This year’s American Society of Clinical Oncology (ASCO) annual meeting in Chicago ended last Tuesday.

The day before the meeting ended was the busiest day at the meeting with re­gard to myeloma research.  It featured a session of oral pre­sen­ta­tions in the morn­ing and a poster session in the afternoon. In addi­tion, an education ses­sion was held in the afternoon that included one myeloma-related talk, given by Dr. Leif Bergsagel of the Mayo Clinic, about progress in the treat­ment of mul­ti­ple myeloma (article in the ASCO 2014 Edu­ca­tional Book).

This update summarizes the myeloma-related studies presented during last Monday's afternoon poster session. An earlier article covered the findings from the oral presentations that were given in the morning.

Most of the key posters at Monday’s poster session focused on results from clinical trials of new com­bi­na­tions of current myeloma treat­ments.

Monday’s session also featured, however, several posters summarizing studies seeking to more precisely determine which patients with smol­der­ing myeloma are particularly likely to progress to active (symptomatic) multiple myeloma.

The content in the Beacon’s daily ASCO 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.  Links to the actual posters presented during the meeting are included in this article for every poster that is discussed.

CyBorD In Relapsed And Refractory Patients

One poster summarized the findings of a study investigating the efficacy and safety of Velcade (bor­tez­o­mib), cyclophosphamide (Cytoxan), and dexamethasone (Decadron), commonly referred to as CyBorD, in re­lapsed and refractory myeloma patients (abstract 8586; poster [pdf] courtesy of Dr. Jorge Monge).

The retrospective study included 55 patients with a mean age of 66 years who had received an average of three prior ther­a­pies; 36 per­cent of patients had pre­vi­ously not received treat­ment with a drug in the proteasome inhibitor class of ther­a­pies (which includes Velcade), and 82 per­cent had pre­vi­ously not received CyBorD.

Overall, 71 per­cent of patients responded to the CyBorD regi­men, with 13 per­cent achieving a complete re­sponse and 13 per­cent a very good partial response. Patients who had pre­vi­ously not received a protea­some inhibitor had a significantly higher over­all response rate (95 per­cent) than those who had (57 per­cent).

Median pro­gres­sion-free survival was 9.2 months from the start of treat­ment, and median over­all survival was 29 months from the start of treat­ment.

After a mean of six cycles, 22 per­cent of patients sub­se­quently received a stem cell trans­plant.

The researchers found that pro­gres­sion-free survival was higher in patients who underwent a stem cell trans­plant after CyBorD ther­apy (19.7 months), compared to those who did not (6.3 months). Progression-free survival also was higher in patients who had pre­vi­ously not received a proteasome inhibitor (14.8 months), compared to those who had (5.2 months), and in patients who had received three or fewer lines of ther­apy (12.1 months) compared to those who had more than three (6.1 months).

The researchers found similar results in regard to over­all survival. Patients who underwent a stem cell trans­plant after CyBorD ther­apy had longer over­all survival (53.1 months), compared to those who did not (26.7 months). Patients who had pre­vi­ously not received a proteasome inhibitor also had longer over­all survival (35.4 months) than those who had (21.2 months).

PVD

The session also included a poster summarizing results of a Phase 1 trial, called MM-005, that was initiated to establish the optimal dose for the com­bi­na­tion of Pomalyst (poma­lido­mide; Imnovid), Velcade, and low-dose dexa­meth­a­sone when treating re­lapsed myeloma patients.  In addi­tion, the study examined the use of sub­cu­tane­ous Velcade as part of the com­bi­na­tion treat­ment (abstract 8589; poster [pdf] courtesy of Dr. Paul Richardson and Celgene).

The trial included 28 re­lapsed and refractory multiple myeloma patients with a median age of 58 years who had received a median of two prior lines of ther­apy.

All patients had pre­vi­ously been treated with Revlimid and were resistant (refractory) to it.  A third of the pa­tients also had been treated with thalidomide (Thalomid).  (Revlimid, thalido­mide, and Pomalyst belong to the same class of drugs, known as immumodulatory agents.)

In addi­tion, all patients were required to have been treated pre­vi­ously with at least two cycles of Velcade or a drug from the same class as Velcade.  Patients could not take part in the trial, however, if they showed signs of being resistant to Velcade treat­ment in the past.

Three quarters of the patients had pre­vi­ously received a stem cell trans­plant.

Velcade was admin­istered sub­cu­tane­ously to 21 per­cent of patients during the trial and intravenously to the rest.

Overall, 71 per­cent of the patients in the study responded to the three-drug regi­men, with 44 per­cent reach­ing at least a very good partial response. Of the pa­tients who received sub­cu­tan­e­ous Velcade, response results were available for five patients; 80 per­cent responded, with 60 per­cent reaching at least a very good partial response.

