This year’s annual meeting of the American Society of Clinical Oncology (ASCO) came to an end yesterday in Chicago.

Monday was the busiest day with regard to myeloma-related research. The day started with an oral presentation session that in­cluded eight talks about im­por­tant new myeloma-related research. A poster session in the afternoon in­cluded several posters about myeloma-related research.

This article summarizes the most im­por­tant findings from Monday's oral pre­sen­ta­tion session. A later article will cover the findings from the after­noon poster session.

The content in our daily updates is based on the actual presentations and posters presented at the meeting, which often differ in terms of their content com­pared to what is avail­able prior to the meeting in abstracts submitted for the meeting.

The Beacon's ASCO updates also in­clude links to presentations and posters that the ASCO presenters have made avail­able to the Beacon's readers for review. The Beacon's meeting-related articles will be up­dated regularly as more presenters make their slide decks and posters avail­able to The Beacon. The "updated" time at the top of updated articles allows readers to see if new files or other content have been added.

Daratumumab

During the morning’s oral presentation session, Dr. Henk Lokhorst from UMC Utrecht in the Netherlands reported results from the Phase 1 portion of a Phase 1/2 study of daratumumab in re­lapsed and refractory multiple myeloma patients (abstract; presentation [pdf] courtesy of Dr. Lokhorst).

Daratumumab is being devel­oped by the Danish bio­technology com­pany Genmab together with Janssen Biotech, a Johnson & Johnson (NYSE: JNJ) sub­sid­i­ary. It is a mono­clonal anti­body, like elotuzumab and siltuximab, that signals the immune sys­tem to kill myeloma cells.

The Phase 1 portion of this study in­cluded 32 re­lapsed and refractory myeloma patients who had been treated with a median of six prior lines of ther­apy.  The Phase 2 portion of the study has thus far enrolled seven patients.

During Phase 1 of the study, patients received varying doses of dara­tu­mu­mab, ranging from 0.005 mg/kg up to 24 mg/kg.

Of the 12 patients who were treated with 4 mg/kg or more of dara­tu­mu­mab, 42 per­cent responded, and all these responses were partial responses.  Another 25 per­cent achieved a minimal response.

The median pro­gres­sion-free survival for this subset of patients has not yet been reached after a median follow-up of 18.4 weeks.

During Phase 1 of the study, 44 per­cent of patients ex­peri­enced mild to severe in­fusion-related side effects.

Patients enrolled in Phase 2 of the study are cur­rently being treated with the maximum tolerated dose from Phase 1 of the study: 8 mg/kg of dara­tu­mu­mab.

The dara­tu­mu­mab trial results were reviewed by Dr. Saad Usmani from the University of Arkansas for Medical Science in a presentation that also took place during the morning session (presentation [pdf] courtesy of Dr. Usmani).

Dr. Usmani described the results as en­cour­ag­ing, especially since the patient pop­u­la­tion was highly refractory.  He described the side effects as similar to those observed with other mono­clonal anti­bodies.

Going for­ward, he would like to see clin­i­cal and biological features of the patients reported because he feels that this in­­for­ma­tion will be critical to identifying which patients will benefit the most from dara­tu­mu­mab.  

Ixazomib

Dr. Shaji Kumar from the Mayo Clinic discussed results from a Phase 1 study of single-agent ixazomib (MLN9708) in re­lapsed and refractory multiple myeloma patients after enrollment for the trial was com­pleted (abstract; presentation [pdf] courtesy of Dr. Kumar).

Ixazomib is an orally admin­istered pro­te­a­some inhibitor, in the same class of drugs as Velcade (bortezo­mib); it is being devel­oped by Millennium Pharma­ceu­ticals, the same com­pany that devel­oped and mar­kets Velcade.

Previous studies have dem­onstrated that ixazomib may be effective in both newly diag­nosed and re­lapsed and refractory myeloma.

The study in­cluded 60 re­lapsed and refractory patients with a median age of 64 years. The patients had been treated with a median of four prior regi­mens, in­clud­ing Velcade (85 per­cent), Revlimid (lena­lido­mide) (97 per­cent), thalidomide (Thalomid) (53 per­cent), and Kyprolis (car­filz­o­mib) (15 per­cent).

