Swiss researchers have published results of a small clin­i­cal trial testing whether nelfinavir, a drug originally used to treat AIDS, can overcome resistance to Revlimid in re­lapsed multiple myeloma patients.

The trial was motivated by pre­vi­ous research showing that nelfinavir can overcome resistance to Velcade, for a period of time, in many re­lapsed myeloma patients.

Unfortunately, the results of the more recent nelfinavir trial are not as en­cour­ag­ing as the pre­vi­ous research involving nelfinavir and Velcade. Less than a third of the patients in the more recent trial responded to the three-drug regi­men of nelfinavir, Revlimid, and dexa­meth­a­sone that they were given during the study. In addi­tion, among the patients who responded to the treat­ment, the median duration of response was just four months.

It might seem en­cour­ag­ing that nearly a third of the trial par­tic­i­pants responded to the treat­ment, given that all patients in the trial pre­vi­ously had been treated with Revlimid and ex­peri­enced dis­ease pro­gres­sion either while they were being treated with the drug, or shortly there­after.

However, the par­tic­i­pants in the trial had a median of just two prior lines of ther­apy, meaning in most cases that their dis­ease was still sensitive to a number of addi­tional treat­ment options.

In addi­tion, the dexa­meth­a­sone dose used in the trial was not incidental. Patients got either 40 mg or 20 mg of dexa­meth­a­sone once a week for every week of the trial, depending on whether they were younger than 75 (40 mg) or not (20 mg). In patients with a median of just two prior lines of ther­apy, the dexa­meth­a­sone alone could account for many of the responses seen in the trial par­tic­i­pants.

Still, the researchers who carried out the trial believe the nelfinavir-Revlimid-dexamethasone regi­men is “active” in patients with Revlimid-resistant dis­ease, noting that, in addi­tion to the 31 per­cent of trial par­tic­i­pants who had at least a partial response to the regi­men, another 38 per­cent had either a minimal response or stable dis­ease for a period of time.

The researchers also point out that, to reduce the cost of conducting the trial, patients received at most four months of treat­ment with the trial regi­men. Given that patients’ deepest responses to Revlimid-based treat­ment can occur after 6, 12, or even 18 months of treat­ment, more responses to the trial regi­men might be observed in real life than were seen during the trial.

Despite these caveats, it seems likely that the inno­va­tive myeloma specialists who use nelfinavir to im­prove treat­ment out­comes for their patients will do so mainly by using the drug in com­bi­na­tion with Velcade or, perhaps, other pro­te­a­some in­hib­i­tors such as Ninlaro (ixazomib). It is in com­bi­na­tion with such treat­ments that nelfinavir seems to have the greatest ability to overcome drug resistance, poten­tially im­prov­ing over­all survival by im­prov­ing the treat­ments physicians have to treat the dis­ease.

(See this recent Beacon column for insight into why im­prov­ing current treat­ments and adding addi­tional effective treat­ments are key to im­prov­ing the survival of myeloma patients.)

Background To The Nelfinavir-Revlimid Trial

Nelfinavir (Viracept) is an orally admin­istered drug that belongs to a class of ther­a­pies called protease in­hib­i­tors. Nelfinavir was approved by the U.S. Food and Drug Admin­istra­tion in 1997 for the treat­ment of human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syn­drome (AIDS).

The original patent for nelfinavir has expired in most countries, so generic versions of the drug are now avail­able (but not yet in the United States). Generic versions of pre­vi­ously patent-protected drugs have the same active ingredient as the original brand name drug, but they usually cost much less.

After laboratory research suggested that nelfinavir might be able to overcome resistance to pro­te­a­some in­hib­i­tors such as Velcade (bor­tez­o­mib) in re­lapsed multiple myeloma patients, trials were carried out to explore whether nelfinavir in com­bi­na­tion with Velcade and dexa­meth­a­sone could im­prove treat­ment out­comes in Velcade-resistant patients.

