The 8th annual Summit of the International Myeloma Working Group (IMWG) took place in Madrid, Spain, from June 19th-21st. More than 100 of the world’s top myeloma specialists gathered to review the IMWG’s recent achievements, address problems, and set an agenda for the coming year’s research. Unlike the annual meetings of EHA, ASH (American Society of Hematology), and ASCO (American Society of Clinical Oncology) – huge conferences that focus on research results – the IMWG Summit is a true workshop meant to encourage lively discussion and brainstorming.
Pathogenesis of myeloma: current concepts
Dr. Leif Bergsagel (Mayo Clinic, Scottsdale, AZ) started the meeting with a presentation on new concepts in the pathogenesis of myeloma. He contends that myeloma only appears to be highly heterogeneous, but can actually be seen as only one of two types (hyperdiploid o r non-hyperdiploid) based on the oncogenes that drive myeloma to proliferate and the enhancer proteins that drive those oncogenes. Dr. Bergsagel believes the way forward is to target the enhancers. Panelists Drs. Wee Joo Chng and Bruno Paiva provided guidance for a discussion of possible treatment strategies and targets for new drugs.
VRd as standard of care for frontline therapy?
Dr. Brian Durie’s publication of the SWOG 0777 study, which showed VRd (Velcade + Revlimid + low-dose dexamethasone) was significantly more effective than Rd (Revlimid + dex), was the basis for a discussion of frontline treatment options. Is VRd significantly superior to VCd (Velcade + Cytoxan + dex) or VTd (Velcade + Thalomid + dex)? There are no head-to-head survival comparisons, so we don’t know the answer to this question. Some patients are able to do well simply with continuous Rd. If a triplet regimen is preferred, cost and availability of drugs can help discriminate which regimen to use. The currently-enrolling, multi-center, US cooperative group ENDURANCE trial compares frontline VRd to KRd (Kyprolis + Revlimid + dex), which may be a better option for high-risk patients. Since VRd is not available in much of the world and is very expensive, a consensus was reached that VRd is the current standard of care for frontline therapy where available.
Role of transplant in myeloma
Dr. Gordon Cook (University of Leeds, UK) accompanied by panelists Drs. Morie Gertz (Mayo Clinic, Rochester, MN), Pieter Sonneveld (University of Utrecht, the Netherlands), and Sergio Giralt (Memorial Sloan-Kettering, New York), stated his fervent hope that this would be the last time the role of transplant in myeloma would need to be validated with further large clinical trials or discussed at the IMWG meeting. Data from the three large transplant trials – IFM 2009, CTN0702, and EMN02/HO95 – overwhelmingly demonstrate the benefit of upfront transplant for almost all sub-groups of patients. All concurred that autologous stem cell transplant remains an important treatment and that not enough US patients are opting for it. A remaining issue in the US is the need to make it possible for patients to store stem cells for later use.
MRD assessment in myeloma
Drs. Hervé Avet-Loiseau (University of Toulouse, France) and Dr. Jesús San Miguel (University of Navarra, Pamplona, Spain) presented data from French and Spanish trials that incorporated MRD testing as a measure of treatment response and discussed the two competing methods of assessing MRD status. Areas of consensus were that while both NGF (next-generation flow) and NGS (next-generation sequencing) have their pros and cons, both methods are sensitive enough to detect one myeloma cell among one million sampled bone marrow cells, and that MRD negativity is a clear indication of superior remission duration and overall survival. There was also consensus that some patients who are MRD-positive after therapy can still have long survival because they have excellent immune recovery.
High-priority questions about MRD status need to be resolved in future trials: Should patients who are MRD- continue or discontinue therapy? Should therapy be changed for patients who are MRD+ ? When should MRD testing occur after treatment and how often should MRD status be monitored thereafter? All discussants agreed that MRD testing can become the official measure of treatment response in myeloma clinical trials.
Dr. Meletios Dimopoulos (University of Athens, Greece) accompanied by panelists Drs. Saad Usmani (Levine Cancer Center, Charlotte, NC) and Ken Anderson (Dana-Farber Cancer Institute, Boston, MA) led a discussion of therapy with approved and experimental monoclonal antibodies. As this new treatment area grows, many questions and some new answers are emerging. We are beginning to see that these antibodies produce late effects on the immune system, with deepening responses over time. While patients who were treated later in the disease course seemed to do better with Empliciti® (elotuzumab) than those treated at first relapse, it doesn’t seem to matter which relapse is treated with Darzalex® (daratumumab) + Rd, as responses are good at any time. There was consensus on these issues:
- Prior treatment history influences the choice of daratumumab combination therapy: patients who are refractory to a proteasome inhibitor should get daratumumab + Rd (DRd), and those who are refractory to IMiDs should get daratumumab + Vd (DVd).
- High-risk patients do better with daratumumab than with elotuzumab.
Questions that remain to be resolved are:
- What is the best drug partner for each monoclonal antibody?
- Should we combine monoclonal antibodies?
- How can we treat patients who are refractory to daratumumab?
- What kind of T-cells are activated by these drugs? Can we augment the ability of immune cells to persist over time?
- What is the proper sequencing of treatments? What should be used first, second, third or fourth?
Breakout sessions focused on four substantive topics requiring action plans, and IMWG members came armed with ideas. The chair of each breakout session presented the participants’ action plans the following morning.
