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The Most Important Questions Facing Myeloma Experts in 2016

Close to one hundred members of the International Myeloma Working Group (IMWG) gathered in Copenhagen from June 7th to 9th, just prior to the European Hematology Association (EHA) meeting, for the seventh annual IMWG Summit. This important and prestigious meeting allows myeloma experts from around the globe to discuss pressing issues and to set an agenda of publications, clinical trials, and advocacy efforts for the coming year.

08.17.16

Close to one hundred members of the International Myeloma Working Group (IMWG) gathered in Copenhagen from June 7th to 9th, just prior to the European Hematology Association (EHA) meeting, for the seventh annual IMWG Summit. This important and prestigious meeting allows myeloma experts from around the globe to discuss pressing issues and to set an agenda of publications, clinical trials, and advocacy efforts for the coming year.

The meeting began with lectures based on unanswered questions facing myeloma specialists in 2016. Each presentation was followed by a lively discussion. Break-out groups based on these questions followed the general session. Following are the questions under discussion, the sub-questions that must be addressed in order to answer the larger questions, and the steps that will be taken going forward.

Are we ready to screen the general population for MGUS? 

Dr. Sigurdur Kristinsson

  • Dr. Sigurdur Kristinsson is about to commence the Black Swan-funded iStopMM trial in Iceland, where everyone aged 40 or older will be screened for MGUS.
  • The study will demonstrate if earlier detection leads to improved overall survival, if quality of life is improved or impaired, if mass screening is cost effective, and if it is possible to identify common genetic mutations among those who develop MGUS.
  • Based on the results of Dr. Kristinsson’s iStopMM trial, we will know if it’s feasible and valuable to screen the general population for MGUS.

What is the role of MRD detection in myeloma?

Dr. Bruno Paiva

  • CR (complete response) without MRD status is not predictive of remission duration or survival. Studies have clearly demonstrated that MRD testing is informative at all stages of treatment.
  • Many questions remain: What is the exact definition of “MRD-negative?” How should it be used to guide therapy? Will it be used to help accelerate development of novel drug combinations? Should it be an endpoint in clinical trials? What are the optimal time points for serial measurement? How should patients who are MRD-positive be treated? Should patients who are MRD-positive but are in an MGUS state, with no active disease, be treated?
  • These questions must be answered through clinical trials with sensitive MRD assays.
  • New International Myeloma Working Group Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma have been accepted for publication in The Lancet Oncology.

What are the optimal imaging methods
for myeloma?

Dr. Elena Zamagni

  • In lieu of whole-body x-rays, which are of limited value, whole-body low-dose CT (WBLDCT) is the proposed standard of care in Europe for staging and diagnostic work-up.
  • Both PET/CT and whole-body MRI (WBMRI) are useful at diagnosis, especially combined with cytogenetics. MRI is best for detection of diffuse bone marrow involvement.
  • For monitoring after therapy, PET/CT is best. Standard MRI is not good because of a high false-positive rate.
  • To assess smoldering myeloma (SMM), MRI is the standard of care. A new Black Swan research project for SMM was proposed using diffusion-weighted-imaging (DWI) MRI administered every six months for two years.
  • PET/CT must be standardized by lesion type, area, and number of lesions.
  • An IMWG paper on PET/CT will be completed in the near future.

How do we best use new immune therapies in myeloma?

Dr. Joseph Mikhael

  • At this time, we have many questions that must be addressed in clinical trials.
  • Currently, the approved immunotherapies (Empliciti and Darzalex) are approved for use later in the disease course.
  • In clinical trials Darzalex is demonstrating efficacy throughout the disease course and in all types of myeloma patients regardless of their risk status.
  • We need to better define the role of Empliciti.
  • The cost of these therapies in combination with other drugs is staggering.
  • It’s still too early to formally recommend CAR T-cell therapy for myeloma. Targets are still being explored, such as T cells, NK cells, SLAM F7, and B-cell maturation antigen (BCMA), combined with either auto or allo transplant.
  • Checkpoint inhibitors (e.g., pembrolizumab, nivolumab) do not have single-agent activity, but are proving themselves in combination. Checkpoint inhibition is “a revolution in cancer treatment.”
  • Remaining questions include:
  • Should immune therapies be used up front, in relapse, as maintenance, or throughout the disease course?
  • Which drugs are they best combined with?
  • Which patients will benefit from each type of therapy? Will there be “boutique” drugs that are effective in small classes of patients, such as venetoclax for patients with t(11;14) myeloma?
  • Could the immune therapies be more cost-effective if combined with cyclophosphamide?
  • Could immune therapy affect the host immune system adversely and make it harder to fight a relapse?

