Novel Treatment Combination Shows Promising Results, Tolerable Side Effects in Multiple Myeloma

Recent study findings showed that Xpovio (selinexor) given in combination with Darzalex (daratumumab), Velcade (bortezomib) and dexamethasone — known as D-Vd — induced encouraging results and manageable side effects for patients with late- and early-relapsed or refractory multiple myeloma.

These findings, which are from the phase 2 GEM-SELIBORDARA trial (NCT03589222), were presented at the 2021 ASH Annual Meeting and Exposition by Dr. Paula Rodriguez-Otero, a specialist in hematology and hemotherapy and coordinator of the Central Unit for Clinical Trials at the University of Navarra in Spain.

“Treatment of multiple myeloma has significantly evolved in the last decade leading to significant improvements in survival,” Rodriguez-Otero said during the presentation. “Still, cure remains elusive and new combinations incorporating drugs with novel mechanism of action are needed to rescue patients becoming resistant to standard of care.”

D-Vd is a combination that is already approved for patients with relapsed/refractory multiple myeloma (RRMM) after one to three prior lines of therapy. Xpovio is also approved in combination with dexamethasone for the treatment of penta-exposed (meaning they have previously received Revlimid [lenalidomide], Pomalyst [pomalidomide], Velcade, Kyprolis [carfilzomib] and Darzalex) RRMM after one to three prior lines.

READ MORE: Dose Reduction of Xpovio Improves Safety and Optimizes Patient Outcomes in Myeloma

To analyze the effects of D-Vd and Xpovio as a combination, researchers treated 57 patients from July 2018 to March 2021. The study was split into two parts. Part one examined 24 patients who had received three or more prior lines, previously treated with proteasome inhibitor (PI) and immunomodulatory drugs and were refractory to the last line or double refractory. Part two looked at 33 patients with RRMM who had one or more prior lines of therapy.

Patients were given 16 mg/kg of intravenous Darzalex at the approved schedule, plus 1.3 mg/m2 of bortezomib (on days 1, 8, 15, and 22 in cycle C, 1 to 8 and days 1 and 15 from C9 onwards), and 40 mg of dexamethasone (days 1, 8, 15, 22), in combination with Xpovio (days 1, 8, 15, and 33). Patients in part one were given 100 mg of Xpovio while patients in part two received 60 mg.

The treatment cycles lasted four weeks in part one and five weeks in part two. Treatment was continued until a patient had disease progression or experienced unacceptable toxicity. They followed the Declaration of Helsinki (a statement of ethical principles for medical research) and ICH GCP guidelines (ethical and scientific quality standards for clinical trials).

In part one, in which patients had a median age of 65.5 years and had received a median of three prior lines of therapy, 96% (MM refractory to last line) and 71% (double refractory) of patients had MM refractory to lenalidomide and a proteasome inhibitor. Among them, 21% of patients had high-risk cytogenetics (HR-CA), meaning high-risk genes for MM, and 12.5% had Revised Multiple Myeloma International Staging System (R-ISS), a staging system for MM, of 3.

The overall response rate (ORR) — which shows how well the tumor is responding to treatment — in part one was 50%. A total of three patients (12%) achieved complete response/stringent complete response (CR/sCR), which is when the tumor is completely gone.

At a median follow-up of 28.3 months, 18 patients had discontinued treatment (14 due to disease progression). The median progression-free survival (or the length of time during and after treatment that a patient is alive with the disease, but it does not progress; PFS) and overall survival (OS) were 7.1 and 27.5 months, respectively.

Part two had a median age of 69 years and had received a median of one prior line of therapy (61% had one). Similar to part one, 45% of patients were refractory to Revlimid — 12% were double refractory and 36% were refractory to last line. There were five patients with high-risk cytogenetics and three with R-ISS 3.

At a median follow-up of 9.8 months, eight patients in part two had discontinued treatment (five due to disease progression). There was an ORR of 82%, and eight patients (24%) achieved CR/sCR. Median PFS was not yet reached, while the median PFS in Revlimid-refractory patients included in this part was 12.1 months. Median OS was also not yet reached.

Side effects were manageable. Researchers recommended supportive care to prevent nausea associated with Xpovio (with or without anorexia), including Zofran (ondansetron) for two days and Zyprexa (olanzapine) daily.

Seventy-seven percent of patients experienced hematological side effects, including thrombocytopenia — a condition where patients have low blood platelet count — (8.4%), and neutropenia — when patients have too few neutrophils, a type of white blood cell — (33%).

Non-hematological side effects were reported in 75% of patients. These included gastrointestinal toxicity (38%), nausea (28%), diarrhea (21%), asthenia — weakness or lack of energy — (35%), and peripheral neuropathy (12.3%).

Dose modifications were required in 35 patients (61.4%), with Xpovio being the most likely to be modified (15 in part one and 14 in part two). It was discontinued in five patients. Only one patient discontinued the study due to side effects. In part one, two patients died.

“All the data in this second cohort is still immature and requires a longer follow-up,” Rodriguez-Otero concluded.

A version of this article originally appeared on OncLive as “Selinexor Plus D-Vd Shows Promising Results and Safety in Patients With Relapsed or Refractory Multiple Myeloma.”

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