Breakout 1: Drug Access and the Cost of Myeloma Care
Prof. Jean-Luc Harousseau (University of Nantes, France), who led the discussio, stated that this is a complex topic, made more difficult to resolve by the differences in healthcare systems, drug costs, and drug availability around the globe. While we know that drug pricing is only one part of soaring healthcare costs, drug costs are the fastest-rising component of the cost of care. The cost of combination therapies, particularly as we add new immunotherapies to the regimens, will ultimately be unsustainable. Even the costs of older drugs continue to rise. The major problem in the US is that Medicare and Medicaid are not allowed by law to negotiate drug prices, while countries with government-provided healthcare have limited resources. Lower-income countries can’t afford drugs, and in some places, there are problems more pressing than healthcare. Suggestions to improve this situation involved payors (insurance companies and governmental agencies), physicians, and patient advocacy groups. There was strong consensus that all stakeholders must sit at the same table – pharmaceutical companies, regulatory agencies, patients, legislators, and doctors.
Breakout 2: Bone and Imaging
Drs. Evangelos Terpos (University of Athens) and Elena Zamagni (University of Bologna, Italy), both of whom have published extensively on this topic, led a discussion of a research project proposal to include a comparison of DWI (diffusion-weighted imaging) MRI versus PET-CT to assess response and MRD status in an autologous transplant treatment trial. The endpoint of the trial would be the non-inferiority of DWI MRI as compared to PET-CT. They are hoping that DWI MRI is non-inferior to PET-CT because CT exposes patients to radiation, while DWI MRI does not. Moreover, DWI MRI images focal lesions very well, shows mixed patterns of diffuse and focal lesions, and shows what is necrotic bone and what is active disease. Results of the trial will enable the publication of standardized procedures for both imaging techniques. Doctors from 12 centers in North and South America and Europe will participate in the proposed trial.
Another project for the coming year is the creation for new IMWG guidelines for the management of myeloma bone disease. Issues to be clarified include the use of whole-body low-dose CT in lieu of whole-body x-ray survey as the standard bone assessment tool, the proper duration and spacing of bisphosphonate therapy, and the use of Xgeva® (denosumab) for a subset of myeloma patients with
Breakout 3: Immunotherapy
Drs. Irene Ghobrial (Dana-Farber Cancer Institute) and Adam Cohen (University of Pennsylvania, Philadelphia, PA) presented questions that must be resolved as we await further data from clinical trials, particularly with checkpoint inhibitors and CAR T-cells.
For checkpoint inhibitors, the questions are:
- Which patients benefit from these therapies?
- Should we adjust the response criteria to include measures of immune status?
- When should these agents best be used? In the newly diagnosed or relapse setting?
- What are the unique toxicities that occur when these agents are combined with IMiDs?
For CAR T-cell therapies, the outstanding issues are:
- Response rates have varied from 44% to 100% in different trials.
- Most of the follow-up is short.
- Cytokine release syndrome remains a concern.
- Can CAR T-cell therapy be combined with checkpoint inhibitors or other immunotherapies?
- Will CAR T-cell therapy take the place of allogeneic transplant?
We will certainly know a lot more a year from now when we have data from the ongoing trials.
Breakout 4: Smoldering Myeloma
Drs. María-Victoria Mateos (University of Salamanca, Spain) and Shaji Kumar (Mayo Clinic, Rochester) have both pioneered studies of treatment of smoldering multiple myeloma (SMM) and have been involved in trying to best define the criteria for high-risk SMM.
Dr. Kumar presented their group’s consensus on outstanding issues:
- A new risk model for progression of SMM needs to be created.
- Sensitive imaging can reveal that up to 35% of patients thought to have SMM actually have active disease.
- We need to identify which patients are at a lower risk of progression so we don’t intervene too early.
- We need to demonstrate that early intervention does not cause treatment-related mortality and preserves quality of life.
- We need to identify genetic and microenvironment triggers for disease progression.
- Dr. Ray Comenzo (Tufts University Medical Center, Boston, MA) announced that he is leading a clinical trial for patients who have lambda light chain-type SMM to determine the risk of progression to AL amyloidosis.
How to Treat High-Risk Myeloma
Dr. Usmani addressed the issue of how best to treat high-risk myeloma, for which there is no current standard of care. He outlined current challenges and what we know so far:
- Ultra-high-risk myeloma can be characterized by two or more adverse cytogenetic features, a high number of circulating plasma cells, and failure to respond to therapy.
- While Velcade, Revlimid, and Pomalyst are currently available therapies that can help overcome some of the high-risk cytogenetic abnormalities, new treatments are needed.
- Current trials with KRd + daratumumab ; venetoclax; selinexor; the BCMA drug conjugate; CAR T-cells; and new monoclonal antibodies may offer some promise.
Dr. Usmani’s summary of trials and his call for new approaches was the perfect introduction to the meeting’s last presentation: a summary of the current portfolio of phase III myeloma clinical trials by Dr. Vincent Rajkumar (Mayo Clinic, Rochester). Among the trial highlights are the following:
- Six randomized trials now include MRD testing.
- Some trials are looking at the need for, and duration of, maintenance therapy among patients who are MRD-positive and MRD-negative.
- Two trials, one in the UK and one in Spain, are aimed at treatments for frail patients.
- A trial in the UK is using risk-adapted therapy after stem cell transplant depending on patients’ MRD status.
As the IMWG Summit drew to a close, Dr. Robert Kyle commended the meeting’s organizers for their leadership, for the meeting’s content, and for their eagerness to listen to a younger generation of doctors in the IMWG. The modest and wise Dr. Kyle advised them always to “Hire the young person who is smarter than you are.” We can rest assured that the future of the myeloma brain-trust is secure.
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