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ASH 2014 Multiple Myeloma Update – Day One: Poster Session

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Published: Dec 8, 2014 7:02 am

Saturday was the official first day of the 2014 American Society of Hema­tology (ASH) annual meeting. The day featured a wide range of in­ter­est­ing pre­sen­ta­tions about mul­ti­ple myeloma.

Oral pre­sen­ta­tions about new treat­ments under devel­op­ment were given mid-day and were summarized in a Beacon ASH Daily Update published yes­ter­day morn­ing.

During Saturday evening, a poster session took place where im­por­tant new re­search findings were summarized in posters dis­played throughout two separate large conference halls.

The stud­ies covered a variety of myeloma-related topics, ranging from new treat­ments being devel­oped for myeloma, com­bi­na­tion ther­a­pies of approved ther­a­pies, to stem cell trans­plan­ta­tion, to minimal residual dis­ease testing, and much more.

New Myeloma Treatments

Saturday's poster session featured a num­ber of posters about re­­sults from clin­i­cal stud­ies of new drugs being devel­oped for the treat­ment of mul­ti­ple myeloma.

One of the posters summarized initial findings from an on­go­ing Phase 1 trial investigating elotuzumab in com­bi­na­tion with Revlimid (lena­lido­mide) and dexamethasone (Decadron) in mul­ti­ple myeloma patients with var­i­ous levels of kidney function (abstract). Twelve per­cent of the patients were newly diag­nosed, the remainder had pre­vi­ously re­ceived treat­ment, in­clud­ing Velcade (bor­tez­o­mib) (81 per­cent), thalido­mide (Thalomid) (42 per­cent), and Revlimid (35 per­cent). Over­all, 75 per­cent of patients with nor­mal kidney function, 67 per­cent of patients with severe kidney im­pair­ment and 56 per­cent of patients with end-stage kidney dis­ease responded to treat­ment.  According to the in­ves­ti­ga­tors, the com­bi­na­tion was well tol­er­ated in all three patient groups. They stated that patients with severe kidney im­pair­ment and with end-stage kidney dis­ease can be treated with 10 mg of elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone.

Another posters pre­sented final re­­sults from a Phase 2a study of NOX-A12 in com­bi­na­tion with Velcade and dexa­meth­a­sone for re­lapsed myeloma (abstract).  NOX-A12 is being devel­oped by Noxxon Pharma.  NOX-A12 binds to a small mol­e­cule called CXCL12 that is known to play a role in drug re­sis­tance. The study in­cluded 28 patients who had re­ceived a median of two prior ther­a­pies. Over­all, 68 per­cent of the patients responded to the com­bi­na­tion. The in­ves­ti­ga­tors point out that re­sponse rates were similar among patients with standard-risk and high-risk dis­ease (70 per­cent versus 67 per­cent). Median pro­gres­sion-free sur­vival was 6.5 months. According to the in­ves­ti­ga­tors, the com­bi­na­tion was well tol­er­ated and merits fur­ther in­ves­ti­ga­tion.

Updated re­­sults from a Phase 1/2 study of TH-302 and dexamethasone with or without Velcade in heavily pre­treated myeloma patients were also pre­sented (abstract). TH-302 is being devel­oped by Threshold Pharma­ceu­ticals (NASDAQ: THLD) and the German pharma­ceut­i­cal com­pany Merck KGaA for the treat­ment of sev­er­al dif­fer­en­t types of cancer. The drug is activated under low oxygen level con­di­tions, which are common in solid cancer tumors and in the bone mar­row of people with blood cancers.

The TH-302 study in myeloma thus far has recruited 24 patients. Of those patients, seven have re­ceived TH-302, Velcade, and dexa­meth­a­sone and been eval­u­ated for re­sponse. These patients had re­ceived a median of eight prior ther­a­pies.  One of the seven patients (14 per­cent) achieved a very good partial re­sponse and another achieved a partial re­sponse. The most common side effects of the treat­ment in­cluded low platelet counts, anemia, and fatigue.

