Earlier this month, The Myeloma Beacon published a news article ^[1] sum­marizing results of a clin­i­cal trial testing the com­bi­na­tion of nelfinavir, Velcade, and dexa­meth­a­sone as a treat­ment for re­lapsed multiple myeloma.

Nelfinavir (Viracept) is an orally admin­istered drug that was approved in the 1990s for the treat­ment of human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syn­drome (AIDS). Nel­fin­avir has not pre­vi­ously been used for the treat­ment of multiple myeloma.

Preclinical research has suggested, however, that nelfinavir might make it possible to re-treat multiple myeloma patients who pre­vi­ously were treated with, and had become resistant to, drugs in the pro­te­a­some inhibitor class of ther­a­pies, which in­cludes Velcade (bor­tez­o­mib), Kyprolis (car­filz­o­mib), and Ninlaro (ixazomib).

The trial described in the Beacon article was conducted in Switzerland. Trial participants had received a median of five prior lines of ther­apy, and all had disease that had become resistant to treat­ment with Velcade or another pro­te­a­some inhibitor.

Almost two thirds of the trial participants responded to the nelfinavir, Velcade, and dexa­meth­a­sone com­bi­na­tion ther­apy, a result that the trial organizers described as “unprecedented.” Although there were a number of side effects that occurred as a result of the treat­ment regi­men, the researchers believe it “warrants further investigation,” including as an option for less heavily pre­treated patients.

Given the sig­nif­i­cance of the Swiss study, The Beacon contacted Dr. Christoph Driessen, director of the Department of Hematology and Oncology at the Cantonal Hospital St. Gallen in Switzerland. Dr. Driessen is the lead author of the Swiss study, and he also spearheaded the pre­clin­i­cal research related to nelfinavir in multiple myeloma and the devel­op­ment of the nelfinavir, Velcade, and dexa­meth­a­sone clin­i­cal trial.

Summary Of Dr. Driessen's Feedback

The Beacon asked Dr. Driessen several follow-up questions related to the trial results and nelfinavir more broadly. In his replies, which can be found below, Dr. Driessen makes it clear that he sees a real role for the com­bi­na­tion of nelfinavir, Velcade, and dexa­meth­a­sone in the treat­ment of myeloma patients. The efficacy the regi­men has dem­onstrated is sig­nif­i­cant, he argues, and he also suggests that using nelfinavir could be a more promising ap­proach for Velcade-resistant patients than treat­ment with a different pro­te­a­some inhibitor, such as Kyprolis or Ninlaro.

At the same time, Dr. Driessen recognizes that there are regu­la­tory, reim­burse­ment, and supply issues in many countries that can make it difficult to use nelfinavir to treat multiple myeloma patients. Despite these challenges, he has heard from a number of physicians worldwide who are using, or intend to use, nelfinavir in the treat­ment of multiple myeloma.

When asked about the side effects asso­ci­ated with nelfinavir treat­ment, Dr. Driessen explains that the drug can seriously compromise a patient’s immune system. For this reason, he now prescribes patients being treated with nelfinavir a com­bi­na­tion of two antiobitic ther­a­pies to reduce the chances that they will develop an in­fec­tion.

Nelfinavir’s effect on the immune system, Dr. Driessen explains, is due to the impact it has on immuno­glob­u­lin levels. In a reply that is likely to delight Beacon readers with a firm understanding of cell biology, Dr. Driessen explains that nelfinavir seems to interfere with the ability of plasma cells to secrete the immuno­glob­u­lins they produce, including the mono­clonal immuno­glob­u­lin produced by a patient’s diseased (myeloma) plasma cells.

This inter­fer­ence with immuno­glob­u­lin secretion causes many of a patient’s plasma cells to die. This is good when the plasma cells that are dying are myeloma cells. The death of other­wise healthy plasma cells, however, means the patient’s over­all immuno­glob­u­lin levels are reduced, thus compromising the patient’s ability to ward off in­fec­tions.

The Full Q&A With Dr. Driessen

Q: Is the com­bi­na­tion of nelfinavir, Velcade, and dexa­meth­a­sone effective enough to use regularly in day-to-day practice? Does it really make sense to use it when you have, for example, other pro­te­a­some inhibitors, such as Kyprolis or Ninlaro, to treat re­lapsed patients?

Dr. Driessen: Nelfinavir overcomes pro­te­a­some inhibitor resistance, i.e., it makes myeloma cells that are no longer sensitive to pro­te­a­some inhibiting drugs sensitive again for pro­te­a­some inhibitor-based ther­apy by combining pro­te­a­some inhibition ther­apy with nelfinavir.

There is very little evi­dence that patients that are refractory to one pro­te­a­some inhibitor can suc­cess­fully be treated with another pro­te­a­some inhibitor. Our data show that such patients can be suc­cess­fully treated with the addi­tion of nelfinavir to Velcade and dexa­meth­a­sone.

