BY JACK AIELLO The IMF’s International Myeloma Working Group (IMWG) membership consists of 170 Myeloma experts from around the world.  They meet twice a year just before ASH and EHA (European Hematology Association) in order to maximize attendance and minimize cost. In Milan, 85 members met to focus on the IMWG goals to develop research initiatives and guidelines brainstorming for the Myeloma community. The following are my notes from these two days of meetings, discussions and collaborations (but may contain some errors or incomplete data). Feel free to contact me jackaiello@comcast.net for any questions. For a nice video summarizing the many IMWG results, look here. As always, please check with your healthcare provider about this information.

OPENING LECTURES

 Dr. Orfao discussed how the  flow cytometry test for minimal residual disease shows that the depth of response can improve overall outcomes. The benefits are that the flow cytometry test is applicable to 95% of patients, more than the PCR and next generation sequencing methods. The test also has fast, same-day results.The limitations are that you need a fresh sample (less than 24 hours old). There have been improvements in standardization of 8 key markers including: CD 138, 27, 19, 45, 56, 117 and an automated software tool for analysis risk and better sensitivity. Open questions include:

1. How do we incorporate standardized flow testing in routine practice?
2. Is 10 ^-5 (1 in 10K) enough sensitivity?
3. Is flow cytometry testing effective in  MGUS detection?
4. Can you determine MRD via peripheral blood?

 Dr. Rajkumar discussed diagnostic criteria for myeloma. For smoldering myeloma, 50% of patients don't progress, but ultra-high-risk smoldering myeloma patients (10-15% of smolderers) are likely to progress within two years. The new criteria for truly active myeloma vs. smoldering myeloma including non-CRAB features is:

1. Greater than 60% myeloma plasma cells (90% of patients with this have progression within 2 years)
2. FLC ratio greater than 100 (80% of patients)
3. More than 1 focal lesion on an MRI (70% of patients)
4. Possible future biomarker criteria includes: 95% clonal plasma cells by flow cytometry, circulating plasma cells, del17p, 1q+, t4;14, M-spike >3 and more than 10% of plasma cells being myeloma cells.

 Dr. Palumbo discussed the treatment of elderly/geriatric myeloma patients. He looks at age, activity level and the Charlson level (a co-morbidity index) which are tied to survivability. He suggests that a Revlimid-dex combo may be best for most patients.  

GROUP PRESENTATIONS/DISCUSSIONS

• Dr. Vincent Rajkumar moderated a discussion of the role of melphalan in the treatment of elderly myeloma patients. The benefits according to Dr. Leleu is that melphalan is inexpensive and effective. But with several possible adverse side effects that impact patients in the long-term, doctors discussed if and how melphalan should be used now that newer therapies are available.
• Revlimid had better results in the melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance in a trial as well as the FIRST trial which compared the combination of melphalan- prednisone-thalidomide with lenalidomide-dexamethasone, given for 18 months and then stopped, or given continuously until disease progression. 
• In the same Dr. Palumbo trial, melphalan- predisone-lenalidomide and melphalan-prednisone arms had similar results. Melphalan may not work well with iMiD drugs (like thalidomide and lenalidomide). Bortezomib- melphalan-prednisone is better than bortezomib-thalidomide-prednisone.