The median time from diag­nosis was 4.9 years, and 72 per­cent of the patients were refractory to their last regi­men.

So far, patients have received a median of two cycles of treat­ment, and 5 per­cent remain on treat­ment.

Of the 50 patients evaluable for response, 18 per­cent responded, with 2 per­cent achieving a very good partial response and 16 per­cent a partial response.  Rates of pro­gres­sion-free and over­all survival are not avail­able at this time.

According to Dr. Kumar, ixazomib is fairly well tolerated and the side effects are in line with those of other drugs in the same category.

Common severe side effects in­cluded low platelet counts (33 per­cent), diarrhea (17 per­cent), low white blood cell counts (16 per­cent), fatigue (8 per­cent), de­creased appetite (7 per­cent), and nausea (7 per­cent). In addi­tion, 18 per­cent of patients ex­peri­enced mild to mod­er­ate drug-related periph­eral neu­rop­athy.

Overall, 32 per­cent of patients required dose reductions and 12 per­cent dis­con­tinued treat­ment due to side effects.

The results of the ixazomib trial also were discussed by Dr. Usmani during his review presentation.

Dr. Usmani said that ixazomib showed good single-agent activity in re­lapsed and refractory patients.  How­ever, he pointed out the there was only a small fraction of patients with high-risk chromosomal ab­nor­mali­ties in­cluded in the study.

He also was con­cerned about the fact that patients with existing mod­er­ate or severe periph­eral neu­rop­athy were excluded from the study. He thinks that the exclusion will call into question somewhat the applicability of the results of the Phase 2 expansion of the trial, because one third of Velcade-exposed patients have mod­er­ate or severe periph­eral neu­rop­athy.

Pomalyst Plus Low-Dose Dexamethasone Versus High-Dose Dexamethasone Alone

Dr. Katja Weisel from the University Hospital in Tübingen, Germany, presented updated results from a Phase 3 study com­par­ing the efficacy and safety of Pomalyst (poma­lido­mide) in com­bi­na­tion with low-dose dexamethasone (Decadron) versus treat­ment with only high-dose dexa­meth­a­sone (abstract; presentation [pdf] courtesy of Dr. Weisel).

Pomalyst is an immuno­modu­la­tory agent in the same class of drugs as Revlimid and thalido­mide. It works by inducing a patient's immune sys­tem to target and destroy myeloma cells.

Interim results of the Phase 3 trial had shown that Pomalyst plus low-dose dexa­meth­a­sone in­creases pro­gres­sion-free survival com­pared to high-dose dexa­meth­a­sone. Based on these findings, the inde­pen­dent review board rec­om­mended that patients on high-dose dexa­meth­a­sone should have access to Pomalyst as well; 50 per­cent of patients received Pomalyst.

At ASCO, Dr. Weisel presented the results of the updated survival analysis.

The study in­cluded 455 re­lapsed and refractory multiple myeloma patients with a median age of 64 years. They had received a median of five prior lines of ther­apy, and 74 per­cent of the patients were refractory to both Revlimid and Velcade.

The updated survival analysis showed that after a median follow-up of 10 months, the over­all response rate for patients who were treated with Pomalyst plus low-dose dexa­meth­a­sone was 31 per­cent, with 1 per­cent achieving a com­plete response, 5 per­cent a very good partial response, and 26 per­cent a partial response.  In comparison,10 per­cent of patients who received high-dose dexa­meth­a­sone responded, with 1 per­cent achieving a very good partial response and 9 per­cent a partial response.

Patients who received Pomalyst plus low-dose dexa­meth­a­sone had a median pro­gres­sion-free survival of 4 months, versus 1.9 months for those who received high-dose dexa­meth­a­sone alone.

The median over­all survival for patients given Pomalyst plus low-dose dexa­meth­a­sone was 12.7 months, com­pared to 8.1 months for patients who were treated with high-dose dexa­meth­a­sone.

Dr. Weisel pointed out the survival benefit was main­tained, despite the fact that 50 per­cent of patients from the high-dose dexa­meth­a­sone treat­ment group crossed over to the Pomalyst plus low-dose dexa­meth­a­sone treat­ment group.

