

2.1. Patients

This open, single-arm prospective study included 10 pts with NDMM with EMM from August 2022 to December 2023 in 3 hospitals. This trial is registered with Chinese Clinical Trial Registry, number ChiCTR2200062860. All pts received XVRd regimen. The diagnosis of extramedullary plasmacytoma was confirmed by pathological biopsy in all patients. Eligible pts were aged ≥ 18 years of NDMM with EMM, meet the updated criteria for the diagnosis of MM in International Myeloma Working Group(IMWG) and an Eastern Cooperative Oncology Group(ECOG) performance status of 0–2⁴. Exclusion criteria: ① patients with active hepatitis B, hepatitis C, and other acquired and congenital immunodeficiency diseases; ② patients with grade 2 or more terminal neuropathy or neuralgia; ③ patients with serious thrombotic events prior to treatment; ④ patients with hepatic insufficiency (ALT and AST ≥ 2 times the upper limit of normal values).

Laboratory tests perfected in all patients before treatment included complete blood count, biochemical tests (serum albumin, globulin, total protein, calcium, lactate dehydrogenase, creatinine), β2-microglobulin, serum protein electrophoresis, immunofixation electrophoresis, serum free light chains, morphological analysis of peripheral blood, bone marrow cytomorphometry, bone marrow biopsy, immunophenotyping, and fluorescence in situ hybridisation (FISH). Other tests included electrocardiogram (ECG), cardiac ultrasound, lung computed tomography (CT), and vertebral magnetic resonance imaging (MRI). Patients with at least one of the following aberrations were considered as high-risk cytogenetics: del(17p), t(4;14), t(14;16), and t(14;20), p53 mutation, gain(1q). All patients were evaluated for EMM based on imaging and lesion size was measured before treatment.

2.2. Treatment, Response, and Outcome

For induction/consolidation(21-day cycles), pts received 8 cycles of XVRd (Selinexor 60 mg PO weekly, Bortezomib 1.3 mg/m² SC days1, 4, 8, 11, Lenalidomide 25 mg PO days 1–14, and Dexamethasone 40 mg PO weekly). Pts suitable for autologous stem cell transplantation (ASCT) received 4 courses of induction therapy and ASCT after efficacy was assessed to be in partial remission and above, after which they continued XVRd consolidation therapy for 4 courses and entered maintenance therapy; pts not suitable for ASCT were treated with the XVRd regimen for 8 courses, after which they entered maintenance therapy. In maintenance (28-day cycles), pts received XR (Selinexor + Lenalidomide) at least 2 years until disease progression, death or withdrawal.

The primary endpoint was overall response rates (ORR) and minimal residual disease (MRD) negative rates by end of induction. The secondary endpoints are complete response (CR), progression free survival (PFS), overall survival (OS) and toxicity. The efficacy of induction therapy was evaluated every 2 courses. All patients were evaluated as progression disease (PD), stable disease (SD), partial response (PR), very good partial response (VGPR), CR, and stringent complete response (sCR) according to IMWG criteria⁵. ORR = sCR + CR + VGPR + PR. The level of MRD was detected by 8-color flow cytometry after induction therapy. After treatment, the efficacy of EMM was evaluated according to imaging, and the lesion size was measured.

Adverse events (AE) during Selinexor containing treatment were characterized according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0⁶. Adjust drug dosage according to AE.

Patient survival was obtained from telephone follow-up and access to outpatient or inpatient records. Follow-up ended on April 30, 2024, with a median follow-up of 15 (5–18) months. OS was defined as the time from initiation of treatment with Selinexor until death or termination of follow-up.

2.3. Statistical Analysis

Using descriptive statistics, we summarized patients’ characteristics as absolute number and percentage, and if not otherwise stated as median and range. The survival analysis was performed with Kaplan–Meier method. These analyses were performed with “IBM SPSS Statistics for Windows. Version 25.0 (Statistical Pac-kage for the Social Sciences, IBM Corp., Armonk, NY, USA)”

3.1. Patients’ Characteristics

10 patients with previously untreated NDMM were included in the study. Five of the patients were female and five were male. Median age was 62 (range 55–81) years. Patients with an ECOG score of less than or equal to one comprised 70% of the cases. R-ISS stage 3 was present in 2 (20%) patients (Table 1). Among all patients, five cases were IgG, one case was IgD, one case was IgA, and three cases were light chain. 3 patients had high-risk cytogenetic from bone marrow biopsy, including 1q21 gain(n = 3, 30%), one of which was combined with 17p deletion (n = 1, 10%). When the patients were examined according to the EMM involvement regions, five patients had cortical bone, one patient had CNS, one patient had kidney, one patient had sinus, one patient had eye, and one patient had soft tissue of chest (Fig. 1). Patients’characteristics are summarized in Table 1.

