Insight into Drug Therapy and Stem Cell Transplant Options for Relapsed Myeloma Patients

<p>A set of guidelines for treating patients with relapsed and refractory multiple myeloma published by the International Myeloma Working Group may not aid&nbsp;researchers in identifying ideal treatment paths for those with relapsed and refractory disease until more genomic data has been gathered.</p>

Philip McCarthy, MD

A set of guidelines for treating patients with relapsed and refractory multiple myeloma published by the International Myeloma Working Group (IMWG) guides general oncologists in making treatment decisions. As treatment options have grown both more promising and complex in the last two years, with the approval of at least 4 new drugs in 2015 alone, and with patients surviving, on average, for 10 years following diagnosis, decisions over which treatment to use have grown more complicated.

The IMWG recommendations published in February inLeukemia,1however, may not aid researchers in identifying ideal treatment paths for those with relapsed and refractory disease until more genomic data has been gathered.

To that end, physicians can look to results from the CoMMpass trial, a genomic study of 1,000 individuals with multiple myeloma being conducted by Baylor University and the Translational Genomics Research Institute (TGen) (NCT01454297), with interim results expected to be presented at the annual meeting of the American Society of Hematology (ASH) this December in San Diego.

Effective New Options Make Treatment Complex

“For induction, we have a pretty good algorithm; we’re moving toward triplet therapy with a proteosome inhibitor and immune-modulatory drug (IMiD),” said Philip McCarthy, MD, professor of oncology and internal medicine at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

“But for relapsed patients, we have to look at whether they are eligible or ineligible for an autologous stem cell transplant, because they could potentially get a second transplant, which makes it a little more complicated,” added McCarthy, a co-author of the February recommendations.

“The recommendations are a bit of a laundry list for the poor community oncologist who treats 40 different cancers. Those with myeloma may be less than 5% of his case mix, and he has so many choices that we try to help guide him,” said Joseph Mikhael, MD, professor of medicine at the Mayo Clinic in Phoenix.

"For example, we do have evidence some of these drugs work better in those with high-risk disease. And drugs like monoclonal antibodies have really minimal side effects, and so are more feasible to combine together with other drugs. Or perhaps the patient lives two-and-a-half hours away, and it’s hard to give them carfilzomib twice a week intravenously, when we have a different drug we could offer them,” added Mikhael, who co-authored another set of guidelines from IMWG last December on the use of stem cell transplants in myeloma patients with relapsed or refractory disease.2

Recent Papers Meta-Analyze Clinical Trials

The mere existence of many alternatives does not mean that oncologists cannot simply repeat the treatment that produced the first remission; the guidelines suggest that “in patients who experience a high-quality, prolonged response with minimal toxicity to initial therapy, re-treatment can be considered if they have obtained at least a 6 to 9 months’ treatment-free interval.”

Thereafter, the guidelines get somewhat more complicated. The paper analyzes reports of clinical trials and discusses a multitude of options and a dizzying array of combinations of old drugs, including thalidomide, cyclophosphamide, and prednisone, as well as newer agents, like pomalidomide, and other treatments.

The article also discusses allogenic and autologous stem cell transplants (ASCT), recommending an autologous transplant for patients who have not had an ASCT in the first-line setting before, or who had a durable response to a prior ASCT.

The authors also recommend “allogeneic stem cell transplantation be discussed in eligible patients with poor prognostic features, preferably in the context of a clinical trial.” According to the December report of the stem cell consensus conference, only 3% to 5% of patients who relapse following an autologous transplant go on to receive an allogenic transplant; the February recommendations suggest this may be due to graft-versus-host disease or other forms of treatment-related mortality.

Two other recent articles also performed a meta-analysis and a review of the literature for treating relapsed myeloma patients.3,4

Anticipating CoMMpass Trial Interim Results

Researchers have not yet determined what distinguishes the fraction of myeloma patients who survive for 20 years. However, an important clinical trial, “Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile” (CoMMpass), is investigating the role of genomics.

“The expected survival in this cohort is in the range of a decade, and we expect 20% to 30% of patients to live two decades,” said Jonathan Keats, PhD, director of bioinformatics at the Translational Genomics Research Institute (TGen) in Phoenix, which is collaborating on the study.

“Our goal is to identify genetic biomarkers that predict response to specific therapies. We’re looking at genes of significance numbering around 20 right now. With a year of follow-up data for this cohort we hope to be able to identify which treatment regimens are most effective given a certain genetic phenotype at baseline,” Keats added.

The trial organizers intend to correlate molecular profiles and genomic tests on bone marrow aspirates from 1,000 patients at baseline with primary and secondary outcomes at 1- and 5-years follow-up, and survival at 8 years. Each of the arms will receive an immunomodulatory agent, a proteosome inhibitor, or both, and physicians can also add additional therapies, and/or transplants. Interim results from the study are expected to be announced at ASH later this year.

New Genomic Analysis for Relapsed Patients

“Seventy percent of patients do poorly, but 30% do fine. In one case we’ve conclusively showed what sets the two groups of patients apart. Tumor protein 53 has been implicated in myeloma, but the hypothesis has been that if the patient has two hits, they’re at high risk. We’ve shown that the biology of a tumor suppressor does matter, if they do not fit the two-hit hypothesis, in other words, if they have just one hit. Clinically, we just test for one hit,” explained Keats.

Experts say that genetic analysis should be part of the standard of care for myeloma patients, and when a patient relapses, the genetic expression of the cancer should be re-analyzed.

Some scientists have determined that 15% of myeloma patients have a high-risk gene signature, so oncologists should initially do a cytogenetic analysis looking at chromosome abnormalities, and fluorescence in situ hybridization (FISH). It’s still not done everywhere, but it should be, and it’s getting better,” said McCarthy.

“And when patients relapse, they definitely need to be FISHed again at a minimum, because of clonal infidelity. You can see changes that pop up that were not there on the original diagnostic sample. If you look at the new ones, the old ones may be gone. It’s not just one cancer all the time,” he added.

References:

  1. Laubach J, Garderet L, Mahindra A, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.Leukemia.2016. 30(5);1005—1017.
  2. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma.Biol Blood Marrow Transplant.2015. 21(12): 2039—2051.
  3. Liu L, Zhao N, Xu W, et al. Pooled analysis of the reports of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma.J Hematol Oncol.2016. 9(1):54.
  4. Zou Y, Ma X, Yu H, et al. Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma: a meta-analysis of 37 trials. [Published online July 21, 2016]Oncotarget.doi: 10.18632/oncotarget.10768.