Selinexor Offers Patients New Path in Relapsed/Refractory Myeloma

Robb S. Friedman, MD, hematologist and oncologist at Massachusetts General Hospitale

Robb S. Friedman, MD

Despite some toxicity concerns, the approval of selinexor (Xpovio) is a significant breakthrough for the treatment of heavily pretreated patients with relapsed/refractory multiple myeloma, said Robb S. Friedman, MD.

"We've developed a wonderful problem to have in multiple myeloma,” said Friedman, a hematologist and oncologist at Massachusetts General Hospital. “Our patients are living much longer with artful combinations of immunomodulatory drugs (IMiDs), proteasome inhibitors, and anti-CD38 agents. Unfortunately, patients will inevitably become refractory to all of these drugs."

In July 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 iMIDs, and a CD38-targeted monoclonal antibody.

The approval was based on part 2 of the phase IIb STORM trial, published findings of which showed that twice-weekly oral selinexor in combination with dexamethasone elicited a partial response rate of 26% (95% CI, 19-35). Moreover, the median duration of response was 4.4 months (95% CI, 3.7-10.8).

"Try it,” Friedman advised. “When patients get into this tough spot, we encourage them to participate in clinical trials, but if they live far from an academic medical center, that is not practical. Give selinexor a try, have a threshold to reduce the dose, and follow the supportive care recommendations. You never know until you try it; 1 in 4 patients have a really nice response [to this agent]."

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Multiple Myeloma, Friedman shared insight on the emergence of selinexor in the treatment paradigm for patients with relapsed/refractory multiple myeloma.

OncLive: What treatment options are available for patients with relapsed/refractory multiple myeloma?

Friedman: We don't have good options for this patient population. Anti-BCMA and CAR T-cell therapy is largely experimental.

I practice in some of [Massachusetts General Hospital's] community network sites. Some of the patients [I treat] are unwilling to go into the city for clinical trials or are too frail to make the trip. We don't have a good option [for those patients] other than old-fashioned chemotherapy, which is tough for patients to tolerate.

There is a study that showed patients have a median overall survival of around 3 months after they become refractory [to 3 therapies].

How has the introduction of selinexor impacted outcomes for patients with triple-class refractory multiple myeloma?

It is amazing because, now, we have another option [for this patient population]. Selinexor is a novel, first-in-class agent that basically prevents the exportation of mRNA from the nucleus of oncogenic proteins that make cells malignant. It targets XPO1.

Multiple myeloma cells have a lot of XPO1, though XPO is also a mechanism that is present in many other malignancies. By inhibiting XPO1, the cells end up undergoing apoptosis and dying.

The STORM study is great because it enrolled patients who were elderly, frail, cytopenic, and had [failing kidneys]. The trial reflected the fragile population of triple-refractory multiple myeloma.

Patients were given 80 mg of selinexor in combination with dexamethasone on days 1 and 3. These patients had a median of 8 prior therapies. Some had up to 18 prior therapies, which is incredible because I don't know 18 therapies [that are used] in multiple myeloma.

Not everyone responded [to selinexor], but those who did had wonderful responses. The ORR was somewhere around [25%]. Many of the 122 patients had stable disease, and some patients achieved a stringent complete response. That is incredible for patients who had, on average, 3 months to live.

What toxicities are associated with selinexor?

It is a “spicy” drug with a lot of thrombocytopenia and nausea. The majority of patients [in the STORM trial] ended up having dose reductions. [Karyopharm Therapeutics, the developer of selinexor, provides] educational materials for our doctors and nurses to inform them how to manage the toxicities of the drug. It is an oral therapy, so it is manageable for our elderly patients. It is a new lease on life.

What are the next steps with selinexor?

More studies have been undertaken [to evaluate selinexor in other settings]. I think of the STORM study as a proof-of-concept. The BOSTON trial, which is combining selinexor with bortezomib (Velcade), and the STOMP trial, which is combining selinexor with multiple agents, [are ongoing].

How are you currently approaching treatment with selinexor in the community setting?

Although this might make some of my colleagues cringe, I take care of a lot of older, frail patients who do not want to [make the trip] into Boston. They are very happy in the suburbs, so I see them in the community.

We do a good job of artfully sequencing the different available therapies, but inevitably patients require a fourth line of therapy. [With selinexor], I follow the label on the drug for triple-class refractory patients.

In my experience, you have to be quick to dose reduce for these older, frail patients. They require a lot of supportive care.

Oncology is a team sport with the hematologist, nurses, and nurse practitioners. The supportive care needed with selinexor is a wonderful opportunity for our nurses to be involved.

Therefore, that is where I have used selinexor, for patients who, for one reason or another, can't manage to enroll in a clinical trial and who have become triple-class refractory.

What does the future hold for selinexor?

I've been practicing for 15 years. I am old enough to remember when we were using thalidomide (Thalomid). I am old enough to remember when lenalidomide (Revlimid) and bortezomib [were approved]. I am old enough to remember when we did not have iMIDs or proteasome inhibitors. Patients lived an average of 2 years.

That still sometimes happens if a patient has very aggressive disease, but it is rare. Today, people are living for a long time [with multiple myeloma].

One of my goals when I treat patients with myeloma is to give them the best quality and duration of life. It means everything to a patient to take an oral medication rather than receive an intravenous infusion or a shot. It makes treatment sustainable and gives them time away from the clinic with their family and friends. They can have a life.

I see selinexor as an incredible new therapy to help our patients. It hasn't been out long and not everybody responds to it, but when a patient does, it is a great response.

We are going to see [more data with this drug from] the BOSTON and STOMP studies. We are going to see the addition of selinexor to other lines of therapy and moved in earlier lines of treatment.

Additionally, I am excited to see how selinexor performs in diffuse large B-cell lymphoma and potentially in myelodysplastic syndromes. I believe there are some studies looking at the agent for solid tumors as well, so I am interested to see how it will work in those settings.

Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor—dexamethasone for triple-class refractory multiple myeloma. N Eng J Med. 2019;381(8):727-738. doi: 10.1056/NEJMoa1903455.