ASCO 2014 Multiple Myeloma Update – Day Four: Poster Presentations

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.
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For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2014 coverage.
Related Articles:
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- ASCO 2018 Update – Expert Perspectives On The Key Multiple Myeloma-Related Oral Presentations
- Researchers Shed More Light On Risk Of MGUS In Close Relatives Of People With Multiple Myeloma
Thanks for the article on poster presentations about MM from ASCO 2014. One poster that I found to be interesting was the last one, on the topic of the drug metformin, a treatment for diabetes, seeming to slow the progression of MGUS to MM, as shown by a retrospective study. From the abstract, because of the hypothesis that the insulin signalling pathway may be in involved in multiple myeloma, researchers checked a drug that inhibits diabetes, but that is not insulin. I suppose that this shows how our biochemical pathways are interdependent. Perhaps more research would determine whether or not diabetic myeloma patients should be taking metformin, rather than insulin, as a treatment! (However I see from a 'Wikipedia' article on metformin that it is contraindicated for patients with kidney problems.) This is an example of how probably only a really well informed myeloma specialist would be aware of this sort of research.