The 2016 annual meeting of the American Society of Clinical Oncology (ASCO) is now history, but there's still plenty of news to report from the meeting.

In this edition of the Beacon's ASCO multiple myeloma updates, the focus is on pre­sen­ta­tions that took place the last two days of the ASCO meet­ing – this past Monday and Tuesday – and which con­cerned poten­tial new multiple myeloma ther­a­pies.

There was a block of oral pre­sen­ta­tions related to poten­tial new myeloma ther­a­pies that took place Tuesday morning, and all those pre­sen­ta­tions are covered in this article.

In addi­tion, there was a myeloma-related poster session on Monday morning, and several posters during that session in­cluded results related to poten­tial new myeloma ther­a­pies. These also are summarized in this article.

Overall, new re­search results for five poten­tial new myeloma ther­a­pies – Venclexta (venetoclax), Keytruda (pem­bro­lizu­mab), isatuximab (SAR650984), MOR202, and selinexor – are discussed in this article.

Because so many new ther­a­pies are discussed, this ASCO update is once again rather long. Readers may wish to first consult the quick overview, which is directly below, and then use headings through­out the article to decide which results they wish to read about in more detail.

Quick Overview Of The Results

The results for Venclexta are very promising. The drug is showing a high level of single-agent activity in patients with the t(11;14) chromosomal ab­nor­mal­ity. More im­por­tantly, data for an admittedly small group of patients sug­gests the com­bi­na­tion of Venclexta, Velcade, and dexa­metha­sone may be as active in re­lapsed myeloma as any three-drug com­bi­na­tion that in­cludes Velcade – in­clud­ing Darzalex, Velcade, and dexa­metha­sone.

New results for Keytruda in­di­cate that it, too, is active against multiple myeloma, but its activity depends on the presence of other anti-myeloma ther­a­pies – in this case Revlimid and dexa­metha­sone. The re­sponse­s seen with that com­bi­na­tion are not as promising as initially reported late last year, but they still are at a level sug­gesting that the three-drug regi­men may be very effective.

Results for isatuximab, which like Darzalex (dara­tu­mu­mab) is a CD38 mono­clonal anti­body, mainly serve to con­firm that isatuximab's anti-myeloma activity is in the same general ballpark as that of Darzalex.

Finally, the new data for MOR202 and selinexor that were pre­sented are rel­a­tive­ly limited in scope. Thus, they do not really alter what is known thus far about those poten­tial new poten­tial new myeloma ther­a­pies.

A Few Reminders

As was the case with the Beacon's previous ASCO 2016 multiple myeloma update, which covered the first three days of the meeting, this article in­cludes links to pre­sen­ta­tion slides and posters from the meeting, when they are avail­able. Additional links will be added in the coming week or two.

Readers also are reminded that the Beacon has compiled lists of all ASCO 2016 multiple myeloma-related oral pre­sen­ta­tions, poster pre­sentations, education session pre­sen­ta­tions, and e-abstracts. The lists in­clude pre­sen­ta­tion titles, authors, and links to each pre­sen­ta­tion's abstract and the related slides or poster (when avail­able). Links to these pages with these lists cur­rently can be found near the top of the Beacon's sidebar, on the right side of every Beacon page.

Venclexta (Venetoclax)

There were two pre­sen­ta­tions at ASCO on Monday and Tuesday about Venclexta (venetoclax) as a poten­tial myeloma ther­apy. One was an oral pre­sen­ta­tion on Tuesday about Venclexta in com­bi­na­tion with Velcade and dexa­metha­sone in re­lapsed and re­frac­tory myeloma. The other was a poster that reported updated results from a Phase 1 trial of Venclexta mono­therapy in re­lapsed and re­frac­tory multiple myeloma.

Venclexta is an orally admin­istered drug that targets Bcl-2 and Bcl-2-related proteins, which reg­u­late cell death. Venclexta has shown promising anti-myeloma activity in laboratory studies, par­ticu­lar­ly in myeloma cells with the chromosomal ab­nor­mal­ity t(11;14). The drug was approved by the U.S. Food and Drug Admin­is­tra­tion in April for the treat­ment of chronic lympho­cytic leukemia with 17p deletion.

Venclexta is mar­keted jointly in the United States by the U.S. pharma­ceutical com­pany AbbVie and the Genentech sub­sid­i­ary of Roche. Outside of the United States, the drug will be mar­keted solely by AbbVie.

