Experts Discuss Strategies for Boosting Frontline Responses in Myeloma

Saad Z. Usmani, MD

During the past decade, the treatment of multiple myeloma has significantly changed, enabling more patients to achieve deep and durable responses.^1,2 Several new drug classes with highly effective therapies have emerged, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors.²

Goals of Therapy for Symptomatic Patients

Greater understanding of tumor biology has also enabled the use of novel treatment combinations and spurred new drug development, particularly as more cytogenetic abnormalities have been discovered.² The heterogeneity of multiple myeloma has led the National Comprehensive Cancer Network to recommend risk-adapted approaches that individualize treatments to improve patient outcomes.² OncLive^® convened a Peer Exchange^® panel with moderator Keith Stewart, MB, ChB, and other experts in multiple myeloma to discuss the goal of achieving deep and durable responses in more patients, including older adults who are not able to tolerate highly aggressive treatments. During the discussion, the panelists provided personal perspectives and discussed the newest information on the goals of therapy in symptomatic disease, testing for minimal residual disease (MRD), role of transplantation, and the use of maintenance therapy. “We continue to see dramatic shifts in the management of multiple myeloma,” said Stewart.The panelists agreed that the goal of therapy is to achieve MRD-negative complete remissions, but that the timeline for achieving this goal varies by patient. “For elderly patients, I think you must compromise a little bit on efficacy for the tolerability and safety…achievement of a deep response is important for these patients, but it may take a little longer than in the younger patients,” said Saad Z. Usmani, MD, FACP. This approach was supported by Thomas G. Martin III, MD who concurred that the road to a complete response (CR) can be significantly longer in older populations. “I tell them, ‘You’re going to be on therapy for, potentially, upwards of a year. Hopefully each month [the need for therapy] will go down—slowly, slowly, slowly,’” he said.

In contrast, patients with more severe disease often require a quick response. “I think if there’s a patient who presents in extremis, in acute renal failure, then the rapidity of the reduction of the disease burden is important,” said Ivan M. Borrello, MD, who acknowledged those presentations are rare. “[In most patients], if the trend is going in the right direction, I think [we can] deliver therapy with potentially less intensity and less toxicity over a longer period of time,” he said.

Frontline therapy choices among the panelists varied based on patient factors and institutional practices, but all panelists reported using combination regimens, with most incorporating bortezomib (Velcade) and lenalidomide (Revlimid) into their protocols, preferring 3-drug regimens for younger, more fit patients, and 2-drug regimens for older and more frail patients. “For the transplant-eligible patient, our upfront regimen of choice is bortezomib with lenalidomide and dexamethasone. For the older, truly frail patient, it’s probably lenalidomide and dexamethasone. And now there may be talk about an antibody there,” said Sagar Lonial, MD, FACP. Although 2-drug regimens were generally regarded as safest for less robust patients, Borrello said his institution has used 3-drug regimens in some elderly populations, although at lowerdose intensities.

MRD Testing

Most panelists did not routinely use carfilzomib (Kyprolis) combinations upfront, but Martin reported using it with lenalidomide and dexamethasone in younger and more fit patients and in those with high-risk cytogenetics, such as 17p deletion, t[4;14] deletion, or 1q gain. Others noted they might start using it as an upfront therapy based on emerging data. The most unique regimen was reported by Gareth Morgan, MD, FRCP, FRCPath, PhD, whose institution uses combinations with classic chemotherapy agents to enable harvesting stem cells for eventual stem cell transplantation. “We are aiming each point in the process to achieve increasing remissions— aiming for MRD negativity, ultimately,” he said.Because improved multiple myeloma treatments have led to higher CR rates, there has been a need to redefine response criteria to enable identification of deeper responses than were conventionally possible.¹ This has led to the emergence of flow cytometry and, more recently, next-generation gene sequencing to identify residual tumor cells in the bone marrow.¹ The panelists identified numerous pros and cons with each testing method.

Flow cytometry was reported to provide results more quickly, typically within 24 hours, whereas gene sequencing results have been slower, often taking a week or longer to obtain. Reported benefits of next-generation sequencing included not needing a fresh sample and more consistent results. “There’s a lot of variability with flow cytometry that’s operator-dependent, antibody panel—dependent, and many other things,” explained Borrello.

While the panelists varied in their testing methods and preferences, Morgan reminded that both flow cytometry and next-generation gene sequencing have roles to play and might sometimes be beneficial when used in combination. “We have MRD flow cytometry, which is a variable sensitivity—10-4, 10-5 [ie, 1 in 105 nucleated cells or better]—when you see the patient. If somebody is negative, you can consider sending it off for sequencing,” he said.