Another poster summarized re­­sults from a Phase 1 study investigating PRLX93936 in re­lapsed and re­frac­tory myeloma patients (abstract). PRLX93936 is being devel­oped by Prolexys Pharma­ceu­ticals. It is a small-molecule anti-cancer treat­ment that targets the RAS pro­tein. Unfortunately, the drug did not show sig­nif­i­cant ac­­tiv­ity as a single agent, although ac­­tiv­ity im­proved when dexa­meth­a­sone was added. So far, 14 patients who have re­ceived a median of four prior lines of ther­apy have been en­rolled in the trial.  Among the 13 patients eval­u­ated for re­sponse, the best re­sponse observed was a minor re­sponse, which was seen in 18 per­cent of the patients; all of these patients re­ceived PRLX93936 in com­bi­na­tion with dexa­meth­a­sone.

Combinations Of Approved Therapies

A num­ber of posters pre­sented re­­sults from clin­i­cal stud­ies testing com­bi­na­tions of already approved anti-myeloma drugs.

One poster summarized re­­sults from a Phase 1b/2 study of Kyprolis (car­filz­o­mib) plus Pomalyst (poma­lidomide; Imnovid) and dexa­meth­a­sone in myeloma patients who had pre­vi­ously re­ceived Revlimid but not Velcade (abstract).  Re­search pre­sented at last year’s ASH annual meeting showed that this com­bi­na­tion is highly ef­fec­tive in heavily pre­treated patients (see re­lated Beacon news). The re­­sults of the cur­rent study show this com­bi­na­tion is also highly active in this less pre­treated patient pop­u­la­tion – in this case, patients who had re­ceived a median of two prior ther­a­pies. Of the 28 patients in­cluded in the study, 71 per­cent responded to the treat­ment. According to the in­ves­ti­ga­tors, re­sponses were rapid and durable. Progression-free sur­vival was 18.9 months. The most common severe side effects were blood-related.

Updated re­­sults were also pre­sented from a Euro­pean Phase 1/2 study of Kyprolis in com­bi­na­tion with thalido­mide  and low-dose dexa­meth­a­sone (KTd) for newly diag­nosed, trans­plant-eligible myeloma patients (abstract).  Patients re­ceived four cycles of induction ther­apy with es­ca­lat­ing doses of Kyprolis (27 mg/m2 to 56 mg/m2), thalido­mide, and low-dose dexa­meth­a­sone, followed by stem cell trans­plan­ta­tion, and four cycles of KTd con­sol­i­da­tion ther­apy. The share of patients who achieved at least a very good partial re­sponse in­creased from 68 per­cent after induction ther­apy to 76 per­cent after trans­plan­ta­tion and 89 per­cent after con­sol­i­da­tion ther­apy, re­spec­tively. The over­all re­sponse did not differ sig­nif­i­cantly be­tween the first three dose levels (27 mg/m2 to 45 mg/m2).  According to the in­ves­ti­ga­tors, the com­bi­na­tion was well tol­er­ated.

One study pre­sented at Saturday evening's poster pre­sen­ta­tion session was an "extension" study in­ves­ti­gat­ing the long-term ef­fi­cacy and safety of Kyprolis (abstract). It in­cluded 91 myeloma patients who had pre­vi­ously taken part in a Phase 1 or 2 clin­i­cal trial of single-agent Kyprolis and opted to con­tinue treat­ment with Kyprolis via the extension study. During the extension study, patients could con­tinue on single-agent Kyprolis at their pre­vi­ous dose, change the dose or dosing schedule, or com­bine other drugs with the Kyprolis.

The median duration of Kyprolis treat­ment (initial study plus extension study) was 89 weeks (a total of 22.5 treat­ment cycles).  Over­all, 79 per­cent of patients opted for one or more regi­men changes during the extension study; 31 of these patients con­tinued re­ceiv­ing single-agent Kyprolis at a dif­fer­en­t dose/schedule, and 69 per­cent changed to com­bi­na­tion ther­apy. When the treat­ment regi­men changes oc­curred due to dis­ease pro­gres­sion, many patients were able to get a re­sponse to the new Kyprolis-containing regi­men.  The over­all re­sponse rate was 20 per­cent after first pro­gres­sion, 35 per­cent after sec­ond pro­gres­sion, and 31 per­cent after third pro­gres­sion. According to the in­ves­ti­ga­tors, the types and rates of side effects observed in the extension study were similar to those observed for single-agent Kyprolis.