For patients who received Pomalyst plus low-dose dexa­meth­a­sone versus high-dose dexa­meth­a­sone alone, the most common severe to life-threatening side effects in­cluded low white blood cell counts (42 per­cent versus 15 per­cent), anemia (27 per­cent versus 29 per­cent), and in­fec­tion (24 per­cent versus 23 per­cent).

Kyprolis Plus Melphalan And Prednisone

Later in the session, Dr. Cyrille Touzeau from the University Hospital in Nantes, France, presented results from a Phase 1/2 study of Kyprolis plus melphalan (Alkeran) and prednisone in newly diag­nosed myeloma patients over the age of 65 (abstract; presentation [PDF] courtesy of Dr. Touzeau).

Kyprolis is a pro­te­a­some inhibitor in the same class of drugs as Velcade and ixazomib (MLN9708).

Phase 1 of the study in­cluded 24 newly diag­nosed multiple myeloma patients over the age of 65 years.

Patients in this study received escalating doses of Kyprolis, be­tween 20 mg/m² and 45 mg/m², plus mel­phalan and pred­ni­sone to de­ter­mine the maximum tolerated dose of Kyprolis when used in this com­bi­na­tion.  The dosing of Kyprolis approved by the U.S. Food and Drug Admin­istra­tion is no more than 27 mg/m² per admin­istra­tion.

Two patients treated with 45 mg/m² of Kyprolis ex­peri­enced dose-limiting toxicities. Thus, the maximum tolerated dose was de­ter­mined to be 36 mg/m².

In Phase 2 of the study, 44 addi­tional newly diag­nosed elderly patients were enrolled and treated with 36 mg/m² of Kyprolis in com­bi­na­tion with mel­phalan and pred­ni­sone. Overall, the patients from both phases of the study had a median age of 72 years.

The median follow-up time was 12 months.

Of the 68 patients from both phases of the study who were eval­u­ated for response, 91 per­cent responded to treat­ment, in­clud­ing 6 per­cent who achieved a com­plete response, 50 per­cent a very good partial response, and 35 per­cent a partial response.

At a median follow-up of 12 months, the median pro­gres­sion-free survival was 22 months, and the esti­mated 2-year over­all survival rate was 87 per­cent.

The most common side effects of Kyprolis plus mel­phalan and pred­ni­sone were low red blood cell counts (54 per­cent), in­fec­tions (52 per­cent), and fatigue (40 per­cent). In addi­tion, 43 per­cent ex­peri­enced heart-related com­pli­ca­tions and 6 per­cent of patients ex­peri­enced mod­er­ate to severe periph­eral neu­rop­athy.

Overall, 11 per­cent of patients dis­con­tinued treat­ment due to side effects.

In his review of these results, Dr. Usmani said that he was very en­cour­aged by the high response rates of the com­bi­na­tion. However, he added that he is con­cerned about the high rate of heart-related side effects observed in this trial because elderly patients frequently already have heart disease.

Nevertheless, he feels this com­bi­na­tion is a good treat­ment option for trans­plant-ineligible, newly-diagnosed myeloma patients.

Melphalan-Prednisone-Revlimid Versus Tandem Transplantation

Dr. Antonio Palumbo from the University of Torino in Italy reported results from a study com­par­ing a combi­na­tion regi­men of melphalan (Alkeran), prednisone, and Revlimid (lena­lido­mide) (MPR) with tandem stem cell trans­plan­ta­tion. This study also examined the effect of Revlimid main­te­nance ther­apy fol­low­ing either of these treat­ment regi­mens (abstract; presentation [pdf] courtesy of Dr. Palumbo).

The study in­cluded 402 newly diag­nosed multiple myeloma patients with a median age 58 years.

All patients in the study first received four 28-day cycles of Revlimid com­bined with low-dose dexa­metha­sone.

Next, the patients were ran­domly assigned to one of four groups.  Two of the groups received six cycles of MPR.  One of these two groups also received Revlimid main­te­nance ther­apy after their MPR ther­apy ended, while the other received no further treat­ment.

The other two groups received tandem stem cell trans­plants.  Once again, one of these two groups also received Revlimid main­te­nance ther­apy after the trans­plants, while the other received no further treat­ment.