Venclexta Plus Velcade And Dexa­meth­a­sone In Re­lapsed And Re­frac­tory Multiple Myeloma

At Tuesday's multiple myeloma oral pre­sen­ta­tion session, Dr. Cyrille Touzeau of the University Hospital in Nantes, France pre­sented updated findings from a Phase 1b trial of Venclexta in com­bi­na­tion with Velcade (bor­tez­o­mib) and dexa­metha­sone in re­lapsed and re­frac­tory myeloma (abstract).

The study in­cluded 54 patients with a median age of 65 years and a median of three prior lines of ther­apy; 79 per­cent of the patients had pre­vi­ously re­ceived Velcade and 37 per­cent were Velcade-refractory (resistant). Eleven per­cent of the patients had the chromosomal ab­nor­mal­ity t(11;14).

Overall, 58 per­cent of patients achieved a partial re­sponse­ or better with the Venclexta com­bi­na­tion. The re­sponse­ rate was sig­nif­i­cantly higher in patients who were not re­frac­tory to Velcade com­pared to those who were (84 per­cent versus 16 per­cent, re­spec­tive­ly). The best re­sponse­ observed in patients who were re­frac­tory to Velcade was a partial re­sponse­.

The highest over­all re­sponse­ (91 per­cent) was observed in 23 patients who were not re­frac­tory to Velcade and who had re­ceived a median of one to three prior ther­a­pies. The re­sponse­s were fre­quently deep re­sponses. More than a third of the 23 patients – 35 per­cent – had a com­plete or stringent com­plete re­sponse­ (CR or sCR) to the Venclexta, Velcade, and dexa­metha­sone regi­men.

Dr. Touzeau and his colleagues also found that the over­all re­sponse­ rate was higher among patients in the trial whose myeloma cells produced higher levels of the Bcl-2 protein com­pared to those whose cells produced low levels of the protein (71 per­cent versus 22 per­cent, re­spec­tive­ly).

The most common side effects of the three-drug treat­ment regi­men in­cluded constipa­tion (37 per­cent), diarrhea (37 per­cent), nau­sea (33 per­cent), and low platelet counts (30 per­cent). In most cases, the gastro­intestinal side effects were mild or mod­er­ate in terms of their severity. Only two of the 54 patients dis­con­tinued treat­ment due to side effects.

Following Dr. Touzeau's pre­sen­ta­tion of the Venclexta trial results, Dr. Jonathan Kaufman of the Winship Cancer Institute at Emory University discussed the results as well as other re­search related to Venclexta as a poten­tial myeloma ther­apy (presentation slides [PDF] courtesy of Dr. Kaufman). Dr. Kaufman has par­tic­i­pated in clin­i­cal re­search related to Venclexta as a myeloma ther­apy.

Dr. Kaufman told The Beacon that, for patients whose dis­ease is not yet resistant to Velcade, the re­sponse­ rate of the Venclexta, Velcade, and dexa­metha­sone regi­men is “very impressive.” It “compares favorably,” he added, “to any other three-drug regi­men in part­ner­ship with Velcade and dexa­metha­sone” – in­clud­ing Darzalex, Velcade, and dexa­metha­sone, based on the results of the CASTOR trial pre­sented on Sunday at ASCO (see related Beacon news article).

Venclexta Monotherapy In Re­lapsed And Re­frac­tory Multiple Myeloma

On Monday, a team of French and U.S. team of re­search reported update results of Phase 1 trial testing single agent Venclexta as treat­ment for heavily pre­treated multiple myeloma. The results were pre­sented in a poster dis­played during Monday's poster session at the meeting (abstract, poster [PDF] courtesy of Dr. Shaji Kumar).

A total of 66 multiple myeloma patients par­tic­i­pated in the trial, which was designed to assess the safety of Venclexta in multiple myeloma, estab­lish­ a dose to be used in a later Phase 2 trial, and get a sense of the drug's efficacy in myeloma.

The 66 trial par­tic­i­pants had a median of 5 prior lines of ther­apy. Almost all patients had been pre­vi­ously treated with both Revlimid (lena­lidomide) and Velcade, and 61 per­cent were now resistant (refractory) to both those drugs.

Almost half the patients in the trial (46 per­cent) had the t(11;14) chromosomal ab­nor­mal­ity.

Across all patient, the over­all re­sponse­ rate to single-agent Venclexta at all the tested doses was 21 per­cent.

Patients with the t(11;14) ab­nor­mal­ity, how­ever, were much more likely to respond to the drug. The over­all re­sponse­ rate in t(11;14) patients was 40 per­cent, and the median duration of re­sponse­ and time to pro­gression in t(11;14) patients was 10 months and 6 months, re­spec­tive­ly.

The most common side effects of any severity were gastro­intestinal-related (for example, diarrhea and nau­sea), fatigue, and low blood cell counts. Side effects that were more than just mild or mod­er­ate in severity were mainly the low blood counts.

