New clin­i­cal trial results for selinexor, a poten­tial new myeloma treat­ment, were released last week by Karyopharm Therapeutics, the U.S. com­pany devel­op­ing the drug.

The new results are “top line” findings, so they are very limited in scope. They are con­sis­tent, how­ever, with the favorable results pre­vi­ously seen in trials of selinexor com­bined with dexa­meth­a­sone in heavily pre­treated multiple myeloma patients. Taken together, the results suggest the selinexor-based two-drug com­bi­na­tion has noteworthy anti-myeloma activity.

Karyopharm (NASDAQ:KPTI) accompanied last week’s release of the new selinexor data with an update on its regu­la­tory plans for the drug. The com­pany said it in­tends to submit a new drug appli­ca­tion for selinexor to the U.S. Food and Drug Admin­istra­tion in the second half of this year. The appli­ca­tion will seek approval of selinexor as a new treat­ment for re­lapsed myeloma patients who have failed most cur­rently avail­able myeloma ther­a­pies, in­clud­ing Revlimid (lena­lido­mide), Velcade (bor­tez­o­mib), Pomalyst (poma­lido­mide / Imnovid), Kyprolis (car­filz­o­mib), and Darzalex (dara­tu­mu­mab).

The com­pany also plans to file in early 2019 a mar­ket­ing authori­za­tion appli­ca­tion for selinexor with the European Medicines Agency.

The com­pany’s regu­la­tory timelines for selinexor suggest the drug could be approved in the United States, and thus avail­able for use outside of clin­i­cal trials, by the middle of 2019. Likewise, a European approval could occur by late in 2019.

Selinexor, XP01, And Tumor Suppressor Proteins

Selinexor is an orally admin­istered drug. It is not cur­rently approved for use as a treat­ment for any disease, but it is being in­ves­ti­gated in clin­i­cal trials as a poten­tial treat­ment for several dif­fer­en­t kinds of cancer, in­clud­ing multiple myeloma.

Selinexor is designed to inhibit the activity of XP01, a “nuclear export protein” (more on that terminology in a moment). Cancer cells use XP01 to defend themselves against so-called “tumor sup­pressor proteins,” which are used by the body to fight cancer.

Tumor sup­pressor proteins enter the nucleus of a cancer cell and either sup­press its ability to reproduce or en­cour­age the cell’s early death. XP01 interferes with tumor sup­pressor proteins by attaching itself to those proteins and “exporting” (ejecting) them from the cancer cell’s nucleus; hence, XP01’s classification as a “nuclear export protein.”

The New Selinexor Trial Results

The new selinexor results released last week are from the second part of the so-called “STORM” clin­i­cal trial of the drug. This part of the single-arm Phase 2b trial enrolled 122 myeloma patients who had been treated with a sig­nif­i­cant number of prior ther­a­pies. In particular, patients had to be “penta-refractory” to par­tic­i­pate in the trial. The protocol for the trial defined penta-refractory as pre­vi­ously having been treated with

• At least one alkylating agent (such as melphalan or cyclophosphamide)
• A steroid (such as dexamethasone or prednisone)
• The two immunomodulatory agents Revlimid (lenalidomide) and Pomalyst (pomalidomide)
• The two proteasome inhibitors Velcade (bortezomib) and Kyprolis (carfilzomib), and
• The monoclonal antibody Darzalex (daratumumab).

Each patient in the second part of the STORM trial received 80 mg of selinexor and low-dose (20 mg) dexa­meth­a­sone twice per week, every week. There were no weeks off.

Among the 122 trial par­tic­i­pants, 31 responded to treat­ment, for an over­all response rate of 25.4 per­cent. Two of the 31 responses were stringent com­plete responses, and one of the patients who achieved a stringent com­plete response also was found to be minimal residual disease (MRD) neg­a­tive.

The median duration of response was 4.4 months among the patients who responded to treat­ment. There are 17 trial par­tic­i­pants who are still on treat­ment, in­clud­ing the two patients who achieved a stringent com­plete response. Karyopharm there­fore believes the median duration of response is likely to climb a bit before reaching its final value.

The response rate seen in Part 2 of the STORM trial, and the asso­ci­ated duration of response, will seem very limited to many Beacon readers. In assessing them, how­ever, readers should keep in mind that the patients in the STORM trial already had been treated with, and stopped responding to, many dif­fer­en­t existing ther­a­pies. Their myeloma had ad­vanced to a stage where it is very dif­fi­cult to treat.

Karyopharm also reported that the side effects observed during the second part of the STORM trial were mostly mild to mod­er­ate and in line with those observed in pre­vi­ous studies. The most common side effects in­cluded nausea, vomiting, fatigue, and reduced appetite. The most common blood-related side effects were mod­er­ate to severe low blood cell counts.

During a conference call with financial analysts re­gard­ing the new selinexor trial results, Karyopharm man­agement emphasized that the latest results raise no new safety con­cerns.

Comparison With Previous Selinexor Results

The newly released selinexor trial results are in line with those pre­vi­ously published for Part 1 of the STORM trial, and they also align with the results of the Phase 1 trial that initially in­ves­ti­gated the safety and efficacy of single-agent selinexor and selinexor com­bined with dexa­meth­a­sone.

