The International Myeloma Working Group Summit is held annually each June, between two of the year’s largest cancer conferences, the American Society of Clinical Oncology (ASCO) in Chicago and the European Hematology Association (EHA).
Report from the 2018 Summit of the International Myeloma Working Group
The ninth annual Summit of the International Myeloma Working Group (IMWG), held just prior to the annual meeting of the European Hematology Association (EHA), took place June 11–13 in Stockholm, Sweden. The Summit convened 100 of the world’s top myeloma experts to review works in progress, set the agenda for future myeloma research projects, and learn from those who are exploring new frontiers in the biology and/or treatment of this disease.
CRISPR in Myeloma
At the Summit’s opening reception and dinner, guest speaker and out-of-the-box thinker Dr. Arun Wiita of UC San Francisco’s myeloma research lab, presented a talk entitled “CRISPR in Myeloma: More Than Just Knockouts.” He introduced the IMWG members in attendance to his cutting-edge work with CRISPR in myeloma cells, presenting new intellectual territory. Dr. Wiita’s lab is currently the only one in the world investigating the use of CRISPR to edit genes in myeloma cells. While we think of CRISPR as a means to delete “bad” genes from DNA, Dr. Wiita opened our eyes to other possibilities that CRISPR technology can offer.
Dr. Wiita is currently experimenting with CRISPR to make therapies more effective and less toxic. Rather than cutting out genetic sequences from DNA, he is bringing other material to the DNA in myeloma cell lines to turn on and off certain genes and thereby increase or decrease myeloma cell surface receptors. This work is just beginning and remains, as Dr. Wiita put it, “challenging.” Thus far, he has determined that the technique his lab is using targets the myeloma cells with great specificity, that it is highly “penetrant,” meaning it reaches 100 percent of the myeloma cells, and that it holds great potential for the future.
Imagine a world where CRISPR could be used to insert a “death switch” to turn off MGUS, or where oncogenes that turn on myeloma cells could be deleted, or where therapy could be truly personalized to each patient’s myeloma cell genetics.
A packed agenda greeted the IMWG members early Tuesday morning. First up was Dr. David Murray, a pathologist and head of Mayo Clinic’s Special Protein Lab. He predicts that use of mass spectrometry, a rapid, consistent, and highly sensitive means to detect monoclonal protein in the blood and urine, will not only change how myeloma is diagnosed and monitored, but will change the diagnostic criteria for myeloma.
Dr. Murray is gathering data from myeloma patients at Mayo Clinic, and currently has over a thousand patient samples. He is finding that “mass spec” is able to detect MGUS consistently at lower levels than the current techniques, serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE).
Mass spectrometry also allows the pathologist to identify relapse earlier than existing techniques, and to determine if the monoclonal protein seen in relapse is from the originally diagnosed myeloma clone or from a new clone. Unlike SPEP and IFE, mass spectrometry can also determine if a new spike seen after therapy is an oligoclonal spike (a sign of profound immune response) or residual disease.
Do I Need a Transplant?
Dr. Vincent Rajkumar and Yelak Biru (IMF Board member, support group leader, and myeloma patient) improvised a discussion between a reluctant newly diagnosed patient and his doctor about whether and when to have a transplant. Yelak gave Dr. Rajkumar a delightfully difficult time. Their dialogue did raise some important and unresolved questions. We are awaiting longer-term overall survival (OS) data from the IFM 2009 trial of RVd (Revlimid® + Velcade® + dexamethasone) with or without transplant followed by Revlimid maintenance, and from the DETERMINATION trial at Dana-Farber Cancer Institute in Boston (formerly the US half of the IFM trial) so that we can finally answer the question of the need for transplant and whether there is an advantage to doing it after induction or at first relapse.
Early Relapse: Treatment Decisions
Fortunately, there are many treatment options for patients in early (first) relapse. Dr. Philippe Moreau gave an excellent overview of the available options, with an emphasis on the many combinations available to patients who are refractory to Revlimid. He noted that the patient’s frontline therapy guides everything that follows. Points of consensus include the following:
- We need to determine the optimum sequencing of drugs, which is still not known.
- Access to treatments is limited in most of the world.
- We need to know more about disease biology in various patient subgroups.
- A decision must be made whether to treat at biological relapse (when there are no symptoms but the monoclonal protein level goes up) or at symptomatic relapse.
- Patient choice and patient convenience have to be incorporated into any treatment decision.
- The patient’s side effects to first therapy must guide treatment choices at relapse.
- There is no one regimen that works best for every patient.
MRD in 2018: Open Questions
The IMF’s Chief Medical Officer, Dr. Joseph Mikhael, used an automated response system (ARS) to poll the audience about their opinions on MRD-related issues. Consensus was reached on the following:
- MRD testing is an important new endpoint for clinical trials,
- The test must be able to detect one myeloma cell in one million cells tested (10-6) for the result to be meaningful, and
- If a patient is MRD-negative, this does not mean that the patient needs no further treatment.
However, some of the responses highlighted areas we simply don’t have definitive answers for and in which further research is needed. Does a positive MRD result mean that the patient should continue with current therapy or change therapy? Which MRD test should be used: NGF (next-generation flow cytometry), NGS (next-generation DNA sequencing), or both?