Another poster summarized re­­sults from a restrospective analysis showing that the addi­tion of Velcade to a commonly used salvage ther­apy in myeloma, dexa­meth­a­sone, cyclo­phos­pha­mide, etoposide, and cisplatin (DCEP), is ef­fec­tive and safe (abstract).  The over­all re­sponse was 40 per­cent for patients who re­ceived V-DCEP as a treat­ment to reduce the myeloma tumor burden before stem cell trans­plan­ta­tion; these patients had re­ceived a median of one prior line of ther­apy. The over­all re­sponse for patients who re­ceived V-DCEP as salvage ther­apy was 52 per­cent; these patients had re­ceived a median of three prior lines of ther­apy. The pro­gres­sion-free sur­vival for the two groups was 23 months and 8 months, re­spec­tively. Median over­all sur­vival was 79 months for patients who re­ceived V-DCEP as a treat­ment to reduce tumor burden before stem cell trans­plan­ta­tion and 43 months who re­ceived V-DCEP as salvage ther­apy.

Minimal Residual Disease Testing

Several posters in this session covered re­search on minimal residual dis­ease (MRD) testing.

One poster summarized the re­­sults of an on­go­ing study at the Uni­ver­sity of Pennsylvania investigating an MRD test based on samples from a patient's blood, rather than the bone mar­row.  It is investigating the use of the assay to detect and char­ac­ter­ize myeloma cells in patients with mul­ti­ple myeloma and its precursor dis­ease, smol­der­ing myeloma and mono­clonal gam­mop­athy of undetermined sig­nif­i­cance (MGUS) (abstract).

Another study pre­sented at Saturday's session com­pared next-gener­a­tion sequencing and multicolor flow cytometry for the assess­ment of minimal residual dis­ease (abstract). The re­­sults show that minimal residual dis­ease detection by next-gener­a­tion sequencing com­pared favorably to multicolor flow cytometry,  since all patients with residual dis­ease by multicolor flow cytometry were also MRD pos­i­tive by sequencing. In addi­tion, next-gener­a­tion sequencing picked up addi­tional patients with MRD who were MRD neg­a­tive by multicolor flow cytometry. The re­­sults also showed that MRD negativity by multicolor flow cytometry and next-gener­a­tion sequencing were both asso­ci­ated with sig­nif­i­cantly better pro­gres­sion-free sur­vival.

Survival

One poster pre­sented during the Saturday session reported re­­sults of an interim analysis of data from the "Connect MM" registry of newly diag­nosed mul­ti­ple myeloma patients in the United States. The registry, which is sponsored by the pharma­ceu­tical com­pany Celgene, has collected in­­for­ma­tion since 2009 on almost 1500 mul­ti­ple myeloma patients diag­nosed.  Patients did not have to be treated by Celgene-marketed myeloma ther­a­pies, how­ever, to be entered into the registry (abstract).

The interim analysis found that age, dis­ease stage, and the presence of health prob­lems other than mul­ti­ple myeloma im­pact over­all sur­vival irrespective of a myeloma patient's risk status. Initial treat­ment with three-drug regi­mens was asso­ci­ated with a sig­nif­i­cantly longer over­all sur­vival re­gard­less of dis­ease risk status. Patients with high-risk dis­ease did not have sig­nif­i­cantly lower over­all sur­vival com­pared to patients without high-risk features, except for patients with the chromosomal ab­nor­mal­ity del(17p), who had shorter over­all sur­vival. The sur­vival of these patients was im­proved, how­ever, with the use of triplet ther­apy.

Another poster summarized findings of a pop­u­la­tion-based study con­ducted in the Netherlands which also in­ves­ti­gated over­all sur­vival of newly diag­nosed myeloma patients (abstract).  Data collection for the study began in 2005 and in­cludes all newly diag­nosed myeloma patients in a spe­cif­ic province of the Netherlands.  The analysis of the study re­­sults shows that age, the presence of other dis­eases, and the num­ber of "CRAB" symp­toms – such as high cal­cium levels and im­paired kidney function – were asso­ci­ated with lower over­all sur­vival. The use of novel agents, on the other hand, was asso­ci­ated with im­proved over­all sur­vival.

