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 ^[1] 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 ^[2] in com­bi­na­tion with Revlimid ^[3] (lena­lido­mide) and dexamethasone ^[4] (Decadron) in mul­ti­ple myeloma patients with var­i­ous levels of kidney function (abstract ^[5]). Twelve per­cent of the patients were newly diag­nosed, the remainder had pre­vi­ously re­ceived treat­ment, in­clud­ing Velcade ^[6] (bor­tez­o­mib) (81 per­cent), thalido­mide ^[7] (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 ^[8] in com­bi­na­tion with Velcade and dexa­meth­a­sone for re­lapsed myeloma (abstract ^[9]).  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  ^[10]and dexamethasone with or without Velcade in heavily pre­treated myeloma patients were also pre­sented (abstract ^[11]). 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 ^[12] in re­lapsed and re­frac­tory myeloma patients (abstract ^[13]). 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 ^[14] (car­filz­o­mib) plus Pomalyst ^[15] (poma­lidomide; Imnovid) and dexa­meth­a­sone in myeloma patients who had pre­vi­ously re­ceived Revlimid but not Velcade (abstract ^[16]).  Re­search pre­sented at last year’s ASH annual meeting showed that this com­bi­na­tion is highly ef­fec­tive in heavily pre­treated patients (see re­lated Beacon ^[17] 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 ^[18]).  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 ^[19]). 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 ^[20]).  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 ^[21]).

Another study pre­sented at Saturday's session com­pared next-gener­a­tion sequencing and multicolor flow cytometry for the assess­ment of minimal residual dis­ease (abstract ^[22]). 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 ^[23]).

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 ^[24]).  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 ^[25]). 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 ^[26]).

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 56^th Annual Meeting, in­clud­ing the final pre­sen­ta­tion schedule and all meeting abstracts, please see the ASH annual meeting ^[27] website.