Can we cure myeloma?

Dr. Bruno Paiva and Dr. Shaji Kumar

Dr. Paiva presented for Dr. San Miguel, who was delayed coming from the ASCO meeting in Chicago.

  • The Spanish researchers’ approach to curative therapy for high-risk smoldering myeloma (HR SMM) uses six cycles of Kyprolis + Revlimid + dexamethasone (KRd) followed by high-dose therapy and autologous stem cell rescue (i.e. what is commonly called “autologous stem cell transplant” or ASCT), two cycles of consolidation therapy with KRd, and two years of maintenance therapy with Rd. (This is the CESAR trial, which is already accruing patients in Spain.)
  • Mayo Clinic, Landgren at the NCI, and the Spanish group found that there is a survival benefit with early treatment of HR SMM.
  • We now have the tools to achieve deep responses and to evaluate treatment efficacy: MRD assessment via PET/CT and immuno­phenotypic (next-generation flow cytometry) or molecular (next-generation sequencing of DNA) testing.
  • High-risk patients as defined by cytogenetics, extramedullary disease, early relapse, and primary refractoriness should be identified and treated early and aggressively.
  • Myeloma is the only cancer that is not routinely treated early.

Dr. Kumar presented the Black Swan Research “Cure Trial.”

  • The IMF Black Swan Research Initiative’s approach to cure for HR SMM is four cycles of KRd + Darzalex followed by either ASCT or four more cycles of KRD + Darzalex, followed by four cycles of KRd + Darzalex consolidation, and maintenance therapy for one year with Kyprolis, low-dose Revlimid, and Darzalex given every other month.. (This is called the ASCENT trial, and it is has not yet opened for patient accrual.)
  • SMM might be the right time to cure myeloma before there is a high proportion of malignant plasma cells with significant genetic mutations.
  • If we treat myeloma early and cure it, we will make it less expensive to treat myeloma.
  • Unanswered questions are:
  • Are we striving to achieve complete clonal deletion or a return to the MGUS signature?
  • What is the risk of harm to the patients?
  • What is the cost of care?
  • What is the impact on quality of life?
  • Is there enough time to identify and treat high-risk SMM if the disease is aggressive?
  • How do we square treatment of asymptomatic disease with the treatment-associated risks of Kyprolis and stem cell transplant?
  • Should we be thinking about treating MGUS and not waiting for SMM?

How do we approach treatment of patients who are in complete response but are still MRD-positive?

Dr. Vincent Rajkumar

  • About half of the patients in CR after stem cell transplant are MRD-positive.
  • Is it right to provide the results of MRD testing without having answers to the question of what to do about it?
  • Until clinical trials determine the best approach for a patient in CR who is MRD-positive, we should not do anything unless there is disease progression. We don’t want to harm patients by over-treating them.
  • With good immune recovery after treatment, many patients’ immune systems will control reemergence of the remaining clone. A recent report from the PETHEMA group shows that evidence of normal plasma cell recovery and normal B cell maturation was associated with improved survival outcomes irrespective of MRD status.
  • Genomics can help determine the stability or instability of the remaining clone.
  • There needs to be a consensus about how to counsel patients who are MRD positive so that they do not go from doctor to doctor trying to figure out if they need further treatment.

When should we use genome sequencing in myeloma? Does the genetic signature of HR SMM support early treatment?

