The 58th Annual Meeting & Exhibition of the American Society of Hematology is upon us, starting in San Diego on December 3rd and running through December 6th. This year, there are more than 700 myeloma-related presentations, with 114 oral abstracts, and 573 posters covering sessions on Saturday, Sunday, and Monday.

Genetic and molecular focus

About half of the oral abstracts deal with genetic and/or molecular analyses and “pre-clinical” laboratory-based studies. The huge emphasis on molecular studies ends up reaffirming what we already know: genetic changes in myeloma are numerous and complex. I will discuss details during an upcoming IMF teleconference. The true driving, or key, mutations linked to disease progression and to resistance to current therapies remain elusive. The large number of mutations frustrates efforts to target any one (or few) of them. An interesting abstract from the Heidelberg team (Abstract #235) somewhat negates the idea of sequential clonal evolution by showing that the genetic abnormalities and clones are present at diagnosis.

New therapies

The first question on patients’ minds is what about new therapies? Well, there are not a lot of really new treatment reports this year, but several interesting points. Firstly, Abstract #487 presents a completely new treatment: combining the AIDS (HIV) treatment, a protease inhibitor Nelfinavir (NFV) with the proteasome inhibitor bortezomib (Velcade®) to overcome Velcade resistance. This group from St. Gallen, Switzerland reports a 65% response rate, suggesting a potential new important option for refractory patients. I’m sure many will want to hear the full details at the meeting.

Another, relatively new treatment is Venetoclax (VEN), a BCL-2 inhibitor which induces apoptosis (myeloma cell death), especially for patients with the t(11;14) or “good risk” (high BCL-2; low BCL-XL; low MCL-1) type of myeloma. In Abstract #488, a 40% response rate is reported with Venetoclax alone. In Abstract #975, a 68% response rate is reported for the combination with Velcade/ dexamethasone: both very promising.

Trials with existing drugs

Drugs which we have heard about before include Selinexor (nuclear export inhibitor), Pembrolizumab (PD-1 [check point] inhibitor), and daratumumab (Darzalex® [“dara”]). The results with Selinexor/dexamethasone (Abstract #491; the STORM trial) are quite encouraging, including responses in so-called “penta-refractory” patients (refractory to five agents: Revlimid®, pomalidomide, Velcade®, Kyrpolis®, and daratumumab). This is important since this satisfies the FDA category of “unmet need” for possible FDA approval.

At ASH 2016, updates will be presented for the POLLUX trial (daratumumab/ Revlimid/ dexamethasone (Abstract #489 and Abstract #1151); the CASTOR trial (daratumumab/ Velcade/ dexamethasone (Abstract #1150 and Abstract #3313); the Pembrolizumab trial (Abstract #490); and a trial using dara/ pomalidomide/ dexamethasone (Abstract #492). All continue to show promising results for these active combinations. An interesting note is that the use of dara by SC (subcutaneous) injection (versus IV) is reported (Abstract #1149). This may reduce early toxicity and provide helpful convenience over time.

There has been much interest in CAR T-cells as a type of immunotherapy, and several abstracts provide updates, including Abstract #974 (anti-CD19); Abstract #1147,  and Abstract #1148 (anti-BCMA).

There are a number of reports about what are now “older” combinations, such as Kyprolis with Revlimid/ dexamethasone (Rd) or thalidomide/ dexamethasone (Td) or pomalidomide/ dexamethasone (Pd), as well as maintenance regimens, all of which I will discuss on the teleconference.

Role of MRD testing

As expected, there is again a strong emphasis on the role of minimal residual disease (MRD) testing. Abstracts address questions about the use of NGS (Next-Generation Sequencing); NGF (Next-Generation Flow); ASO-PCR (allele-specific oligonucleotide- polymerase chain reaction); PET/CT (positron emission tomography/computed tomography) scanning; combined Freelite + Hevylite; and new blood-test approaches. Again, I will provide details on the teleconference, but some especially important points. Clearly, more work is required before MRD testing can be used for clinical decision-making. The Spanish team in several abstracts (Abstracts #373; #375; #801; #2078; #3283; #4442; and #4454) illustrate the advantages of NGF testing, including: identification of HRSMM (high-risk smoldering multiple myeloma); identification of patients with MDS (myelodysplastic syndrome), a poor risk group at diagnosis; ability to study myeloma cells in the blood; comparison with NGS in bone marrow and blood; as well as the potential for sequential immune profiling. A Boston group looks at single-cell analyses of myeloma cells in the blood (so-called “liquid biopsy”) (Abstract #800). The Pavia team from Italy shows results from MRD testing in amyloidosis (Abstract #3261).

From Melbourne, Australia, details are presented of DNA analyses in blood showing RAS mutations (Abstract #3280). Several teams presenting at ASH 2016 focus mainly or exclusively on NGS or ASO-PCR, and others evaluate the role of PET/CT scanning. Both the Bologna and Little Rock teams especially emphasize the need for PET/CT as a part of serial monitoring to detect extramedullary relapse. An interesting abstract (Abstract #3260) from Denmark shows that high uptake on a PET scan correlates with poor-risk genetic features.  

“Clinical pearls”

As usual, there are many “clinical pearls”— little bits of information which help with day-to-day patient treatment decisions:

-  The IFM team again shows that serial Freelite testing is excellent to track light-chain responses versus urine testing (Abstract #376). The Bologna team really shows the role of PET/CT testing (Abstract #992), and the Heidelberg team, the value of WBLD-CT (whole-body low-dose computed tomography) (Abstract #4468).

-  Several groups assess the role of autologous stem cell transplant as frontline treatment and salvage therapy, for example in the setting of older patients (over 75) (Abstract #3453).

-  There will be a full session at ASH 2016 on the treatment of amyloidosis, including the value of carfilzomib at relapse (Abstract #645) and the benefit of dara in the treatment of cardiac amyloidosis (Abstract #4525).

-  A rather unique abstract (Abstract #3257) assesses diet and the risk of MGUS (monoclonal gammopathy of undetermined significance). The group from the University of Iceland shows that a traditional “fish diet” in early life was very good, whereas a heavier meat diet in later life was a poor risk factor.

So, you can see, there is quite a range of topics this year. Life in the myeloma community goes forward strongly in many and diverse ways, all leading to better outcomes for patients. More details to come! 

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I was diagnosed in 1993 with Multiple Myeloma, SMM or EMGUS was not invented yet. So instead of a highly recommended bone marrow transplant procedure, (no stem cell transplants were invented yet), I opted for 5 cycles (7 days self injected shots) over five months as treatment, and achieved complete deep remission for 23+ years. What ever happened to the possibilities of Interferon as a front line defense?

Good question! Interferon – what we call “alpha interferon” – was indeed used as a maintenance but was ultimately set aside because although it prolonged remissions, overall survival was not improved. Nonetheless, a few patients, especially those with IgA myeloma, DID benefit, so I still keep it in mind for the occasional patient. Obviously, in 2016/2017 much more active immune therapies are available.

Hope this clarifies!
Brian Durie

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