After a couple days change of pace, time to return to “myeloma 101.” Except suzierose’s column this week is very technical–more graduate school level. But don’t let that detour you! This weekend our very own Myeloma Cinderella finds more morsels of hope for high risk multiple myeloma patients:
Part One of Disease vs Therapy
Is it the Disease or the Therapy that is Determinative of Risk?
One of the things Pat consistently tells readers is that we should not read too much into what any of the median statistics say. After all, he rightly admonishes, we are not a statistic. This sage advice is even more pertinent when it comes to all the variables that have been identified as risk factors with myeloma.
(HELLO!! ..waving both hands in the air here, with 24 months stamped in shape of a big dog on profile.)
In my very first post, we looked at what we know from long-term studies in large trials. Where Avet Loiseau, identified what variables have been associated with a 75% chance of 8 year survival. Did you fit that group? If not, recall that only 20% of over 500 patients in the sub-analysis did. Let’s look now–in this first of a 3 part series–at what risk means as it relates to trial outcomes in terms of the disease being called standard or high risk multiple myeloma (HR-MM).
Ola Langren, one of the top 3 myeloma experts in the world at NIH, delivered a symposium at ASH 2012 where he discussed how factors associated with risk have been defined by the trial outcomes. And so we tend to look at myeloma, the disease as having multiple risk factors. Dr. Langren contends that risk changes with the therapy used.
For example, myeloma patients with t (4:14) were categorized as high risk prior to proteasome inhibitors becoming a staple of therapy but today many of these formerly high-risk patients, have PFS that approaches that of the patient profile without t (4;14). IOW’s this factor associated with high risk does not show up as an independent risk variable in statistical sub-analysis as predictive of poor outcomes when the proteasome inhibitor, bortezomib, is part of the therapeutic regimen.
Did their disease change or did the therapy change?.
Let’s look at three ASCT trials and see whether they support Dr. Langren’s contention. In these trials all of the patients received high-dose chemotherapy followed by their own stem cells being re-infused (ASCT) some had maintenance others did not.
In 2005, Chang published an article in Bone Marrow Transfusion, entitled Genetic risk identifies multiple Myeloma Patients Who Do Not Benefit from Autologous Stem Cell Transplantation. Chang provides a table with OS and PFS based on genetic abnormalities that shows genetic abnormalities in high risk patients are determinative of outcome. He then concludes that patients with 13q deletions, t(4;14) or p53 deletions and especially those with two or more of the above genetic variants have dismal outcomes from ASCT and should be candidates for innovative treatments.
This study caught my eye since, in 2011 despite having ‘the big dog,’ both my community oncologist and the Mayo nephrologist recommended ASCT as the best therapy regimen option, for me.
Ok, cytogenetic abnormalities, Chang concludes, trump all other variables when it comes to patients who should receive a ASCT.
Is that true? Well, let’s examine outcomes in a few large ASCT trials. In particular, let’s look at 2 trials considered as benchmarks today for outcomes in patients who receive ASCT.
The first benchmark ASCT large study is BMT-CTN 0102 by Krishnan (Lancet 2011) showing 3 year PFS&OS rates of 45 vs 75% respectively for tandem transplants. (710 patients) And, the second is CALGB 10104 by McCarthy (NEJM 2012) showing 46% vs 27% for median time to progression, for single HD- ASCT with and without lenalidomide, respectively. (460 patients)
So, despite a significant delay (regardless of B2M level) in time to progression with lenalidomide maintenance, tandem outcome rates were better than single ASCT with and without maintenance. These benchmarks are what guide clinicians when they recommend HD therapy followed by re-infusion of your own stem cells. They tell us why clinicians in the field of myeloma recommend tandem HD-ASCT and why the experts recommend maintenance following HD-ASCT.
Now what happens to these numbers when we look at just the patients in these same trials who had cytogenetic abnormalities. Does, that change the outcomes, as Chang concluded in 2005?
Seven years after Chang, at ASCO 2012 Scott (University of Oregon) presents data on a subset of 252 high risk ASCT patients. Dr. Scott shows a 2 yr overall PFS and OS rate of 47% and 72% in this cohort of patients from the aforementioned benchmark trials. Sixty percent of the patients relapse within 18 mos post ASCT and there is reduced PFS in patients with del 17p (26%), chromosome 1 (27.4%), del 13q (22%) vs. 47%. And overall survival is also reduced from 72% to 52% with chromosome 1 and 46.2% if you had both chromosome 1 and del 13q. Yep, the high-risk cohort had markedly poorer outcomes.
So, pretty much seven years later, 2 benchmark trials and a sub-analysis of high risk myeloma (HR-MM) patients from the benchmark trials are consistent with what Chang concluded in 2005 about patients with cytogenetic abnormalities having worse outcomes when it comes to overall survival following ASCT. Scott’s cohort analysis in 2012 of HR-MM ASCT patients for the most part affirms the conclusions Chang made in 2005.
But then we have a notable ASCO 2012 highlight, data of Jonathan Kaufman from Winship Cancer Institute at Emory. Dr. Kaufman, at ASCO 2012 presents survival outcomes following the use of the combination of lenalidomide, bortezomib and dexamethasone (RVD) with maintenance in a small group of patients with high-risk myeloma (HR-MM)
Kaufman’s data does not parallel that of Scott or Chang. We are still talking ASCT patients. Granted, Kaufman’s data is a very small group of HR-MM patients, only 37, with high risk features [del17p (n=16), t(4;14) (n=1), t(14;16) (n=4) by FISH/CTG. But his outcome numbers tell a different story.
Following induction, and post ASCT, 22% of patients have a sCR and CR, and then following maintenance the numbers almost double for sCR to 41%. That is highly significant, particularly in a group of HR-MM ASCT patients who were projected to have dismal outcomes based on the cohort from two very large ASCT trials (Scott’s data 2012) as well as prior Chang’s data in 2005.
For some reason, almost half the HR-MM patients in Kaufmann’s trial are achieving sCR. Kaufman concludes, that early ASCT followed by RVD consolidation in high risk patients results in an increase in CR with each stage following induction, post-ASCT and maintenance.
What could account for this? What changed for the patients with HR-MM in the last trial?. Kaufman’s data is consistent with Ola Langren’s contention that risk is determined by therapy not the disease.
Perhaps, Ola Langren is on to something.
In part 2 of this series , we will look at the changes in therapy and what could account for these differences, based on what Dr. Paul Richardson at Dana Farber shared during ASH 2012.
Are you looking up those drug regimens used in those benchmark trials?
Wow! Highly technical post and homework, too! I read through this several times. Each time I learned and noticed something different. My question for suzierose this week: So don’t keep us in suspense. Is it better for high risk patients to use ASCT therapy or skip-it?
Have a great weekend all! Feel good and keep smiling! Pat