INTERNATIONAL MYELOMA WORKSHOP 2015, ROME, SEPT 23-26, 2015
BY JACK AIELLO
This is my second time attending an International Myeloma Workshop (IMW) meeting which is held every 2 years. This 4-day meeting consists of nearly 3000 attendees, mostly hematologists (70%) with smaller numbers of pharma reps (15%), researchers, and nurses. This 15th IMW meeting contrasts with the first one held in 1987 with 34 attendees (including Drs Robert Kyle and Brian Durie).
Major Discussion Topics
Economic Concerns (aka Drug Costs) versus Innovation and Quality of Care
This topic was the initial lecture and was referenced throughout the four days. Dr. J.L. Harousseau indicated the health industry has two challenges: Increased Life Expectancy and Increased investment for Innovations, which make it very difficult to reign in prices. However, US prices for Revlimid ($13.7K/cycle), Velcade ($6.6K/mo) and Thalidomide ($4.9K/mo) seem outrageous. So many questions: What is a fair price from Pharma? How do Health Organizations such as the FDA assess the Incremental Cost Effectiveness Ratio (ICER = Cost/QALY, which is Quality Adjusted Life Years)? Is it the physician's responsibility/burden to consider costs when suggesting treatment choices? Should payers cover the cost to treat a disease rather than cost to pay for a drug?
Perhaps Minimum Residual Disease (MRD) measurements will help guide treatment courses as well as treatment costs (e.g. should MRD- mean a shorter duration of maintenance?). So much more needs to be done.
Minimal Residual Disease
Speaking of MRD, it was also discussed throughout the meeting. NGF (Next Generation Flow, 2x8-color tubes, although I also heard 10-color) requires a fresh bone marrow sample while NGS (Next Generation Sequencing) can use frozen samples. Both seem to have 10 [-6] accuracy with NGF costing less. One meta-analysis from Dr. N. Munshi examined 21 studies which used MRD (less accuracy than 10 [-6]) to examine 500 patients considered by blood tests to be in a CR (Complete Response). It turns out that one-third of these patients were MRD+. MRD- showed better progression free survival (60/36mo), overall survival (Not reached/82mo) and 5yr overall survival (78/60%). Remember, all these patients were in complete response. It is therefore obvious that MRD- is a much better goal than CR.
There are fewer breaking news announcements at this meeting compared to ASH and ASCO. More instructional presentations are provided such as revised International Myeloma Working Group criteria for multiple myelom/smoldering myeloma a reminder that MRI detects focal lesions better than lytic lesions.
Newly Diagnosed Multiple Myeloma Young Patients
- Dr M. Attal broke news that the French part of the IFM/DFCI DETERMINATION Clinical Trial shows better progression free survival (PFS) for early autologous transplant, so auto transplant will likely remain the standard of care (more details at ASH).
- Dr A. Jakubowiak said of his Phase II trial of 75 patients comparing Kyprolis, Revlimid and dex plus or minus auto transplant, that the transplant arm improved complete response by 40 points and is trending toward better progressio-free survival and overall survival results. He noted that the optimal induction was probably three drugs, but perhaps monoclonal antibodies will make it 4.
- Dr H. Einsele showed that allo transplants for high-risk patients provided benefit. Dr M. Cavo said that 40-50% of patients fail to achieve complete response after transplant, thus the need for consolidation which increases CR by 10- 20%.
- Dr. P. McCarthy said that Velcade maintenance is particularly beneficial for patients with renal failure and/or deletion 17p, while Dr S. Giralt said that 70% of US patients received Revlimid maintenance after a stem cell transplant.
Newly Diagnosed Multiple Myeloma Elderly Patients
Dr S. V. Rajkumar said For patients older than 75, just give 20 mg of dex per week whereas Dr P. Richardson explained we need to "throw a net" over the multiple myeloma to catch evolving clones. In the near future, this net might be all oral combination of Rev-Ixazomib-dex. And we might even add a monoclonal antibody: Elotuzumab, Daratumumab, or SAR (Isatuzimab). They suggested that we apply the best possible treatment at all stages of treatment. Dr. A. Palumbo has published data on developing treatment adjustments for Fit-Unfit-Frail patients, which can be scored at www.myelomafrailtyscorecalculator.net developed by the International Myeloma Working Group.
Relapsed/Refractory MM Patients
There were talks on treating relapsed/refractory myeloma patients including those with extramedullary disease and serious adverse events as well as providing palliative care.
- Dr K. Anderson summarized that immunomodulatory drugs (iMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), checkpoint inhibitors, vaccines and CAR-T (the latter 4 being Immunotherapy) will all play a role to make immune systems more effective. He noted that monoclonal antibodies against CD38 might be safer than CAR-T for CD38 since CAR-Ts are so powerful and CD38 is found elsewhere on other cells besides the myeloma cells. "BCMA might be a favorite target."