The most common severe side effects in patients receiving IV Velcade included low white blood cell counts (45 per­cent), low platelet counts (32 per­cent), and pneu­monia (22 per­cent). For patients who received sub­cu­tane­ous Velcade, the most common severe side effects included low white blood cell counts (17 per­cent) and elevated creatinine phosphokinase levels (17 per­cent).

The researchers did not observe any severe periph­eral neu­rop­athy (pain and tingling in the extremities), nor did they observe any dose-limiting side effects.  There was, however, one death among the patients treated with sub­cu­tane­ous Velcade.  The death, which was due to a heart attack, was determined to be unrelated to treat­ment.

The recommended dosing established in this Phase 1 trial is now being used in an ongoing Phase 3 trial of the three-drug regi­men. The dosing is as follows: 4 mg of Pomalyst on days 1 to 14, 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 for the first 8 treat­ment cycles and days 1 and 8 thereafter, plus 20 mg of dexa­meth­a­sone (10 mg for patients over 75 years) on days 1-2, 4-5, 8-9, 11-12 for the first 8 treat­ment cycles and days 1-2 and 8-9 thereafter.

Weekly High-Dose Kyprolis

Results from the initial phase of the so-called CHAMPION Phase 1/2 study of once-weekly (rather than twice-weekly), high-dose Kyprolis (car­filz­o­mib) plus dex­a­meth­a­sone for re­lapsed or refractory myeloma were also presented during the poster session (abstract 8594; poster [pdf] courtesy of Dr. James Berenson and Onyx).

A total of 27 patients were enrolled in the initial, dose-finding phase of the study. The patients had a median age of 64 years and had received a median of one prior ther­apy.  Most of the patients (85 per­cent) had been treated with Velcade as one of their pre­vi­ous ther­a­pies; Velcade and Kyprolis are both in the proteasome inhibitor class of drugs.

The poster does not mention how many of the patients in the study had received a stem cell trans­plant as one of their prior ther­a­pies.

The patients in the initial phase of the study received Kyprolis infusions once a week for three weeks out of each four-week treat­ment cycle.  After an initial starting dose of 20 mg/m² – which is also the standard starting dose for Kyprolis – patients sub­se­quently received doses of Kyprolis ranging from 45 mg/m² to 88 mg/m².  (The standard maximum dose of Kyprolis is 27 mg/m².)

In addi­tion, patients received 40 mg of dex­a­meth­a­sone once every week.

Patients stayed on treat­ment until disease pro­gres­sion or until they could no longer tolerate treat­ment.  The median length of treat­ment was 8.3 months.

The maximum tolerated dose of Kyprolis was established to be 70 mg/m².

Overall, 81 per­cent of the patients achieved at least a partial response to the weekly high-dose Kyprolis and dex­a­meth­a­sone ther­apy. The median time to response was just 1.6 months.

At the maximum tolerated dose, 93 per­cent of patients achieved at least a partial response.

The one-year pro­gres­sion-free survival rate was 75 per­cent.

The most common severe side effects included low platelet counts (7 per­cent), increased blood creatinine levels (7 per­cent), shortness of breath (7 per­cent), and upper res­pira­tory tract in­fec­tion (7 per­cent).  There were no deaths reported while patients were on treat­ment.

The researchers note that the Phase 2 portion of the trial is cur­rently recruiting patients; it is using the 70 mg/m²  dose of Kyprolis.

Smoldering Multiple Myeloma

The poster session last Monday featured several posters summarizing research seeking to more precisely determine which patients with smoldering myeloma are particularly likely to progress to active (symptomatic) multiple myeloma.  Such patients are often described as having “high-risk”, or “ultra high-risk,” smol­der­ing myeloma.

There is heightened interest in this topic due to results of a Spanish clinical trial that were published last year.  The trial found that actively treating high-risk smol­der­ing patients improved survival compared to a strategy of delaying active treat­ment until patients progress to symp­tomatic multiple myeloma (see related Beacon news).

Penn Update To The Mayo Clinic Risk Model

One of the posters related to smol­der­ing myeloma was from researchers at the University of Pennsylvania. It summarizes a new model for categorizing smol­der­ing myeloma patients based on their risk of pro­gress­ing to symp­tomatic multiple myeloma. The model is similar in structure and in the way it was developed to the well-known three-factor model developed by the Mayo Clinic  (abstract 8607; poster [pdf] courtesy of Dr. Adam Waxman).

The Penn researchers developed the new model partly in an attempt to validate the Mayo Clinic model, and partly to ensure that the new model is based on data from an ethnically diverse patient population.

The original Mayo Clinic model was developed based on data for patients seen primarily at Mayo's original Minnesota location.  The Penn model, in contrast, draws on data for patients seen within the University of Pennsylvania Health System, which is based in Philadelphia.

Like the original Mayo model, the revised Penn model makes use of three risk factors.  Two of the factors are the same as in the Mayo Clinic model – bone marrow plasma cell per­cent­age, and serum free light chain ratio – but the cutoffs for the variables used to classify patients differ between the two models.