Two patients died during the trial for reasons other than dis­ease pro­gres­sion. From in­for­ma­tion in the poster and poster abstract, it appears that at most one of those deaths may have been treat­ment-related.

Emory's Dr. Kaufman also spoke with The Beacon about the results summarized in the poster pre­sentation. He is one of the re­searchers in­volve­d with the study, and he described the single-agent activity of Venclexta in t(11;14) patients as “very impressive”. He noted, as well, that he and the other re­searchers will seek to im­prove the re­sponse­ by combining Venclexta with dexa­metha­sone.

Keytruda (Pembrolizumab)

A second pre­sen­ta­tion during Tuesday's oral pre­sen­ta­tion session at ASCO was by Dr. Maria-Victoria Mateos from the Universidad of Salamanca in Spain. She pre­sented final results of the “KEYNOTE-023” Phase 1 trial of Keytruda (pem­bro­lizu­mab) in com­bi­na­tion with Revlimid and dexa­metha­sone in re­lapsed and re­frac­tory myeloma patients (abstract, presentation slides [PDF] courtesy of Dr. Mateos).

Background to the Latest Keytruda Results

Keytruda is a mono­clonal anti­body known as a “checkpoint in­hib­i­tor.” It interferes with the inter­action be­tween molecules known as PD-L1 and PD-L2 found on the surface of cancer cells, and a protein known PD-1 found on immune sys­tem cells. By interfering with the inter­action be­tween PD-1 and the PD-L1 and PD-L2 molecules, Keytruda can cause more immune sys­tem cells to attack cancer cells.

Due to the way it works as an anti-cancer ther­apy, Keytruda is often described as an “anti-PD-1” mono­clonal anti­body.

Keytruda was approved in the United States in 2014 for the treat­ment of mel­anoma and in Octo­ber of last year for the treat­ment of non-small cell lung cancer. It also has been approved for the treat­ment of mel­anoma in other countries. Keytruda is mar­keted by the U.S. pharma­ceu­tical com­pany Merck.

Initial results of the KEYNOTE-023 trial of Keytruda, Revlimid, and dexa­metha­sone in re­lapsed myeloma were pre­sented at last year's American Society of Hematology (ASH) meeting. At the time, re­sponse­ data were avail­able for 17 patients in the trial, and the over­all re­sponse­ rate was 76 per­cent (abstract).

This re­sponse­ rate was perceived by many re­searchers to be very promising given how many prior treat­ments the patients in the trial had re­ceived. The ASH trial results there­fore sparked antic­i­pa­tion that the three-drug regi­men might prove in the long-term to have very high anti-myeloma activity.

Efficacy & Safety Results Reported at ASCO

In her pre­sen­ta­tion this Tuesday at ASCO, Dr. Mateos reported that the KEYNOTE-023 trial even­tu­ally en­rolled 51 re­lapsed multiple myeloma patients who had re­ceived a median of four prior ther­a­pies. A fifth of the patients had re­ceived five or more prior lines of ther­apy, and 75 per­cent of the patients were re­frac­tory (resistant) to Revlimid.

Of the 40 patients evaluable for re­sponse­, 50 per­cent responded, with 3 per­cent achieving a stringent com­plete re­sponse­, 13 per­cent a very good partial re­sponse­, 35 per­cent a partial re­sponse­. An addi­tional 48 per­cent of patients achieved stable dis­ease, which is generally viewed as a pos­i­tive out­come in later-stage patients. Among the patients who were re­frac­tory to Revlimid, 38 per­cent responded.

With a median follow-up time of 9 months, the median duration of re­sponse­ was 11.3 months and the median time to achieve the first objective re­sponse­ was 1.5 months.

The most common side effects among the patients in the trial in­cluded low platelet counts (41 per­cent), low white blood cell counts (37 per­cent), diarrhea (28 per­cent), and fatigue (26 per­cent). The low blood counts could sometimes be very low; a third of the patients in the trial, for example, ex­peri­enced very low neu­tro­phil levels (Grade 3 or higher neu­tro­penia). Only 6 per­cent of the trial par­tic­i­pants, how­ever, dis­con­tinued treat­ment due to side effects.

There were two side effect-related deaths during the trial: one case of veno-occlusive dis­ease (obstruction of small veins in the liver), and one ischemic stroke.

According to Dr. Mateos, the side effects seen during the KEYNOTE-023 trial were for the most part con­sis­tent with those seen in patients treated with Keytruda for solid tumors.

The re­searchers did not observe any in­fusion reac­tions, which are commonly seen with mono­clonal anti­bodies.

