Controversies in Myeloma: The Who, When, and Why of Treatment

The recent expansion of treatment options for patients with multiple myeloma (MM) has introduced new opportunities for redefining the goals of therapy. At the 2017 ASH Annual Meeting, several myeloma specialists convened to discuss “Controversies in Myeloma,” including the optimal time to start therapy, the goals of therapy, and the decision between continuous or sequential therapy.

The Value of Molecular Remission

Novel combinations of newly approved agents have led to an increase in the number of patients who can achieve minimal residual disease (MRD) negativity. Given the new opportunities for this type of response, Faith E. Davies, MBBCh, MD, deputy director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock, reconsidered the goals of MM therapy.

“Clearly, my aspirational goal when I treat patients is achieving cure, but potentially, my everyday goal for a patient is trying to induce a long-term, disease-free survival with normal quality of life,” Dr. Davies said. “Within that setting, that question is, what does inducing a molecular remission add?”

Dr. Davies reviewed recent large trials (including IFM 2009, Myeloma IX, POLLUX, and CASTOR) that have confirmed the prognostic significance of MRD, as MRD negativity is associated with better survival outcomes in both transplant-eligible and -ineligible patients. The most recent data have “put this issue to bed,” she said. “We can all agree that MRD negativity is associated with a better prognosis, [but] what does this mean for routine clinical practice, and should we use MRD testing routinely?”

The controversies and questions about the practical use of MRD monitoring in the clinic start with a basic question about the definition of MRD negativity, Dr. Davies noted. “When we are thinking about MRD assessment techniques, we clearly have a number of different technologies [like flow cytometry and next-generation sequencing], but importantly as well, we have a number of different sensitivities [10-4, 10-5, and 10-6],” she said. “Regardless of the technology we use, we have to know its limitations, [which can include] sample processing, sample quality control, and standardization across labs.”

The optimal timing and number of MRD assessments is also unknown. In the transplant setting, timepoints for monitoring are guided by the stages of therapy; the timing is less clear for transplant-ineligible patients. Again, Dr. Davies said, the answer depends on the desired depth of response. In general, MRD assessments conducted at multiple timepoints throughout treatment can provide “a better picture” of a patient’s disease.

Defining the role of MRD monitoring and optimal sensitivity of assessment in practice depends on what clinicians want to use the results for: forming a prognosis or guiding treatment decisions. “If we are just using MRD as a simple prognostic factor, using [a threshold of] 10-4 might be okay, but to use it as a treatment decision tool, we may need to use a lower level,” she explained. “We shouldn’t be reporting MRD as a yes or no binomial; we need to be reporting the actual level of MRD negativity.”

Also, Dr. Davies noted, the jury is still out on whether MRD detected in the bone marrow “gives us the full picture.” The role of anatomic or functional imaging, in combination with MRD assessment, is still undefined, but research has suggested that it is possible to have low MRD per flow cytometry and have evidence of lesions on imaging, she explained. “However, when MRD assessment is performed to a deeper sensitivity, none of those patients had active lesions,” she added, further highlighting the importance of using the lowest possible detection level.

Despite these limitations, Dr. Davies contended that MRD negativity should be the ultimate goal of treatment – and it doesn’t matter how that goal is achieved. “Another controversy has been surrounding the treatment effect,” she said. “If you are able to achieve MRD negativity, does it matter how you get there? Is there a difference as to whether you’ve taken an intensive approach to become MRD negative or not?” Results from the IFM 2009 study that compared lenalidomide, bortezomib, and dexamethasone with and without transplant “clearly showed that regardless of the treatment arm, those patients who were MRD negative achieved a longer progression-free survival (PFS),” she reported. Findings from the POLLUX and CASTOR trials, which enrolled patients with relapsed disease, also support this assertion: Patients who were treated with triplet combinations and achieved MRD negativity had better survival than those who did not.

“My own personal conclusion [about] the controversy is we should be aiming for molecular remission, because it’s the prerequisite for a cure,” Dr. Davies concluded. “However, we do need to understand the MRD cells that we are trying to eliminate in more detail.”