Dr. Gareth Morgan and Dr. Ola Landgren

Dr. Morgan:

  • Gene sequencing technology is robust and is cheaper, faster, and more accurate than FISH (fluorescence in situ hybridization) testing. Gene sequencing would enable creation of a more effective International Staging System than FISH currently does.
  • We MUST segment myeloma into different sub-types using gene sequencing, and then find and target the driver mutations: KRAS, NRAS, and MYC.
  • Gene copy number loss and loss of both alleles is most important in calculating risk.
  • We need to form a consensus on the proper sequencing panel to use worldwide and then abandon FISH.

Dr. Landgren:

  • The NF-kappa B pathway is implicated in the pathogenesis of myeloma. The more mutations in this pathway, the lower the level of complete response (CR).
  • Up to 50 percent of HR SMM patients had mutations in NRAS and KRAS genes.
  • The lack of significantly recurring mutations in patients with HR SMM is suggestive of treatment-responsive disease biology, and supports the notion of early treatment of HR SMM.
  • Dr. Landgren is in the process of sequencing the DNA and RNA of another 100 patients with HR SMM, and there is Swedish data on 100 MGUS patients who developed MM and 100 who did not. He will explore the mutational landscapes of these patients.

Should we be doing transplant up front or delaying it until relapse in this era of novel therapies?

Debate between Drs. Sergio Giralt and Sagar Lonial

Pro: Dr. Giralt

  • The magnitude of benefit with early transplant is 41 months of progression-free survival (PFS) versus 26 months in the IFM/DFCI trial that randomized patients to transplant or no transplant following induction therapy with VRD. The IFM data at 4 years of follow-up shows a survival benefit of 13 months for upfront transplant.
  • There is, however, a three-fold increase in the rate of death from second primary malignancy in those who had transplant in this trial. Nine out of 100 patients died from transplant-related mortality, and anything over 1 percent is not acceptable.
  • The symptom burden is cumulatively worse for patients who do not have early transplant.

Con: Dr. Lonial

  • Not every patient must have an up-front transplant. Therapy should be tailored for each individual patient. The doctor must evaluate what is the best tool to give a patient at any given time.
  • Don’t ask a transplant doctor if patients should have upfront transplant.
  • The IFM DFCI trial does not yet have overall survival data (only the IFM data is available at this time, and it still needs further follow-up).
  • If you attained MRD with or without transplant, the IFM data tells us that survival thus far is the same.
  • There is no data to demonstrate that patients who are MRD negative after induction therapy will benefit from transplant.
  • We are seeing a signal for higher mortality in the transplant group in the IFM/DFCI trial.

And the results of the debate? Dr. Giralt won the case for early transplant by a large margin.

New combinations, new issues: how to use them, how to develop them?

Drs. Moreau, Durie, Palumbo, and Rajkumar

Statement of the problem:

  • There are now six classes of agents to treat myeloma, with at least 30 combinations available. What is the optimal option for each patient? We don’t know.
  • We lack biomarkers to determine or predict efficacy.
  • We do not have cost-effectiveness comparisons for various regimens.
  • We currently have no well-defined surrogate markers of cure.
  • There is a lack of funding for investigator-initiated clinical trials.
  • Gene sequencing is not widely available.

We need to develop the following clinical trial strategies to:

  • Prevent progression from SMM to MM.
  • Define the best triplet therapy for relapse that is cost effective.
  • Define molecular sub-types of myeloma that respond better to one drug than another.
  • Determine if modifying therapy based on response or MRD detection will improve outcome.
  • Establish MRD negativity as a surrogate for cure with either NGF or NGS and PET, sequentially performed and negative at several time points.
  • Use MRD testing to figure out when to stop treating patients.
  • Create new IMWG guidelines on safety, efficacy, and cost of treatment.
  • Formally address quality of life (QOL) with a validated patient questionnaire.
  • Involve patients in the design of clinical trials and a QOL assessment tool.
  • Work with pharma and regulatory agencies to define optimal trials to answer strategic questions and get drugs approved.
  • Create a global database about first relapse and treatment outcomes.  

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