Perspective on the Results

In a pre­sen­ta­tion discussing the results of the trial, Dr. Hearn Jay Cho, a myeloma specialist at Mt. Sinai Hospital in New York City, said that anti-PD-1 com­pounds seem to have little single-agent activity in multiple myeloma. However, in com­bi­na­tion with immuno­modu­la­tory agents such as Revlimid and Pomalyst, they can yield “substantial” re­sponse­s (presentation slides [PDF] courtesy of Dr. Cho).

The Beacon asked Dr. Cho how he qualitatively would compare the anti-myeloma activity to that of other myeloma treat­ment regi­mens. Dr. Cho replied:

“In my opinion, the KEYNOTE-023 results are not mature enough to draw broad conclusions. It is a rel­a­tive­ly small sample size and the follow up is not long enough to draw conclusions of efficacy – for example, no pro­gres­sion-free sur­vival or over­all sur­vival data were pre­sented. However, the re­sponse­ rate of 50% in re­lapsed, re­frac­tory patients is notable, similar to the elotuzumab [Empliciti], Revlimid, and dexa­metha­sone com­bi­na­tion.

“It should be noted that the initial results with ipilimumab [Yervoy] and other checkpoint in­hib­i­tors in solid tumors did not show a dif­fer­ence in pro­gres­sion-free sur­vival, but there was a dif­fer­ence in over­all sur­vival, with responders demonstrating prolonged benefit from treat­ment. The pro­gres­sion-free sur­vival benefit was only seen with com­bi­na­tions of checkpoint in­hib­i­tors or checkpoint in­hib­i­tor + other drug com­bi­na­tions. The KEYNOTE-023 results are im­por­tant because they show that checkpoint in­hib­i­tors are active in multiple myeloma, and pave the way for the com­bi­na­tion studies described in my discussion pre­sen­ta­tion.

“Although this trial is im­por­tant for estab­lish­ing activity of checkpoint in­hib­i­tors in myeloma, the Keytruda, Revlimid, and dexa­metha­sone com­bi­na­tion is not nec­es­sar­i­ly the “best” regi­men. There are still a number of open questions re­gard­ing the mech­a­nisms of checkpoint in­hib­i­tors in multiple myeloma and the con­tri­bu­tions – or possible impediments – pre­sented by other drugs. This is just the beginning.“

Isatuximab (SAR650984)

The third pre­sen­ta­tion during the Tuesday oral session at ASCO was by Dr. Ravi Vij from Washington University in St. Louis, Missouri. He pre­sented interim results of two new dose cohorts in a Phase 1b trial of isatuximab (SAR650984) in com­bi­na­tion with Revlimid and dexa­metha­sone in re­lapsed and re­frac­tory multiple myeloma (abstract, presentation slides [PDF] courtesy of Dr. Vij).

Isatuximab is a mono­clonal anti­body ther­apy being devel­oped by the French pharma­ceu­tical com­pany Sanofi. It targets cancer cells that have the CD38 protein on their surface.

The trial discussed by Dr. Vij pre­vi­ously explored three dif­fer­en­t dose levels (3 mg/kg, 5 mg/kg, and 10 mg/kg every other week) of isatuximab. Two new dosing schedules (10 mg/kg weekly and then every other week; and 20 mg/kg weekly and then every other week) were added to the trial based on dosing-related re­search.

Dr. Vij’s pre­sen­ta­tion focused on data for three groups of patients in the study: those in the two new dose-level groups, and those who were in a pre­vi­ously estab­lish­ed 10mg/kg every other week dosing group (a total of 46 patients).

Patients in all three dosing groups were heavily pre­treated, with patients in the two 10 mg/kg groups having a median of four prior lines of ther­apy, while patients in the 20 mg/kg group had a median of 6.5 prior lines of ther­apy. Most of the patients in the study (85 per­cent) were resistant (refractory) to either Revlimid, Pomalyst (poma­lido­mide), or both.

The over­all re­sponse­ rate across all three dosing groups was 57 per­cent, and the over­all re­sponse­ rate was almost as high (54 per­cent) in patients who were re­frac­tory to either. The over­all re­sponse­ was almost as high (54 per­cent) in patients who were re­frac­tory to either Revlimid, Pomalyst, or both.

Dr. Vij mentioned that the side effects seen with this com­bi­na­tion of three drugs was what would have been ex­pec­ted given the side effects seen with each of the drugs in­di­vid­ually.