A major challenge that remains is standardizing the MRD-negativity threshold across clinical trials, regardless of which testing method is used. Currently, the International Myeloma Working Group criterion is set at 10-5, with sustained MRD negativity requiring 2 such determinations on either flow cytometry or next-generation sequencing taken 1 year apart; however, thresholds in clinical trials have ranged from 10-4 to 10-6. ³

Role of Transplantation

The panelists acknowledged that MRD testing is not ready for clinical application outside of clinical trials just yet. The testing mainly serves as a prognostic marker, with MRD-negative patients showing better progression-free survival (PFS) and overall survival (OS) than those who do not achieve MRD negativity, regardless of threshold used. “I don’t think any clinical decisions can be made [based on this testing] at the current time,” said Martin.While the goal has been to eliminate transplantation, the panelists noted that it remains an important therapeutic option despite the advent of many new highly effective therapies. “If you can tolerate [autologous stem cell transplant], it should be one of the major tools for newly diagnosed patients,” said Morgan.

The panelists proceeded to discuss an important study recently published by Attal and colleagues in the New England Journal of Medicine, which showed transplantation to have some benefit over use of a 3-drug regimen alone.4 The study compared induction therapy with 3 cycles of lenalidomide, bortezomib, and dexamethasone (RVD) followed by consolidation therapy with either 5 more cycles of RVD (n = 350) or high-dose melphalan plus stemcell transplantation followed by 2 additional cycles of RVD (n = 350); both groups received 1 year of lenalidomide maintenance therapy.⁴

Patients who received transplantation had a significantly longer PFS than those who received RVD alone (50 vs 36 months, respectively; adjusted HR for disease progression or death, 0.65; P <.001). Additionally, more patients in the transplantation group than in the RVD-only group achieved CR and MRD negativity; however, OS at 4 years was similar between groups (81% and 82%, respectively).⁴

Although no benefit in OS was observed, Usmani noted, “For most transplant trials, you have to wait out 5, 6, or 7 years to see the overall survival curves separate.” Also, several panelists emphasized the importance of the increased MRD negativity observed in the transplant group (ie, 79% vs 65% for the RVD-only group; P <.001). “I think that when you [discuss treatment] with the patient, you want to pick the choice that gives your patient the best chance for getting to a deep remission—MRD negativity&mdash;and that’s what you get with early transplant,” said Usmani.

Maintenance Therapy

The panelists also discussed the StaMINA trial, which is the largest trial to date assessing transplantation in patients with multiple myeloma.⁵ The study results were presented at the 2016 American Society of Hematology Annual Meeting, but have not yet been published. “The StaMINA trial compared single transplant with a tandem transplant and a single transplant with consolidation, with the hypothesis that deeper remission would result in longer progression-free survival,” said Stewart. “It didn’t really seem to show that very conclusively,” he noted. The thought has been that the study’s findings might lead to fewer second transplants, supporting a less-is-more approach,⁶ but follow-up is ongoing and many panelists felt that it is premature to draw such conclusions. “It’s just a little bit early for that trial to have reported—about 5 years too early,” suggested Morgan, who noted that his institution performs tandem transplants and that they are commonly performed in Europe. He also suggested that evidence from other studies has been showing benefit with tandem transplantation; thus, more data are needed before use of second transplants should be ruled out.The panelists started their discussion of maintenance therapy by examining a trial led by Morgan that assessed the use of lenalidomide in this setting.⁷ In the study, lenalidomide maintenance was associated with a significantly longer median PFS versus observation (HR, 0.47; 95% CI, 0.38-0.60) across all subgroups, including those with high-risk disease. “I think [this trial] was the final piece of evidence that really supports the use of [lenalidomide] maintenance compared with no maintenance…we should have OS data by the end of the year,” said Morgan. Results were improved if maintenance continued past the first year, he noted. While continuation until progression was considered ideal, the panelists acknowledged this is typically not possible because of toxicity.

“At the University of California, San Francisco, we just had a pharmacist look at our data. During the maintenance phase, patients became toxic from fatigue and diarrhea. The average duration of therapy was between 2 and 2.5 years,” said Martin. Several panelists noted that use of medicines that address such toxicities, such as cholestyramine for lenalidomide-induced diarrhea, might enable more patients to remain on lenalidomide maintenance longer, particularly past that first critical year.

Some panelists add bortezomib to lenalidomide during maintenance. “For the translocation t[4;14] patients, we add it,” said Usmani. “The only caveat for bortezomib and lenalidomide in the maintenance setting is considering patients who have not achieved a [very good partial response] before transplant, which tells you that they’re probably not as sensitive to RVD and they’re high-risk,” warned Lonial, noting such patients at his institution receive carfilzomib and pomalidomide maintenance for 3 years. “I think antibodies, though, are going to make the biggest splash in this setting,” he said, indicating that exciting data on such agents are emerging on multiple fronts. “It will be really exciting, over the next 2 to 3 years, to see what we’re going to choose for frontline therapy,” said Martin.