Results of a small Phase 2 trial conducted in Switzerland indicate that the HIV treat­ment nelfinavir, in com­bi­na­tion with Velcade and dexa­meth­a­sone, has promising activity in patients with ad­vanced, Velcade-resistant multiple myeloma.

All 34 patients in the Swiss trial had pre­vi­ously been treated with, and stopped responding to, Velcade. All study par­tic­i­pants also were pre­vi­ously treated with Revlimid (lena­lido­mide) and had a median of five over­all prior lines of treat­ment.

In this heavily pre­treated patient group, the com­bi­na­tion of nelfinavir, Velcade, and dexa­meth­a­sone nevertheless achieved at least a partial response in 65 per­cent of the trial par­tic­i­pants. Another 20 per­cent of the patients had either a minimal response, or a period of stable disease, in response to the three-drug treat­ment regi­men.

The response rates seen in the Swiss trial are sig­nif­i­cant given how treat­ment-resistant multiple myeloma usually is in patients such as those in the trial.

For example, in one study that looked at Velcade retreatment in patients with a median of just two prior lines of ther­apy, less than 40 per­cent of the patients had a partial response or better (reference).

Another study in­cluded 462 patients who in the past had been treated with, and stopped responding to, both an immuno­modu­la­tory agent, such as Revlimid or Pomalyst (poma­lido­mide), and a pro­te­a­some inhibitor, such as Velcade or Kyprolis (car­filz­o­mib). When these patients were treated with regi­mens that in­cluded either Velcade, Revlimid, or thalido­mide, only 12 per­cent has a partial response or better (reference, related conference poster [PDF]).

Indeed, the 65 per­cent response rate achieved in the Swiss nelfinavir trial is greater than the 60 per­cent response rate seen in a trial of the potent three-drug com­bi­na­tion of Pomalyst, Darzalex (dara­tu­mu­mab), and dexa­meth­a­sone in 103 patients with no prior exposure to either Pomalyst or Darzalex, and a median of 4 prior ther­a­pies (reference).

Based on their findings, the Swiss researchers recommend further in­ves­ti­ga­tion of nelfinavir in com­bi­na­tion with Velcade or other pro­te­a­some inhibitors, such as Velcade or Ninlaro (ixazomib), in a wide range of multiple myeloma patients, not just those who are heavily pre­treated.

Background Information

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.

Preclinical research has shown that nelfinavir may overcome resistance to pro­te­a­some inhibitors, such as Velcade, Kyprolis, and Ninlaro (ixazomib), in multiple myeloma cells (see related Beacon news).

Based on these findings, the Swiss researchers sought to assess the efficacy and safety of nelfinavir in com­bi­na­tion with Velcade and dexa­meth­a­sone in multiple myeloma patients who pre­vi­ously had stopped responding to (were "refractory" to) a pro­te­a­some inhibitor-containing treat­ment regi­men. The researchers first organized a Phase 1 clin­i­cal trial investigating the nelfinavir com­bi­na­tion; it showed that five out of six patients responded to the treat­ment (reference).

Given the efficacy and safety seen in the Phase 1 trial, the researchers proceeded with a Phase 2 trial of the treat­ment com­bi­na­tion.

Study Design

The Phase 2 trial in­cluded 34 multiple myeloma patients who had received a median of five prior lines of ther­apy. To par­tic­i­pate in the trial, patients had to be refractory to their most recent pro­te­a­some inhibitor-containing ther­apy and also had to have received at least one immuno­modu­la­tory drug, such as Revlimid, thalido­mide (Thalomid), or Pomalyst.

The median patient age was 67 years old.

Overall, 76 per­cent of the trial par­tic­i­pants had pre­vi­ously received a stem cell trans­plant. All patients had pre­vi­ously received Velcade and Revlimid; all were refractory to Velcade, and 79 per­cent were refractory to Revlimid. Almost half of the patients (47 per­cent) had pre­vi­ously received Pomalyst, and 44 per­cent were refractory to it. Only 6 per­cent of patients had pre­vi­ously received Kyprolis, and all 6 per­cent were refractory to it.

The median time from the last dose of prior ther­apy to trial registration was 27 days.

Patients received 2,500 mg of oral nelfinavir twice daily on days 1 through 14, 1.3 mg/m2 of intra­venous or sub­cu­tane­ous Velcade on days 1, 4, 8, and 11 plus 20 mg of oral dexa­meth­a­sone on days 1, 2, 4, 5, 8, 9, 11, and 12 for up to six 21-day treat­ment cycles. Treatment was limited to a maximum of six cycles due to cost constraints; the drugs used in the trial were not provided free of charge to the researchers, as typically is the case for trials of brand name drugs without generic substitutes.

Preventative treat­ment for in­fec­tions and blood clots was not part of the treat­ment protocol.

The median duration of treat­ment was 4.5 months.

Study Results

Overall, 65 per­cent of patients responded to treat­ment, with 15 per­cent achieving a very good partial response and 50 per­cent achieving a partial response. An addi­tional 9 per­cent of patients achieved a minor response and 12 per­cent had stable disease.

Of the patients who were refractory to both Velcade and Revlimid, 70 per­cent achieved a partial response or better. The response rate was slightly lower for patients who were refractory to both Velcade and Pomalyst (60 per­cent).

The median pro­gres­sion-free survival was 12 weeks, and the median over­all survival was 12 months.

The researchers sus­pect, how­ever, that the clin­i­cal benefit of the treat­ment com­bi­na­tion would have been greater had they been able to offer longer treat­ment for those who responded to the nelfinavir com­bi­na­tion.

The researchers note that they did not observe any unexpected side effects, and that the side effects were similar to those observed with Velcade in heavily pre­treated myeloma patients. The most common side effects in­cluded anemia (97 per­cent of patients), low platelet counts (82 per­cent), high blood pressure (53 per­cent), diarrhea (47 per­cent), fatigue (38 per­cent), and shortness of breath (35 per­cent).

Four patients died during the trial (three of blood in­fec­tion, one of heart failure). The researchers attributed three of those cases to under­lying pneu­monia. Based on these findings, they recommend the use of pro­phy­lactic antibiotics for patients with low white blood cell counts and ad­vanced age who are receiving treat­ment with the nelfinavir-Velcade com­bi­na­tion.

For more in­­for­ma­tion, please see the study by Driessen, C. et al., “Promising activity of nelfinavir-bortezomib-dexamethasone (NeVd) in pro­te­a­some inhibitor-refractory multiple myeloma,” in Blood, September 20, 2018 (abstract).

In­­for­ma­tion about the trial and its results also can be found in a slide deck [PDF, courtesy of Dr. Christoph Driessen] prepared by the Swiss researchers for the 2016 American Society of Hematology annual meeting.