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Introduction Learning Objectives Introduction

Introduction

Despite the introduction of new therapies, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibody therapy, most patients with multiple myeloma (MM) ultimately experience clinical relapse.1

MM is responsible for 80,000 deaths annually,2 with a rising incidence.3 Patients experience a high symptom burden that worsens with disease progression and impacts on physical, cognitive, emotional and social functioning. Bone-pain, fractures and fatigue are reported frequently.4

It is evident that there is a need for new therapeutic targets. Nuclear export, mediated by exportin proteins, is a basic cellular function exploited by cancer cells to evade detection and destruction by innate immune defences.5,6

There are 8 exportins within human cells,7 but research has focused on exportin 1 (XPO1) and demonstrated that overexpression is associated with tumour growth and poor survival.5,6,8

Selinexor is designed to selectively inhibit nuclear export, reactivating tumour suppressor proteins and reducing the level of oncoproteins; promoting apoptosis of cancer cells whilst sparing normal cells.9,10

This educational FEATURE will examine the Phase Ib/II STOMP and Phase IIb STORM studies in patients with quad-refractory and penta-refractory MM,1,9,11 and discuss the patient population of the ongoing, Phase III BOSTON trial.12

Selinexor represents a new approach to fighting cancer and offers a potential advance in cancer therapy for patients with relapsed/refractory multiple myeloma (RRMM).

Selinexor (KPT 330) is an investigational agent, and safety and efficacy have not been established by any agency. Any medical or scientific information provided in this media is intended only for general educational purposes related to medical research. It provides only general information about the investigational agent selinexor (KPT 330) and clinical trials in general.

Learning Objectives

This educational FEATURE on relapsed/refractory multiple myeloma (RRMM) should provide a concise overview of the promising outcomes associated with selinexor, the first-in-class, orally bioavailable, Selective Inhibitor of Nuclear Export (SINE) compound.1,9

Details about the Phase Ib/II STOMP and Phase IIb STORM clinical trials are presented, with clinical outcomes demonstrating the efficacy of selinexor in combination with low-dose dexamethasone in patients with quad-refractory or penta-refractory disease. The STORM trial supports preclinical findings that selinexor re-sensitizes and overcomes resistance to proteasome inhibitors (PIs).

Additionally, the patient population for the Phase III BOSTON trial will be discussed, which investigates patients who have relapsed with a PI or PI-naïve patients who have received ≤3 prior treatments.

Selinexor may have important implications in the treatment of RRMM. This educational FEATURE will examine how selinexor may help maximize therapeutic benefit by allowing patients to stay on treatment for longer, and provide the potential to re-sensitize RRMM to current therapies and overcome resistance to PIs.9,11

touchFEATURE

Exploring novel ways to manage patients with relapsed/refractory multiple myeloma - focus on the clinical development of selinexor

How are we doing with multiple myeloma?

Understanding the current needs of patients with multiple myeloma (MM) may be important when selecting future therapies. Patients experience a high symptom burden that affects their quality of life.4

MM is responsible for 80,000 deaths annually, with 13,300 deaths attributable to the disease in the US alone.2 In Europe, the incidence of MM is expected to increase to over 43,000 new cases in the next 15 years, with patient deaths also projected to increase significantly.3

Can we afford not to develop new therapies?

Is the mode of action of selinexor unique?

In MM and other cancers, an overexpression of exportin 1 (XPO1) enables cancer cells to evade the body’s natural defences of genome surveillance and apoptosis.5,6

XPO1 is also associated with promoting the production of oncoproteins, further fuelling the growth of cancers.20-22

In patients with MM, overexpression of XPO1 leads to inactivation of tumour suppressor proteins,5,23 and correlates with poorer survival as well as higher numbers of bone lesions.8

Selinexor (KPT-330) is a first-in-class, orally bioavailable, Selective Inhibitor of Nuclear Export (SINE) compound that specifically blocks XPO1.1,9

How does the action of selinexor translate into the clinic?

Selinexor is under investigation through an extensive clinical trials programme. The Phase Ib/II STOMP and Phase IIb STORM trials have already completed, providing evidence of selinexor’s efficacy in combination with other treatments used for RRMM, such as low-dose dexamethasone.1,9,11

These studies have already shown significant improvements in patient survival with selinexor.1 The ongoing Phase III BOSTON trial will evaluate the benefits of selinexor with bortezomib plus low-dose dexamethasone in patients treated with a limited number of prior therapies.12

In the following videos, we talk about the Phase Ib/II clinical outcomes and the design of the ongoing, Phase III BOSTON trial.

What are the outcomes so far from clinical trials investigating selinexor for relapsed/refractory multiple myeloma?

Key learnings

Please test your knowledge about the information presented and then feedback on this educational FEATURE.