Also, while the original Mayo model makes use of a patient's M-spike as its third factor, the Penn model uses a patient's albumin level.

Smoldering myeloma patients classified by the Penn model as having the highest risk of progressing to symp­tomatic myeloma have an esti­mated 81 per­cent risk of progressing within two years of their smol­der­ing diag­nosis.

Free Light Chain Assay And Chromosomal Abnormalities

Researchers from the Mayo Clinic also had findings of their own to report related to the risk of pro­gres­sion from smol­der­ing to symp­tomatic myeloma.  Mayo investigators presented a poster showing that results of the free light chain (FLC) assay in com­bi­na­tion with a patient's chromosomal ab­nor­mal­i­ties can identify smol­der­ing patients at a high risk for pro­gres­sion (abstract 8595; poster [pdf] courtesy of Dr. Jeremy Larsen).

The researchers used the chromosomal ab­nor­mal­i­ties t(4;14) and del(17p) as markers of a high risk of pro­gres­sion in smol­der­ing myeloma patients.

For patients who had at least one of the high-risk chromosomal ab­nor­mal­i­ties and an involved FLC level above 40 mg/dL, the two-year pro­gres­sion rate was 89 per­cent, compared to 14 per­cent in patients without a high-risk chromosomal ab­nor­mal­ity and an involved FLC level below 40 mg/dL.

(A patient's "involved" free light chain – either kappa or lambda – is the one that is elevated outside the nor­mal range.)

According to the researchers, patients with at least one of the two high-risk chromosomal ab­nor­mal­i­ties and an involved FLC above 40 mg/dL may be can­di­dates for early treat­ment strategies given their high risk of pro­gres­sion.

Gene Expression Profiling

A poster from researchers at the University of Arkansas summarized the results of study showing that gene expression profiling may be another tool for identifying high-risk smol­der­ing myeloma patients (abstract 8604; poster [pdf] courtesy of Dr. Rashid Khan).

Gene expression profiling simultaneously measures the activity of thousands of genes in a patient’s multiple myeloma cells.

The study made use of gene expression profiling results for 89 patients with asymptomatic multiple my­e­lo­ma – that is, smol­der­ing myeloma or mono­clonal gammopathy of undetermined significance (MGUS) – and 785 patients with pre­vi­ously untreated symp­tomatic multiple myeloma.

The results for these patients were then statistically analyzed to determine two gene expression profiles -- one that is typical of patients with asymptomatic multiple myeloma, and one that is typical of patients with symp­tomatic multiple myeloma.

Once they identified these two typical profiles, the researchers found that asymptomatic myeloma patients who have a gene expression profile closer to the typical symp­tomatic myeloma profile have a significantly shorter time to pro­gres­sion than asymptomatic patients with profiles closer to the typical asymptomatic profile.

Similarly, patients with symp­tomatic myeloma who have a profile closer to the typical asymptomatic my­e­lo­ma profile had longer survival times than symp­tomatic myeloma patients with profiles closer to the typical symp­tomatic myeloma profile.

Large Granular Lymphocytes

Findings from a study conducted at the National Institutes of Health (NIH) were summarized in another poster showing that char­ac­ter­istics of a smol­der­ing myeloma patient's large granular lymphocytes may be a marker for risk of disease pro­gres­sion (abstract 8597; poster [pdf] courtesy of Dr. Talib Dosani).

Large granular lymphocytes (LGLs) are a category of white blood cells that includes natural killer cells, natural killer T-cells, and cytotoxic T-cells.

The NIH researchers found that smol­der­ing myeloma patients who progressed to symp­tomatic myeloma had a different mix of LGLs in their blood 6 to 12 months before pro­gres­sion than other smol­der­ing patients.  Patients who progressed, for example, were less likely than other smol­der­ing patients to have LGLs that have the CD56 antigen, and do not have the CD57 antigen, on their surface.

Influence Of Metformin On MGUS Progression

Finally, researchers from Washington University in St. Louis presented a poster with results showing that  constant use of the diabetes medication metformin is as­soc­i­ated with a reduced risk of transformation from mono­clonal gammopathy of undetermined signifi­cance (MGUS) to symp­tomatic myeloma in patients with diabetes (abstract 1532; poster [pdf] courtesy of Dr. Su-Hsin Chang).

Constant metformin use was defined as filling a prescription for metformin an average of at least once every four months over a four-year period fol­low­ing a patient's MGUS diag­nosis.

The analysis was based on data from the Veterans Health Administration database.  The data included 2,003 patients with diabetes who were diagnosed with MGUS between October 1999 and December 2009.

The findings of this study are particularly interesting given those of a study that was recently published in the British Journal of Cancer (abstract).  The latter study found that, among multiple myeloma patients with diabetes, the use of metformin was asso­ci­ated with a reduced risk of death due to disease pro­gres­sion.

───────────────── ♦ ─────────────────

For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2014 coverage.