Donor Transplantation

In one of the posters pre­sented Saturday, another group of Dutch re­searchers showed that the im­pact on out­come of donor (allogeneic) trans­plan­ta­tion as part of first-line treat­ment de­pends on the type of analysis used to assess out­come (abstract). Specifically, the Dutch re­searchers found that the ef­fi­cacy of donor trans­plan­ta­tion was underestimated by a common method known as "donor versus no-donor" analysis. More appro­pri­ate methods show that donor trans­plan­ta­tion has an im­pact on pro­gres­sion-free sur­vival that is more fa­vor­able than pre­vi­ously thought.

Another poster summarized the re­­sults of a German single-center analysis of sur­vival after donor trans­plan­ta­tion. The analysis was based on data from 95 patients who re­ceived a donor trans­plant be­tween 1994 and 2013. Median age at the time of donor trans­plan­ta­tion was 51 years  (abstract).

With a median follow-up of 70 months, the over­all sur­vival was 36 months, in­de­pen­dent of the con­di­tioning regi­men (reduced-intensity con­di­tioning or myeloablative con­di­tioning). Median over­all sur­vival was sig­nif­i­cant­ly longer for patients who re­ceived the donor trans­plant as their first-line treat­ment (89 months) com­pared to patients who re­ceived it as part of an auto-allo trans­plant (47 months), at relapse after an auto trans­plant (20 months), or at relapse after double auto trans­plants (26 months). Severe acute graft-versus-host dis­ease (GVHD), which de­vel­ops within the first 100 days after trans­plan­ta­tion, had a neg­a­tive im­pact on over­all sur­vival, whereas chronic GVHD of all grades, which oc­curs more than 100 days post trans­plant, did not neg­a­tively affect sur­vival.

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Myeloma pre­sen­ta­tions from Day 2 and Day 3 of the ASH 2014 meeting will be summarized in addi­tional ASH daily up­dates to be pub­lished at The Beacon the next few days.  Further coverage of key re­search re­­sults from the meeting will con­tinue after the meeting in in­di­vid­ual, topic-specific news articles.

Unless other­wise noted, all pre­sen­ta­tion and poster summaries in the Beacon's ASH-related articles report re­­sults pre­sented at this year's meeting.  These data are often more recent or extensive than what is con­tained in the pre­sen­ta­tion and poster abstracts.  In addi­tion, Beacon ASH-related articles will be up­dated on an on­go­ing basis in the com­ing weeks with links to the actual slides and posters pre­sented at the meeting (when avail­able and subject to permission of the lead author).

For more in­­for­ma­tion on ASH’s 56th Annual Meeting, in­clud­ing the final pre­sen­ta­tion schedule and all meeting abstracts, please see the ASH annual meeting website.

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5 Comments »

  • Holt said:

    Hello Beacon Staff. Thanks for these excellent updates from ASH. I read the abstract of the Celgene-sponsored survival study and it raised an analytical issue that has often puzzled me. The median follow-up for the study was 29 months, the median OS was 44.4 months, and the 3-year OS probability was 62.6%. Naively, it has always seemed to me that the median follow-up would have to be equal or close to the median OS and to the time for which OS probability is calculated. I suppose that early mortality could account for the discrepancy seen between follow-up and survival seen in this and other studies, but I can't quite wrap my head around it especially since the upper limit for follow-up was only 49.4 months. Could you provide a citation to the kind of statistics that are used to calculate survival in this and other similar studies? Thanks much.

  • Myeloma Beacon Staff said:

    Thanks for your feedback and question, Holt

    Although we don't always say it in our articles, the survival numbers we report are usually estimates. They are not the final, "true" numbers that can be calculated precisely once the trial has been ongoing for a very long time.

    Before all patients have been followed for a long enough time for survival times to be known with certainty, researchers usually estimate median survival times using what is known as Kaplan-Meier estimation.

    Basically, this statistical tool leverages the information available for the patients who have been been on the trial the longest to estimate median survival times. As more and more patients have been on the trial for longer periods of time, the estimate gets more precise.

    Does that clarify things a bit?

  • Holt said:

    Thanks Beacon Staff. That's very helpful.

  • Rafael M Santiago MD said:

    Thanks for the great coverage and summaries of the new studies presented at ASH meeting. You are providing a great service to MM patients! Since my doctors are currently at the meeting, I have been able to get heads up information that will facilitate discussion on my next appointment. Please keep the good work!

  • Myeloma Beacon Staff said:

    You're welcome, Holt. And thanks for your feedback, Rafael. We're glad you are finding the updates helpful.