The treat­ment dis­con­tinu­a­tion rate was lowest among patients re­ceiv­ing 10 mg/kg weekly/every other week (33 per­cent com­pared to 88 per­cent of patients re­ceiv­ing 10 mg/kg every other week and 64 per­cent of patients re­ceiv­ing 20 mg/kg weekly/every other week). One patient in the 20 mg/kg weekly/every other week dosing group ex­peri­enced a dose-limiting side effect.

Based on the findings of this trial, the re­searchers rec­om­mend using the 10 mg/kg weekly and then every other week dosing for isatuximab in further re­search of this three-drug com­bi­na­tion.

In a review pre­sen­ta­tion fol­low­ing Dr. Vij’s pre­sen­ta­tion, Dr. Rafael Fonseca from The Mayo Clinic said that the findings pre­sented by Dr. Vij con­firm that CD38 mono­clonal anti­bodies “are here to stay” and will likely be­come first-line treat­ments. He added that the agents seem to be very effective in com­bi­na­tion ther­apy, but it is not clear yet which com­bi­na­tion is the most effective (presentation slides [PDF] courtesy of Dr. Fonseca).

MOR202

Speaking of CD38 mono­clonal anti­bodies, another poster pre­sented this Monday provided interim results of an ongoing Phase 1/2b trial of MOR202 in re­lapsed and re­frac­tory multiple myeloma patients (abstract, poster [PDF]).

MOR202 is an in­fused ther­apy being devel­oped by the Germany pharma­ceu­tical com­pany MorphoSys. Like Darzalex and isatuximab, MOR202 is a CD38-targeted mono­clonal anti­body.

The interim results pre­sented on Monday are on data from patients who re­ceived MOR202 with dexa­metha­sone or in com­bi­na­tion with either Revlimid plus dexa­metha­sone, or Pomalyst plus dexa­metha­sone, at several dif­fer­en­t doses.

The results are for a rather limited number of patients for each of the three com­bi­na­tions, so they mainly will be of interest to people who are particularly interested in the devel­op­ment of MOR202. The poster results do not lend themselves well to providing new insights into either the efficacy or safety of MOR202.

For readers interested in the details of the new results, the patients who re­ceived MOR202 plus dexa­metha­sone, or MOR202 in com­bi­na­tion with Pomalyst and dexa­metha­sone, had a median of four prior lines of ther­apy. Patients in the study who re­ceived MOR202 in com­bi­na­tion with Revlimid and dexa­metha­sone had a median of two prior ther­a­pies.

So far 16 patients have been treated with MOR202 and dexa­metha­sone, 5 patients with MOR202 plus Pomalyst and dexa­metha­sone, and 7 patients with MOR202 plus Revlimid and dexa­metha­sone. Of the 25 patients evaluable for re­sponse­, nine have responded to ther­apy, for an over­all re­sponse­ rate of 36 per­cent. Two of the five patients treated with the MOR202, Pomalyst, and dexa­metha­sone com­bi­na­tion have had com­plete re­sponse­s to treat­ment.

The most common side effects were blood count-related. Infusion-related reac­tions, a common side effect with mono­clonal anti­bodies, were observed in four patients and were limited to the first in­fusion. A two-hour in­fusion was feasible in all patients.

Selinexor (KPT-330)

Results of a Phase 1 trial of selinexor (KPT-330) in com­bi­na­tion with Doxil (doxorubicin lipo­somal, Caelyx) and dexa­metha­sone in re­lapsed and re­frac­tory multiple myeloma patients (abstract, poster [PDF] courtesy of Dr. Rachid Baz) also were also pre­sented during Monday's poster session.

Selinexor is an orally admin­istered in­hib­i­tor of the nuclear export protein XPO-1. It is being in­ves­ti­gated in many dif­fer­en­t clin­i­cal trials as a poten­tial treat­ment for a variety of blood and solid tumor cancers.

The selinexor study pre­sented in Monday is being conducted by re­searchers at the Moffitt Cancer Center in Tampa, Florida. Thus far, the trial has recruited 13 patients, who have had a median of six prior treat­ment regi­mens (which probably is equivalent to a median of 4 or 5 prior lines of ther­apy).

The patients in the study have re­ceived dif­fer­en­t doses of selinexor, at dif­fer­en­t in­ter­vals, to de­ter­mine what dose might be best.

Treatment re­sponse­ results are avail­able for 10 of the 13 patients. The over­all re­sponse­ rate thus far is 40 per­cent, with two patients achieving a partial re­sponse­ and two achieving a very good partial re­sponse­. Five of the six other patients have achieved either a minor re­sponse­ or stable dis­ease, so the clin­i­cal benefit ratio is 90 per­cent.

The most common severe side effects of the treat­ment have been low blood counts, gastro­in­tes­ti­nal issues, low blood sodium levels (hyponatremia).