In addi­tion, the nelfinavir com­bi­na­tion had a response rate of over 60 per­cent even in triple-refractory patients who are Pomalyst (poma­lido­mide, Imnovid), Revlimid (lena­lido­mide), and Velcade refractory, and also had a high response rate in Kyprolis-refractory patients. For such patients, active treat­ment is hard to find, in particular the triple refractory group of patients, which have been excluded from the studies that tested pro­te­a­some inhibitors or Pomalyst-based treat­ments in the ad­vanced refractory setting.

Q: Are you and your colleagues, or any other centers that you know of, now using nelfinavir to treat multiple myeloma patients and, if so, in what way, and do the results seen in day-to-day practice match those you saw in your trial?

Dr. Driessen: We have nelfinavir avail­able from an inter­na­tional vendor at our hospital pharmacy and use nelfinavir occasionally as part of the NVd (nelfinavir, Velcade, and dexa­meth­a­sone) regi­men for treat­ment of ad­vanced, drug-refractory myeloma. We con­tinue to see responses similar to the trial results recently published in Blood ^[2] and discussed in the related Beacon news article ^[1].

However, the approval and reim­burse­ment situation in Switzerland and in Europe leaves very little room for this ther­apy for physician and patients. Nelfinavir is no longer approved for HIV treat­ment since 2013 in Europe, essentially because it was withdrawn from the market for commercial reasons. Therefore, it must be imported on a case-by-case basis for users in Europe and Switzerland, and it is not reimbursed, although it has been granted orphan drug status for the treat­ment of multiple myeloma by both the U.S. Food and Drug Admin­istra­tion (FDA) and Swissmedic (the federal agency in Switzerland responsible for drug and medical device reg­u­la­tion).

I do receive communications from inter­na­tional colleagues who use or intend to use nelfinavir in a similar way for multiple myeloma ther­apy, and some of this use has been reported in the literature. See, for example, the recent report by Barlogie and Richter ^[3]. I hope that we will be able to coordinate these efforts inter­na­tionally, and I am more than willing to contribute to any clin­i­cal trial that may be in preparation in this area.

Q: A number of patients in your trial of nelfinavir, Velcade, and dexa­meth­a­sone ex­peri­enced serious (grade 3 or higher) side effects. Do you feel those were due to the nelfinavir in the treat­ment regi­men, or was it due to other factors?

Dr. Driessen: Indeed, quite a number of patients ex­peri­enced serious adverse events during treat­ment with NVd in our Phase II trial in patients with heavily pre­treated, pro­te­a­some inhibitor-refractory myeloma. However, compared to the ex­pec­ted numbers during the natural course of myeloma at this stage, as well as to published results of Phase II and Phase III trials in a similarly heavily pre­treated patient pop­u­la­tion, we do not have the impression that nelfinavir adds clin­i­cally sig­nif­i­cant toxicity to the Velcade-dexamethasone ther­apy back­bone in most cases. Some patients do ex­peri­ence fatigue that seems to be related to the nelfinavir dose used, and the same may be true for diarrhea.

That said, my personal impression is that nelfinavir may in particular contribute to the state of immuno-suppression and non-responsiveness of the humoral immune system, including the total lack of an anti­body response seen in myeloma patients.

We have seen severe systemic bacterial in­fec­tions, some of which were lethal, in nelfinavir-treated patients. Immunoglobulin levels, including the myeloma-related paraprotein (M-spike), drop very rapidly in responding multiple myeloma patients treated with NVd, which may be related to the poten­tial mech­a­nism of action of nelfinavir in multiple myeloma that is likely to affect the normal plasma cell repertoire similarly to the malignant clone.

Our most recent data show that nelfinavir blocks the export of newly synthesized secretory protein from the endoplasmic reticulum (ER), including the immuno­glob­u­lin paraprotein in myeloma cells, thus inducing massive proteotoxic stress in the ER. I sus­pect, therefore, that nelfinavir induces a rapid anergy of the plasma cell pool due to a total block in immuno­glob­u­lin secretion and elimination of immuno­glob­u­lin-producing cells by excessive ER stress.

Unlike our standard protocol during the nelfinavir Phase II trial in multiple myeloma, I now use pro­phy­lactic antibiotic coverage, involving Bactrim (sulfa­methox­a­zole and tri­methoprim) and levo­floxacin (Levaquin, Tavanic) in ad­vanced, pro­te­a­some inhibitor- refractory myeloma patients that I treat with the nel­finavir com­bi­na­tion.

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Please note that, in his feedback for The Beacon, Dr. Driessen usually used generic names, such as “bortezomib” and “pomalidomide,” when referring to drugs, rather than brand names (such as “Vel­cade” and “Pomalyst”). This is common practice among researchers. Dr. Driessen’s feedback was edited, however, to make use of brand names in those cases where brand names are more likely to be recognized by many Beacon readers.