Dr. Alberto Orfao provided an overview of MRD testing methods and challenges. While NGF and NGS test results correlate well, each method has its limitations and benefits. Even at a sensitivity level of 10-6, the problem remains that some patients relapse. Further sensitivity would be better, but is thus far not achievable.
Since myeloma can grow both inside and outside of the bone marrow, and both NGF and NGS are bone marrow studies, PET/CT scanning must accompany present methods of MRD detection. Is detection of circulating tumor (myeloma) cells (cTCs) in the blood a better (more complete and less invasive) option for detecting MRD? The answer is more complicated than a yes or no. Dr. Orfao has found that all cases of myeloma detected in the bone marrow do not show up in the blood, so testing for cTCs cannot replace the bone marrow studies. However, all myelomas with cTCs in the blood do show up in the bone marrow, meaning that circulating tumor cells are a surrogate marker for myeloma in the bone marrow. Since it is much easier to take a blood sample than a bone marrow sample, patients could be tested for cTCs; if they have them, there is clearly myeloma in the marrow, so doing an MRD bone marrow test is not necessary. If there are no cTCs in the blood, the patient would undergo bone marrow biopsy to provide a sample for further MRD testing. Remaining MRD questions include the following:
- The optimal time points for MRD testing,
- How long MRD must be sustained to establish that a patient is cured,
- When maintenance therapy can be safely stopped,
- How therapy should be tailored to MRD status.
There are many ongoing clinical trials in Europe that are designed to answer these questions. In the U.S., the MRD consortium is gathering the necessary data to submit to the FDA for approval of MRD testing as an endpoint in clinical trials.
Approaches to CAR T cell and Other Immune Therapies
Dr. Yi Lin (Mayo Clinic, Rochester, Minnesota) led a panel of researchers in immunotherapies, including Drs. Adam Cohen (University of Pennsylvania, Philadelphia), Jesus Berdeja (Sarah Canon Cancer Research Institute, Nashville, Tennessee), and Suzanne Trudel (Princess Margaret Hospital, Toronto, Canada). Dr. Lin gave an overview of many current CAR T-cell products currently in myeloma clinical trials and the complex interplay of the many factors influencing their efficacy. Thus far, all trials include heavily pretreated and poor-risk patients. Deep responses are being achieved at the price of toxicities, which have been uniform across the various studies.
There was discussion about the 11.8-month median progression-free survival (PFS) in the bb2121 CAR T-cell study presented by Dr. Noopur Raje (Massachusetts General Hospital, Boston) at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO). While some felt that the PFS was disappointing, others pointed out that in a population of patients with aggressive disease and no other options for therapy, remission with a median of one year was an excellent result. As Dr. Raje said, “This is not a curative strategy, but the results were remarkable in that patient population.” The next steps will include determining if it is necessary to do combination CAR T-cell therapy to improve response, and if so, which drugs might best be combined. All of the panelists concurred that myeloma will be the next disease with an approved CAR T therapy.
Dr. Trudel, who presented data at the 2017 annual meeting of the American Society of Hematology (ASH) on the antibody-drug conjugate (ADC) GSK2857916, believes that we need more information on CAR T-cell therapy toxicities and which patients are most at risk. She suggested that for patients who cannot wait the requisite 2 to 4 weeks for their T cells to be engineered and expanded before treatment, or for those who are less able to withstand the toxicities of CAR T-cell therapy, an ADC might be a better option.
New Drugs in Myeloma: Access & Pricing in Europe
The day’s last session was the reality of a long-desired goal: a groundbreaking roundtable that brought together representatives of the pharmaceutical industry (one each from Janssen and Celgene) with a myeloma expert (Dr. Moreau), a health ministry representative (Niklas Hedburg, Swedish Health Authority), a health economist (Catherine Le Gales, Ministry of Health, Paris), and the head of the Swedish Blood Cancer Association patient advocacy group (Lise-Lott Eriksson). The hope was that the members of the roundtable could present different perspectives on drug access problems in Europe and, perhaps, begin to offer some solutions to this global problem using the European model. European governments provide healthcare to their citizens and must decide which drugs to cover based on varying criteria of safety, efficacy, overall value, and cost.
Perhaps the roundtable can be best summarized by a graphic shown by Ms. Eriksson, which demonstrated the pathway through the Swedish bureaucracy that must be followed to get a drug approved and funded. What appeared was an astoundingly dense and complex web of lines, boxes, and arrows that left us wondering whether to laugh or cry. The entire landscape of drug pricing and access is equally complex, and varies not only from country to country, but sometimes also among regions within a country where local government authorities negotiate with pharmaceutical firms, search for ways to establish value-based pricing, and struggle to find funds to pay for drugs without raising taxes to insupportable levels. With prices established in the U.S. (where there is no cost control or government negotiation) and with the cost of combination therapies now at $280,000–$450,000 per year, we have a critical problem with no easy solutions.
In his working group report from the breakout session on Access and Pricing of Drugs in Europe the following morning, Dr. Jean Luc Harousseau, who moderated both the roundtable and breakout session, urged IMWG members to advocate for change in current policies, provide advice in their own countries to health authorities, design clinical trials with the benefit of the patient in mind, educate other doctors, and define assessment criteria for health authorities to use in evaluating drugs.