• They need a trial to show whether stem cell transplant is better than conventional therapy for the fit elderly using Revlimid as the new backbone drug.
• Drs. Siegel & Palumbo showed that in trials where 100% of patients harvested stem cells in preparation for a transplant, only 60% are able to go to late SCT due to comorbidities so EARLY SCT makes more sense the planning for LATE SCT at time of relapse.
• Transplants are A standard of care in the US, but THE standard of care in rest of the world.
• There are four active trials that have some issues: 1) A trial in Italy to study Revlimid-dex/melphalan-prednisone-Revlimid vs. tandem transplants. This study is not using any proteasome inhibitors. 2) A Revlimid/Cyclophosphamide-Revlimid vs. Revlimid with tandem transplants. This study has no proteasome inhibitors. 3) The IFM and Dana Farber Institute study to look at fixed maintenance therapy vs. limited time maintenance therapy. (what is the problem with this study? 4) The European Myeloma Network 2 using Velcade-cyclophosphamide-dex or Velcade-melphalan-prednisone vs. Velcade-cyclophosphamide-dex plus transplant. This study is looking at quality of life. (What is the problem with this study?)
• There are several trials to study tandem transplants. 1. A study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) to study tandem transplants vs. Revlimid-Velcade-dex 2. One vs. two transplants in a new European Myeloma Network 2 trial 3. A HOVON (Dutch group) study showing that tandem transplants may have overall survival benefit.
• There are four active trials, several of which have issues 1) A trial in Italy to study Revlimid-dex/melphalan-prednisone-Revlimid vs. tandem transplants. This study is not using any proteasome inhibitors. 2) A Revlimid/Cyclophosphamide-Revlimid vs. Revlimid with tandem transplants. This study is also not using proteasome inhibitors. 4) The European Myeloma Network 2 using Velcade-cyclophosphamide-dex or Velcade-melphalan-prednisone vs. Velcade-cyclophosphamide-dex plus transplant. This study is looking at quality of life. The issue with this trial is having a consistent quality of life definition. 4) An active study with no issues is the IFM and Dana Farber Institute study looking at fixed maintenance therapy vs. limited time maintenance therapy.
• For very high-risk patients, tandem auto-allo trials may be needed.

• Dr. Durie moderated a discussion of new and active therapies
• Dr. Stadtmauer described immunotherapeutic approaches including monoclonal antibodies, allo approaches, vaccines, and modified T-cells.
• Dr. Russell discussed the measles virotherapy. Patients need to be measles antibody negative in order for it to be effective.
• Dr. Richardson discussed monoclonal antibodies like elotuzumab that targeted the CS1 protein, daratumamab and SAR that target CD38, PD-1 and PDL1 blocking the microenvironment, the panobinostat use in the PANORAMA1 trial. Panobonistat-velcade-dex showed 4 month progression-free survival benefit and better complete remission but more adverse side effects including GI problems, fatigue and low platelet counts. It was effective in high-risk patients. In the PANORAMA2 trial, changing the panobinostat dosage improved the adverse side effects. He discussed the need for a new trial structure to rapidly assess the viability of the drugs. They noted that trials should not be limited to relapsed/refractory patients. He also noted that there needed to be better "standard of care" comparators. He noted that data collection differentiated between relapsed/refractory and 1-3 relapses plus minimal residual disease as a regulatory end point.

•  Dr. Pieter Sonneveld discussed genetic risk stratification, looking at risk factors t 4;14, del 17p, and 1q+ in conjunction with patients who are transplant eligible (TE) and not transplant eligible (non-TE). He began by noting that since Carfilzomib (Kyprolis) is effective against t 4;14 and Pomalidomide is effective for del 17p that the regimen of Car-Pom-dex might be an excellent standard treatment for high-risk myeloma patients. Then specifically for each risk factor he proposed the following guideline: 1) t4;14: For transplant eligible patients, use a Proteasome Inhibitor (PI) indiction followed by SCT followed by PI maintenance (since Rev not so effective for this risk factor. For non-transplant eligible patients, use Velcade-Mel-Prednisone or Rev-dex (Author note: Don’t understand why Rev is being used here); 2) Del 17p: For transplant eligible patients, consider standard treatment, possibly an allo SCT, PI’s and newer monocloncal antibodies (mAb’s). For non-transplant eligible patients, use standard treatment plus monoclonal antibodies  3) 1q+: Standard treatment was recommended for both arms.

• Dr. Dimopoulus identified a need to find early markers for possible renal injury in MGUS and smoldering myeloma - possibly Cystatin-C (cys-c), NGAL, and serum Free Light Chain test.  NOTE: Urine Free Light Chain test is not reliable and should NOT be used ever.
• Dr. Terpos discussed bone management. Whole-body CTs are better than MRI because they detect more lesions in less time. NOTE: MRI does NOT detect lytic lesions but does detect focal lesions