Table 1

Patients’ characteristic
	n	%
Gender
Male	5	50
Female	5	50
ECOG Performance Status
0	3	30
1	4	40
2	3	30
Type of myeloma
IgG	5	50
IgD	1	10
IgA	1	10
Light chain	3	30
R-ISS stage at initial diagnosis
Ⅰ	1	10
Ⅱ	7	70
Ⅲ	2	20
Cytogenetics
Normal	7	70
Del 17p	1	10
1q21 gain	3	30
Del 13q	1	10
Serum beta-2 microglobulin level
<3.5mg/liter	3	30
3.5-5.5mg/liter	5	50
>5.5mg/liter	2	20
Response to Therapy
sCR	2	20
CR	2	20
VGPR	4	40
PR	2	20

3.2. Treatment and Response to Therapy

All patients completed at least 3 courses of treatment, and the median number of courses was 6 (3–15). According to IMWG criteria, the ORR of 10 patients with NDMM was 100%, including 2 sCR, 2 CR, 4 VGPR and 2 PR. Median time to first response in patients with a partial response or better was 1 months (1–2). Among the 10 patients, only 1 patient with plasmacytic leukemia died due to disease progression, and 1 patient changed to other programs due to disease progression after 6 courses. 1 patient evaluated with sCR at the end of the induction period was evaluated with MRD negativity after autologous stem cell transplantation (ASCT). Of the 10 patients, the extramedullary lesions disappeared completely in 4 cases after induction therapy, and the chest soft tissue mass of 1 patient disappeared completely after 2 courses of treatment, while shrinkage of extramedullary lesions was observed in the other 6 patients. Median PFS and OS times were not achieved, one-year PFS rate was 60% and one-year OS rate was 90.0%. This results established that XVRd regimen has a prospective response for MM with EMM.

3.3. Adverse Events (AEs)

All patients were given 5-hydroxytryptamine antagonist (palonosetron 0.25 mg or equivalent) and olanzapine to prevent nausea. The most common grade 3–4 haematological AEs was thrombocytopenia (n=1,10%), and there were no grade 3–4 non-haematological AEs. The most common grade 1–2 haematological AEs were neutropenia (n༝5, 50%), thrombocytopenia ((n༝5, 50%) and anaemia (n༝5, 50%), while non-haematological AEs were mainly gastrointestinal reactions, including nausea in 3(30%)cases and vomiting in 1(10%)cases, anorexia in 2(20%)cases, and abdominal pain in 1(10%)case, all of which were grade 1–2, and were improved after the administration of supportive treatment with antiemetic, gastric mucous membrane protective agents, and gastrointestinal motility-promoting drugs. Other AEs included fatigue in 4 (40%)cases and fever in 1 (10%)case, all of which were grade 1–2. Overall, the severe toxicities were manageable. The adverse events for all patients are shown in Table 2.

Table 2

Complete data of 10 patients
Pat	Age	Gender	Type	DS stage	ISS stage	RISS stage	ECOG * score	FISH	extramedullary involvement	Response	AEs
1	58	Female	IgDλ	ⅢA	Ⅲ	Ⅲ	2	1q21+	Kidney	VGPR	Nausea/Anorexia/ Myelosuppression
2	61	Male	IgGκ	ⅢA	Ⅲ	Ⅱ	1	Normal	Rib	VGPR	Nausea/Vomiting/ Fatigue
3	66	Male	IgGκ	ⅢA	Ⅱ	Ⅱ	0	Normal	Thoracic	sCR	Fever/ Myelosuppression
4	59	Male	κ	ⅢA	Ⅱ	Ⅱ	0	Normal	Thoracic	CR	Fatigue
5	55	Female	IgGλ	ⅢA	Ⅱ	Ⅱ	0	1q21+/13q-	Humerus/femur	sCR	Fatigue/ Myelosuppression
6	56	Male	IgAκ	ⅢA	Ⅰ	Ⅰ	1	Normal	Nasal cavity	VGPR	Nausea/Anorexia
7	69	Female	IgGκ	ⅢA	Ⅱ	Ⅱ	2	Normal	CNS	PR	Fatigue
8	68	Female	IgGλ	ⅢA	Ⅱ	Ⅱ	2	Normal	Lung	CR	Celialgia/ Myelosuppression
9	81	Female	κ	ⅢA	Ⅲ	Ⅲ	1	17p-/1q21+	Eye	PR	Thrombocytopenia
10	63	Male	λ	ⅡA	Ⅱ	Ⅱ	1	Normal	Ilium	VGPR	Myelosuppression

Pat—Patient; DS—The Multiple Myeloma Durie-Salmon Staging System; ISS—The Multiple Myeloma International Staging System; RISS—Revised International Staging System; VGPR—very good partial response; PR—partial response; ECOG—Eastern Cooperative Oncology Group; FISH—Fluorescence In Situ Hybridization; AEs—Adverse Events.