Response rates after MPR or trans­plan­ta­tion were not reported during the presentation.

However, among patients who received Revlimid main­te­nance ther­apy, the over­all response rate was 78 per­cent, with 23 per­cent achieving a com­plete response, 25 per­cent a very good partial response, and 30 per­cent a partial response.

Similarly, the over­all response rate for patients who did not receive Revlimid main­te­nance was 77 per­cent, with 19 per­cent achieving a com­plete response, 29 per­cent a very good partial response, and 29 per­cent a partial response.

After a median follow-up of 45 months, the median pro­gres­sion-free survival was 24 months for patients treated with MPR, com­pared to 38 months for patients who underwent tandem trans­plan­ta­tion.

The median pro­gres­sion-free survival for patients who received Revlimid main­te­nance ther­apy was 37 months, versus 26 months for patients who did not receive main­te­nance ther­apy.

The five-year over­all survival rate from the time of diag­nosis was 62 per­cent for patients treated with MPR, 71 per­cent for patients who underwent tandem trans­plan­ta­tion, 75 per­cent for patients who received Revlimid main­te­nance ther­apy, and 58 per­cent for patients who received no main­te­nance ther­apy.

The trial results were reviewed by Dr. Sagar Lonial from the Winship Cancer Institute at Emory University in another review presentation (pdf, courtesy of Dr. Lonial).

According to Dr. Lonial, the current findings show the clear benefit of high-dose chemo­ther­apy plus stem cell trans­plan­ta­tion as well as main­te­nance ther­apy.

Dr. Lonial also pointed out that Dr. Palumbo’s findings suggest that over­all response rates as defined today cannot be used as the best way to assess the long-term benefit of a ther­apy, given that response rates were similar for those who did and did not receive Revlimid main­te­nance ther­apy, but pro­gres­sion-free and over­all survival were so dif­fer­en­t be­tween the two treat­ment groups.  In his opinion, pro­gres­sion-free and over­all survival are cur­rently the two factors that best define the long-term benefit of a treat­ment.

Secondary Cancers

Dr. Palumbo also reported results from a meta-analysis investigating the rela­tion­ship be­tween treat­ment with Revlimid and the likelihood of devel­op­ing a sec­ond­ary cancer (abstract; presentation [pdf] courtesy of Dr. Palumbo).

Previous research has shown that patients taking Revlimid main­te­nance ther­apy may be more likely to develop a sec­ond­ary cancer than patients who do not receive Revlimid main­te­nance ther­apy (see related Beacon news articles).

In the current analysis, the researchers retro­spec­tive­ly eval­u­ated data from 6,383 myeloma patients who par­tic­i­pated in ran­domized clin­i­cal trials.  Some were treated with Revlimid, while others were not. The patients had a median age of 69 years.

After a median follow-up of 30 months, 6.6 per­cent of patients devel­oped sec­ond­ary cancers. This in­cluded 2.9 per­cent who devel­oped blood cancers and 3.6 per­cent who devel­oped solid tumors.

Solid tumors were similarly common among patients treated with and without Revlimid.

However, the frequency of blood cancers was sig­nif­i­cantly higher in patients treated with Revlimid. The investi­gators found, though, that this in­creased risk was limited to patients treated with Revlimid in com­bi­na­tion with mel­phalan.

In a review presentation that was also part of the morning session, Dr. Jonathan Kaufman from the Winship Cancer Institute at Emory University said that, despite the in­creased risk of second cancers in patients treated with Revlimid and mel­phalan, he still feels that Revlimid’s benefits con­tinue to outweigh its risks in the post-transplant setting.  Thus, he will con­tinue to discuss the benefits and risks of Revlimid main­te­nance ther­apy with his relevant patients.

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Myeloma presentations from the rest of Day 4 will also be summarized in a Beacon ASCO daily update to be published later today. Additional coverage of key research results from the meeting will con­tinue after that with individual, topic-specific news articles.  For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2013 coverage.

Note: Electronic copies of conference presentations and posters made avail­able to the Beacon's readers are for personal use only. Further transmission or publication of the files is not permitted, although hyperlinks to the files are permitted with attribution to the author and to The Beacon (for example, "courtesy of Dr. Jane Doe and The Myeloma Beacon.")