MRD is a valuable tool, she contends, but measuring it is not enough. “Learning about those cells is going to teach us how we can therapeutically manipulate them so we can induce a cure,” Dr. Davies said. For instance, recent evidence has suggested that the microenvironment is enabling these treatment-resistant cells. “We need to figure out how we’re going to get rid of this microenvironment protection because, as those cells continue [to survive] and mutate, the inevitable is going to happen – patients are going to relapse.”

“We can all agree that MRD negativity is associated with a better prognosis, [but] what does this mean for routine clinical practice, and should we use MRD testing routinely?”

—Faith E. Davies, MBBCh, MD

Too Long, Too Short, or Just Right?

Heinz Ludwig, MD, from the Wilhelminen Cancer Research Institute in Vienna, Austria, posed the question of treatment duration among patients with MM, which has become a crucial issue in the myeloma treatment landscape.

Dr. Ludwig started by reviewing the fundamentals of treatment decision-making for patients with MM: patient-specific characteristics (i.e., age, fitness, and comorbidities) and disease-specific characteristics (i.e., cytogenetic profile and rate of disease progression). “When we go back 10 years, let’s say in 2007, the treatment paradigm was quite straightforward in MM: We had induction therapy, transplant in young patients, fixed-duration therapy (6, 9, or 12 months) for older patients, less-intense therapy for frail patients, and a couple of treatment cycles for relapsed patients,” he said.

“Now, we have double transplantation, consolidation therapy, maintenance therapy, continuous therapy in transplant-ineligible patients, and prolonged therapy in relapsed patients. It is not only which therapy, but how long should we use the therapy?”

In addition to patient- and disease-specific characteristics, the risks and benefits of continuous therapy also need to be considered in the decision-making process. The benefits, Dr. Ludwig explained, are straightforward: With longer-duration therapy, clinicians aim to achieve deeper, longer-lasting responses, thereby improving PFS and rates of MRD negativity.

“With the use of immunomodulatory agents and monoclonal antibodies, we may augment the patient’s anti-myeloma immune system, which may prove quite important,” he said, “but there are also inherent limitations and disadvantages [of this approach].” This treatment may lead to an increase in the development of treatment-resistant mutations, for example, or the risk for selection of more aggressive clones. Of course, he added, increased toxicity and costs also are concerns with longer-duration therapy.

Given the disadvantages of prolonged therapy, who is most likely to benefit from continuous therapy?

Reviewing evidence from recent large, international trials, Dr. Ludwig reached the following conclusions:

  • Double autologous hematopoietic cell transplantation is a good option for transplant-eligible patients (even those with high-risk disease), according to results from the EMN02/HO95 study, followed by consolidation therapy. (U.S. studies have not shown such an advantage to a second transplant.) The role of maintenance therapy was more controversial, with maintenance associated with improved PFS and overall survival (OS) in patients with standard-risk disease, but only PFS for those with high-risk disease.
  • For transplant-ineligible patients, long-fixed duration of carfilzomib, lenalidomide, and dexamethasone (18 cycles) induced high rates of MRD-negativity and long PFS and OS, but again, the OS benefit of continuous therapy after induction was less clear-cut.
  • Patients with relapsed or refractory MM had high rates of response and improvement in the quality of response when treated with continued therapy, according to results from the MM09 and MM10 trials.

He also placed importance on discussing the patient’s actual willingness to accept more intensive or prolonged therapies. “If you suffer from aggressive disease [and have] significant symptoms, of course your willingness to accept aggressive and prolonged therapy is quite pronounced,” he reasoned. “This is less pronounced if you are without symptoms or have standard-risk disease that is well controlled. And, of course, if you are older or frail, you are not interested in continuous therapy.”

Dr. Ludwig concluded that “the benefit is biggest in the [standard-risk] group.” However, given the limited and conflicting data, he pointed to the need for more definitive research. “What we need is a randomized, prospective comparison between regimens with different treatment durations and identification of predictive factors for better selection for patients who will likely benefit or not,” Dr. Ludwig added. “This would allow restriction of therapy to those who benefit and avoid overtreatment.”