The results of these trials were very en­cour­ag­ing. In a Phase 2 trial with Velcade-resistant patients who had received a median of five prior lines of ther­apy, 65 per­cent of the patients had at least a partial response to treat­ment with nelfinavir, Velcade, and dexa­meth­a­sone (see related Beacon news article and myeloma specialist interview).

These results en­cour­aged researchers to organize a trial to explore whether nelfinavir also could overcome Revlimid (lena­lido­mide) resistance in multiple myeloma patients.

Design Of The Nelfinavir-Revlimid Trial

Between May 2012 and De­cem­ber 2016, researchers at seven treat­ment centers in Switzerland recruited 29 re­lapsed / refractory multiple myeloma patients for par­tic­i­pa­tion in the trial.

To par­tic­i­pate in the trial, patients had to be refractory to Revlimid, which was defined as having progressed during or within 60 days of termination of Revlimid-containing ther­apy of two or more months duration.

The median patient age was 64 years old. Approximately one third of the patients (31 per­cent) presented with high-risk chromosomal ab­nor­mal­i­ties (t(4;16), t(14;16), or del(17p)).

Patients had received a median of two prior ther­a­pies. All patients had pre­vi­ously received Revlimid and 83 per­cent had prior Velcade exposure. All were refractory to Revlimid, and 34 per­cent were double refractory to Revlimid and Velcade. More than half of the patients (62 per­cent) had pre­vi­ously received a stem cell trans­plant.

The Phase 1 part of the trial was designed to estab­lish­ the target dose to be used in the Phase 2 part of the trial.  Thus, during Phase 1, patients received be­tween 1,250 mg and 1,875 mg of oral nelfinavir twice daily on days 1 through 21, 25 mg of Revlimid on days 1 through 21 plus 20 mg / 40 mg of oral dexa­meth­a­sone on days 1, 8, 15, and 22 for up to four 28-day treat­ment cycles. Treatment was limited to a maximum of four cycles due to cost constraints.

A total of 10 patients par­tic­i­pated in the Phase 1 part of the trial. The researchers observed two incidents of dose-limiting side effects at 1,850 mg of nelfinavir twice daily. As a result, in the Phase 2 part of the trial, all patients received 1,250 mg of oral nelfinavir twice daily plus Revlimid and dexa­meth­a­sone at the same doses as in the Phase part of the trial.

A little more than half of the patients (52 per­cent) com­pleted all four treat­ment cycles. The remaining patients dis­con­tinued treat­ment due to progressive dis­ease (28 per­cent), unacceptable side effects (14 per­cent), or patient refusal (7 per­cent).

Results Of The Nelfinavir-Revlimid Trial

Overall, 31 per­cent of patients responded to treat­ment, with 10 per­cent achieving a very good partial response and 21 per­cent achieving a partial response. An addi­tional 24 per­cent of patients achieved a minor response and 14 per­cent had stable dis­ease.

Of the patients who were refractory to both Velcade and Revlimid, 40 per­cent achieved a minor response or better. Among patients who had high-risk chromosomal ab­nor­mal­i­ties, 78 per­cent achieved a minor response or better.

The median duration of response was 4 months.

The median pro­gres­sion-free survival was 3.4 month, and the median over­all survival was 21.6 months.

According to the researchers, the treat­ment was well tolerated. They note that they did not observe any unexpected side effects, and that the side effects were similar to those observed with the in­di­vid­ual drugs.

The most common side effects of all grades in­cluded gastro­in­tes­ti­nal symp­toms (31 per­cent of patients), and metabolic disorders (31 per­cent). The most common severe side effects in­cluded anemia (24 per­cent), low platelet count (21 per­cent), low white blood cell count (24 per­cent, in­clud­ing patients with low white blood cell counts accompanied by fever), and shortness of breath (10 per­cent).

For more in­for­ma­tion, please see the study by Hietz, F. et al., “Nelfinavir and lena­lido­mide / dexa­meth­a­sone in patients with lena­lido­mide-refractory multiple myeloma. A phase I/II Trial (SAKK 39/10),” in Blood Cancer Journal, August 27, 2019 (full-text) and the description of the nelfinavir-Revlimid clin­i­cal trial at clin­i­caltrials.gov.