- Dr E. Stadtmauer updated the UPenn CD19 CAR-T for 10 myeloma patients: So far one patient has had a long, great result, one relapsed, others are too early to say.
- Finally Dr J. Zonder spoke about bi-specific Antibodies (bsAb) designed to be both a receptor and signaler on an myeloma cell or perhaps receptors between myeloma and natural killer cells. He said "It's never been a better time to be a mouse with multiple myeloma." I can't wait to see all this translated to the clinic.
Pharma companies sponsored 90 minute symposiums within the IMW agenda.
- Novartis speakers discussed HDAC inhibitors including Panobinostat studies, indicating increased efficacy when combined with proteasome inhibitors and immunomodulatory drugs as well as probably future mAb's and CAR-T's.
- Amgen featured talks on Proteasome Inhibitors (***although I missed this section due to AMN meeting...discussed later).
- Celgene focused talks on future role of iMiDs.
- Janssen (Daratumumab) sponsored talks on mAb's. Dr. S. Lonial said "mAb's are risk-agnostic." Dr. P. Moreau talked about IRR events (Infusion-Related Reactions) for Daratumumab: nasal congestion, throat irritation, cough, chills so give pre-meds to avoid these symptoms. If IRR occurs, stop the infusion and resume at half-speed drip. By the way, Daratumumab can actually add to IgG results so SPEP may be less accurate resulting in a new blood test called DIRA. A better blood test might also be needed for other monoclonal antibodies.
Other interesting agenda item were presenters assigned to debate sides of certain topics:
- Should Therapy change for High Risk versus Low Risk patients?
- Should MRD/Imaging or FISH/Age guide treatment?
- Dr. O. Landgren pointed out the best responses to Kyprolis/Revlimid/dex are at 5.5 cycles so perhaps the "standard" 4 induction cycles should be 6. Or maybe MRD can correlate treatment with number of cycles. Or perhaps we should automatically add 2 cycles after reaching MRD- (up to 8)?
- Dr P. Sonneveld said that age reflects a patient's condition - The FISH test should indicate a patient's prognostic risk before treatment and then the MRD test should indicate a patient's condition after treatment. He noted that a patient who is MRD negative without FISH cytogenetic abnormalities does better than a MRD negative patient with FISH cytogenetic abnormalities.
Other debates included: Can we cure MM by 2020? [Dr B Barlogie said we already have.] Should newest agents be combined or given in sequence? I find these debates entertaining, and of course, there's no one right answer. Perhaps when we get to Precision Medicine there will be.
(1) Described by Dr P. Forsberg for newly diagnosed myeloma patients: Kyprolis/dexamethasone (2 cycles) ->
and Biaxin-Revlimig-dex (BiRD) (2 cycles) [-> SCT] -> R maint 10mg. Induction results so far overall response rate (ORR) 90% (64% >= Very Good Partial Response) which is great considering half the patients were High-risk. Some cardiac events at the Kyprolis 56mg/m2 dose (rather than 45 mg/m2).
(2) Dr A. Spencer discussed a phase I PMd (Pom-Marizomib-dex) for relapsed/refracotry myeloma patients with prior Revlimid, Velcade and half Carfilzomib. Interim results at the end of cycle 1: 10 of 14 patients showed some response (so response is rapid) and ORR 62% which has increased to 71% with Phase II dosage. He also indicated that oral Marizomib (another proteasome inhibitor) will be entering Phase I.
1) A 5-drug induction regimen ACVDL (Adriamycin, Cytoxin, Velcade, Dex, and Rev) showed good ORR (80%) using lower Rev (15mg) which may benefits pts with ASEs from Rev 25mg.
2) An early Phase 1/2 study with another CD38 monoclonal antibody MOR202 in relapsed/refractory meyloma patients is showing single agent responses and will be combined with other drugs in future trials.
Finally, the IMW agenda also included presentations by Susie Novis-IMF and Daniel Auclair- MMRF. Speaking of the IMF, preceding the IMW meeting, I attended a meeting of the IMF's Global Myeloma Action Network (GMAN). Perhaps 15 countries, mostly European, had myeloma advocates there to discuss their own organizations and learn from each other. While we in the US face exorbitant drug prices, we have it much better than many countries with limitations on drug access, fewer myeloma experts and practices, strong government controls and more.
(***) I mentioned that I missed the Takeda sponsored event because the IMF invited me to attend a two-hour meeting of the AMN (Asian Myeloma Network). I found it quite fascinating to watch myeloma docs from China, Japan, South Korea and other countries report on current Asian trials and develop new ones. I learned that IgD multiple myeloma has twice the occurrence in Asia as compared with the US and the average age of MM at diagnosis is 62 years old in Asia, compared with 69 years old in the US.
PS. I try to be accurate with my note taking but material is presented quickly. If you have any questions, please feel free to email me firstname.lastname@example.org.