Q1. Selinexor selectively inhibits exportin 1 in cancer cells. Overexpression of exportin 1 is associated with:

Blocking transport of tumour suppressor proteins from the cell nucleus Activation of tumour suppressor proteins Poorer event-free and overall survival Reduced numbers of bone lytic lesions

Correct!

Selinexor is designed to selectively inhibit nuclear export,1,9 reactivating tumour suppressor proteins and reduce the level of oncoproteins;8 promoting apoptosis of cancer cells whilst sparing normal cells.10

Functional inactivation of tumour suppressor proteins5,23 correlates with poorer event-free and overall survival, as well as higher numbers of bone lytic lesions.8

Incorrect!

In patients with MM, overexpression of XPO1 leads to functional inactivation of tumour suppressor proteins,5,23 and correlates with poorer event-free and overall survival, as well as higher numbers of bone lytic lesions.8

Q2. Phase IIb clinical trial outcomes suggest that a combination of selinexor and low-dose dexamethasone shows efficacy in patients with quad-refractory and penta-refractory disease.

True False

Correct!

The Phase IIb STORM trial demonstrated that the ORR was similar for patients with either quad-refractory (21%) or penta-refractory (20%) disease. Among patients with high-risk cytogenetics, the ORR was 35%.1

The median PFS and OS times were 2.3 and 9.3 months across all selinexor patients, respectively. Patients with at least a minimal response after one cycle demonstrated significantly improved overall survival versus patients with stable or progressive disease (median, not reached versus 7.2 months, respectively; p=0.01).1

Incorrect!

The Phase IIb STORM trial demonstrated that the ORR was similar for patients with either quad-refractory (21%) or penta-refractory (20%) disease. Among patients with high-risk cytogenetics, the ORR was 35%.1

The median PFS and OS times were 2.3 and 9.3 months across all selinexor patients, respectively. Patients with at least a minimal response after one cycle demonstrated significantly improved overall survival versus patients with stable or progressive disease (median, not reached versus 7.2 months, respectively; p=0.01).1

Q3. Which of the following is true about selinexor?

First-in-class Orally bioavailable Selective Inhibitor of Nuclear Export (SINE) Designed for combination therapy All of the above

Correct!

Selinexor is a first-in-class, orally bioavailable, Selective Inhibitor of Nuclear Export (SINE) compound that specifically blocks XPO1.1,9 Selinexor is under investigation in the ongoing, Phase III BOSTON trial in combination with bortezomib plus low-dose dexamethasone.12

Incorrect!

Selinexor is a first-in-class, orally bioavailable, Selective Inhibitor of Nuclear Export (SINE) compound that specifically blocks XPO1.1,9 Selinexor is under investigation in the ongoing, Phase III BOSTON trial in combination with bortezomib plus low-dose dexamethasone.12

Q4. The STORM trial supports preclinical findings that selinexor re-sensitizes and overcomes resistance to PI.

True False

Correct!

The open label, randomized Phase Ib/II STOMP trial reported efficacy across all treatment arms, with a high response in PI-relapsed or PI-naïve patients compared with expected responses from bortezomib and low dose dexamethasone (ORR, 84% versus ≤65%, respectively).9

An ORR of 43% was reported in PI-refractory patients, supporting preclinical findings that selinexor re-sensitizes and overcomes resistance to PI.9,11

Incorrect!

The open label, randomized Phase Ib/II STOMP trial reported efficacy across all treatment arms, with a high response in PI-relapsed or PI-naïve patients compared with expected responses from bortezomib and low dose dexamethasone (ORR, 84% versus ≤65%, respectively).9

An ORR of 43% was reported in PI-refractory patients, supporting preclinical findings that selinexor re-sensitizes and overcomes resistance to PI.9,11

Q5. What patient population was selected for inclusion in the Phase III BOSTON trial?

Penta-refractory disease MM refractory to both a PI and IMiD only Patients with PI-relapsed or PI-naïve patients who have received ≤3 prior treatments MM refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide Patients who had been diagnosed <4 years previously

Correct!

The open label, randomized dose Phase Ib/II STOMP trial reported efficacy across all treatment arms, with a high response in PI-relapsed or PI-naïve patients.9,11

In PI-relapsed or PI-naïve patients with ≤3 prior treatments, the selinexor combination was associated with an ORR of 83% and a PFS >13 months.9 This patient population has been targeted in the Phase III BOSTON trial.9,11

Incorrect!

The open label, randomized dose Phase Ib/II STOMP trial reported efficacy across all treatment arms, with a high response in PI-relapsed or PI-naïve patients.9,11

In PI-relapsed or PI-naïve patients with ≤3 prior treatments, the selinexor combination was associated with an ORR of 83% and a PFS >13 months.9 This patient population has been targeted in the Phase III BOSTON trial.9,11

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