The treatment of MM combined with extramedullary plasmacytoma remains very challenging, with a lack of prospective study results and no targeted standard treatment protocols in clinical practice. Exportin 1 (XPO1) — the sole known nuclear exporter of tumor suppressor proteins, the glucocorticoid receptor, and oncoprotein messenger RNAs (mRNAs) — is overexpressed in myeloma and correlates with increased bone disease and shorter survival^7,8. Selinexor is a potent, oral, selective inhibitor of nuclear export that binds to Cys528 in the cargo-binding pocket of XPO1,12–14 forcing the nuclear localization and functional activation of tumor suppressor proteins, trapping IκBα in the nucleus to suppress nuclear factor κB activity, and preventing oncoprotein mRNA translation^9,10. In addition, SINE compound has synergistic effect with cytotoxic drugs, proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs)^11,12. The STORM study has preliminarily demonstrated the therapeutic activity of Selinexor in patients with EMM. At present, both domestic and international guidelines recommend VRd as first-line therapy for high-risk MM patients, but the efficacy of VRd for NDMM patients with EMM is not ideal.

The results of this study showed that the median number of effective courses of XVRd induction therapy was 1 course, and the ORR reached 100%. 2 of 10 patients underwent ASCT, and 1 patient evaluated with sCR at the end of the induction period was evaluated as MRD negative after transplantation. Therefore, Selinexor can achieve deep remission in NDMM patients with EMM. Patients eligible for transplantation may have further sequential ASCT to prolong progression-free survival. Complete disappearance or shrinkage of extramedullary lesions was observed in 10 cases. One patient with CNS involvement had an extramedullary mass that decreased by > 50% in volume after 2 courses of treatment, and one patient with a 5*4 cm chest soft tissue mass completely disappeared after 2 courses of treatment. The results showed that XVRd regimen achieved good response rates and survival outcomes in MM patients with extramedullary plasmacytoma. Among the 3 patients with high risk cytogenetics, 1 patient complicated with plasmacytic leukemia died after 3 courses of treatment, 1 patient changed other treatment regimen after 6 courses of treatment, and 1 patient achieved sCR after 4 courses of treatment.

The protocol is safe and the AEs can be controlled, and no new AEs have been observed in this study. Hematological AEs were the most common AEs during the treatment, especially when used in combination with drugs with bone marrow suppressive effects such as IMiDs, more attention should be paid. The frequency and severity of AEs are similar to those observed in the STORM trial, and can be controlled by active prophylactic and supportive therapy, dose adjustments, and other measures, and are progressively better tolerated by patients as the duration of treatment increases. Most hematological AEs occur within the first 2 treatment cycles. Complete blood counts should be closely monitored, symptomatic treatments such as TPO agonists and platelet transfusion should be applied as soon as possible, and selinexor can be reduced or discontinued if necessary. Only one patient had a grade ≥ 3 Thrombocytopenia. The most common non-hematological AEs in this study were nausea, anorexia, and fatigue, which were mostly grade 1–2. Prevention is more important than treatment. Our current study has limitations, such as a limited clinical sample size, which needs to be further expanded in the future.

XVRd as induction prior ASCT is safe and allows deep responses in NDMM patients with EMM. It is worthy of further study based on the preliminary efficacy results. Longer-term results still require more pts have been enrolled.

AUTHOR CONTRIBUTIONS

Junjing Yin：Conduct research, collect data, analyze/interpret data, write papers；Xia Zhou and Xuemei Li：Conduct research and collect data；Chenglu Yuan, Xiaoxia Chu, Lumei Hao and Hongying Wu：Screening cases and conduct research；Yuping Zhong: designed and supervised the trial, reviewed the data, reviewed and approved the paper.

FUNDING INFORMATION

This research was supported by the Beijing Natural Science Foundation Research Project (Approval number :Z20J00076).

CONFLICTS OF INTEREST STATEMENT

The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

Data are available upon reasonable request from the corresponding authors with permission of the institution.

ETHICS STATEMENT

This study was conducted in accordance with the Declaration of Helsinki and was approved by the independent ethics committee of Qingdao Municipal Hospital (no. 2022Y042).

PATIENT CONSENT STATEMENT

All patients provided written informed consent.

CLINICAL TRIAL REGISTRATION

ChiCTR2200062860.

Supplementary Information

Below is the link to the electronic supplementary material.

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Yee, A. J. et al. Response to Therapy and the Effectiveness of Treatment with Selinexor and Dexamethasone in Patients with Penta-Exposed Triple-Class Refractory Myeloma Who Had Plasmacytomas. Blood 134, 5 (2019). https://doi.org:10.1182/blood-2019-129038
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You are reading this latest preprint version

Selinexor combined bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma with extramedullary disease: a multicenter study

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Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1. Patients

2.2. Treatment, Response, and Outcome

2.3. Statistical Analysis

3. Results

3.1. Patients’ Characteristics

3.2. Treatment and Response to Therapy

3.3. Adverse Events (AEs)

4. Discussion

5. Conclusions

Declarations

References

Supplementary Material

Additional Declarations

Status:

Version 1