Part 1 of STORM Trial

Part 1 of the STORM trial in­cluded both penta-refractory and quad-refractory myeloma patients. The latter are patients who have had the same prior ther­a­pies as penta-refractory patients, except quad-refractory patients have not had prior treat­ment with Darzalex.

The over­all response rates in penta-refractory and quad-refractory myeloma patients in Part 1 of the STORM trial were 20 per­cent and 21 per­cent, re­spec­tive­ly (related journal article).

These rates are a bit lower than seen in the Part 2 trial results released last week. It has been reported, how­ever, that some of the patients in Part 1 took selinexor and dexa­meth­a­sone three out of every four weeks, rather than every week, as in Part 2 of the trial.

In addi­tion, patients apparently could be excluded from participating in Part 2 of the trial if their hemoglobin level was too low. Part 1 of the trial did not have such an exclusion criterion. Thus, par­tic­i­pants in Part 2 of the trial are likely to have been healthier, over­all, than those in Part 1.

Both the dosing dif­fer­ence and the change in the hemoglobin require­ment would tend to make the response rate observed in Part 2 of the trial higher than was seen in Part 1, which is exactly what was observed.

Phase 1 Trial of Selinexor And Selinexor + Dexamethasone

A Phase 1 trial of selinexor in­cluded 81 multiple myeloma patients and three patients with Waldenström’s macroglobulinemia (related journal article). Although these patients had a median of six prior ther­a­pies, only 23 (27 per­cent) had been treated with Revlimid, Velcade, Pomalyst, and Kyprolis, and just two of those 23 patients also had been treated with Darzalex. So these patients were not as heavily pre­treated as those in the STORM trial.

A number of dif­fer­en­t selinexor doses and dosing regi­mens were explored during the Phase 1 trial. The majority of patients in the trial, how­ever, received selinexor at doses com­parable to those seen in the STORM trial. Patients were treated with either single-agent selinexor (57 patients), or selinexor and low-dose dexa­meth­a­sone (27 patients).

The over­all response rate in the patients treated with selinexor and dexa­meth­a­sone in the Phase 1 trial was 22 per­cent.

The response rate was only 4 per­cent, how­ever, for the patients in the trial who received single-agent selinexor. The clin­i­cal benefit ratio, which in­cludes response as well as minimal responses, was 21 per­cent.

Comparison With Results For Other Myeloma Therapies

To place selinexor’s anti-myeloma activity into perspective, Karyopharm frequently notes responses rates for cur­rently avail­able myeloma treat­ment regi­mens when they were tested in “double refractory” patients (that is, patients who have been treated with at least one immuno­modu­la­tory agent and at least one pro­te­a­some inhibitor). Those response rates were

• 28 percent for the combination of Pomalyst and dexamethasone
• 23 percent for single-agent Kyprolis
• 29 percent (approximately) for single-agent Darzalex

In comparison, selinexor and dexa­meth­a­sone has had response rates be­tween 20 and 25 per­cent in patients who were more heavily pre­treated.

That said, in discussions The Beacon has had with myeloma specialists about selinexor, questions have been raised about both the efficacy and tolerability of the drug. In regard to the drug’s efficacy, its limited single-agent activity (a 4 per­cent response rate in double-refractory patients) raises some warning flags, and managing the drug’s side effects apparently requires sub­stan­tial effort.

There is sup­port for selinexor, how­ever, among a number of myeloma specialists. Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston, for example, has spoken pos­i­tively about selinexor on many occasions, in­clud­ing during the conference call Karyopharm organized last week to discuss the new STORM trial results.

The Beacon also received very pos­i­tive feedback about selinexor from Dr. Edward Libby, a myeloma specialist at the Seattle Cancer Care Alliance. In response to a request for his perspective on the latest STORM trial results, he wrote:

"Everyone caring for multiple myeloma patients welcomes this [recent] news of a novel drug that can produce sig­nif­i­cant responses in heavily pre­treated patients. In this Phase 2b trial in which re­lapsed / refractory patients received the active drug selinexor plus dexa­meth­a­sone, the results are provocative. Similar results were seen with dara­tu­mu­mab when it was studied in such later stage patients. The findings of the STORM trial are there­fore in line with what one would ex­pec­t in a more heavily treated study group.

"The achieve­ment of a com­plete remission in two patients is from my perspective especially convincing data on the poten­tial power of selinexor. An oral option for patients with a tolerable side effect profile is another plus. There are more and more patients who fit into the quad- and penta-refractory category, so we desperately need new drugs with novel mech­a­nisms of action to overcome resistance.

"Rational com­bi­na­tions of selinexor with other drugs will be the next step to test its full poten­tial. The side effects of selinexor appear to be acceptable and man­ageable and have been low enough for most patients to remain on the drug. Based on what we know now, the activity of selinexor is similar to dara­tu­mu­mab in heavily pre­treated multiple myeloma patients.  Because of this, we should move ahead quickly to test its poten­tial in com­bi­na­tion ther­apy."

For more in­­for­ma­tion, please see the Karyopharm press release about the latest STORM trial results. Information about clin­i­cal trials testing selinexor in myeloma patients can be found at this list of currently open and recruiting trials at clin­i­caltrials.gov. There also are several discussions in the Beacon’s forum about selinexor and ex­peri­ences with it.