Characterization of Relapse-Defining Events Through Patient Evaluation and Advanced Imaging Improves Treatment Selection in Multiple Myeloma

Despite the wealth of available treatment options, selecting the appropriate regimen for a given patient with relapsed/refractory multiple myeloma can prove difficult but can be guided by the type of relapse, according to Matthew Brunner, MD.

National Comprehensive Cancer Network guidelines currently recommend several triplet regimens for the treatment of relapsed/refractory multiple myeloma. Preferred category 1 options for early relapses include ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone or bortezomib (Velcade), lenalidomide, and dexamethasone. Patients who are refractory to treatment with lenalidomide or bortezomib may also choose from daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone or carfilzomib, pomalidomide (Pomalyst) and dexamethasone.

Patients who progress after 1 line of therapy, including lenalidomide and a proteasome inhibitor are recommended daratumumab, pomalidomide, and dexamethasone, while those who progress after 2 prior lines can receive isatuximab-irfc (Sarclisa), pomalidomide, and dexamethasone.¹

“[Treatment selection] in the relapsed setting is [more of an] art opposed to [a set of] clear guidelines,” said Brunner, who is an assistant professor and specialist in Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin Carbone Cancer Center. “[Relapsed] myeloma can [differ] in terms of symptoms, how quickly it [occurs], and how aggressive it is, so it is good to be familiar with the variety of relapse-defining events.”

In an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar, Brunner discussed how key patient factors, the use of advanced imaging modalities, and the relationship between community and academic centers influence treatment approaches in relapsed/refractory multiple myeloma.

OncLive^®: Why is it important to characterize the type of relapse in multiple myeloma?

Brunner: Myeloma relapse is very heterogeneous. Patient evaluation and different patient factors [will] affect treatment decisions. Advanced imaging and bone marrow biopsies [can also be] useful in this setting.

Relapse in myeloma includes different [symptoms]. Someone can have a biochemical relapse, which is an increase in their [monoclonal spike (M)] protein on the [serum protein electrophoresis (SPEP) test]. [They can show] an increase in free light chains. [Patients] can also have a radiographic relapse, where a new bone lesion, old bone lesion, or extramedullary plasmacytoma is growing. Sometimes [radiographic relapse] is just an increase in the number of plasma cells in the bone marrow. Clinical relapse [includes] anemia, renal dysfunction, and hypercalcemia. In rare cases, [there is] an increase in plasma cell leukemia. [Overall,] there [are many] symptoms that [clinicians should] be aware of when checking labs and [evaluating] patients.

What patient characteristics influence treatment selection once relapse is identified?

[Treatment selection] in the relapsed setting is [more of an] art as opposed to [a set of] clear guidelines. At first relapse, most patients will have a wide variety of options available and [will receive] a triplet therapy. If they haven’t [received] a CD38 antibody or a second-generation proteasome inhibitor like carfilzomib in the frontline setting, [they will] get that in the second or third line.

There’s some latitude in [determining] what patients might [benefit from] daratumumab [or] a drug they’ve already seen like bortezomib vs a completely novel combination. Those novel combinations [include] daratumumab combined with carfilzomib or pomalidomide [Pomalyst] or bortezomib. [There are] no head-to-head comparisons of these [combinations], [as] all the phase 3 [trials] were looking at triplets vs doublets in the second line. [Therefore,] choosing [the best regimen] comes down to patient comorbidities and [potential adverse] effects.

What is the relationship between community and academic centers in the management of multiple myeloma, and how does this affect treatment recommendations?

We have a good relationship with our community providers, so there’s a wide variety of treatments that they feel comfortable giving. [These include] most standard myeloma pharmacologic drugs [like] daratumumab, carfilzomib, and pomalidomide. For more specialized immune therapies like autologous stem cell transplant, CAR T-cell therapy, and bispecific T-cell engagers [patients are typically] referred to an academic setting because [they have the] infrastructure to deliver those therapies safely. As academic consultants, our job is [not just] taking care of those patients but also communicating with our community colleagues. [They need to know] what [therapies are] commercially available, what clinical trials are available, and when it is the right time to refer a patient to us. [This helps us] deliver these more specialized therapies in the right setting and when they’re more likely to succeed.

In what scenarios would a patient undergo advanced imaging, and how might a clinician determine the best imaging modality to use?

Many studies have [investigated] advanced imaging in multiple myeloma, and there’s a lot of growth in this area. More recent [data have shown that] PET CT [scans appear] comparable to MRI imaging in the IMAJEM study [NCT01309334]. There [have been] improvements in MRI functional imaging using diffusion weighting, and PET MRI is now [an option]. My talk was focused on when [to utilize] advanced imaging for relapsed patients, and how to choose [a modality]. The standard imaging in the relapsed setting is a PET CT, because [a patient is] more likely to have extramedullary disease and PET-avid disease in this setting. A PET CT scan not only allows you to find those things but allows you to use the initial image as a benchmark to track [patient] response [during treatment]. As you’re seeing a patient’s serologic markers, biomarkers, and anemia improve, you’d also like to see their imaging improve.

MRI [imaging] is more sensitive for certain applications and it [provides] a better anatomic picture. If you have structural concerns, and [may require] radiation oncology or a surgical procedure, [MRI may be the preferred option.]

A PET CT can be prognostic for patients relapsing in later lines. It allows [for] a thorough response assessment and can [identify important characteristics that may] change your treatment [approach]. [For example,] you [may find] a high-risk, asymptomatic lesion that needs immediate radiation or surgical fixation before proceeding [with treatment]. Imaging has evolved from [conducting] skeletal surveys to the routine use of advanced imaging throughout the course of the disease.

Is there any ongoing or upcoming research in multiple myeloma at Carbone Cancer Center that you’d like to highlight?

One of the big areas of interest and [unmet] needs in multiple myeloma is managing patients who don’t respond [well] to initial therapy. We know that patients who [achieve] deep remission after their induction and transplant can remain in remission [for] several years on maintenance therapy. [However,] we do have patients who don't have good responses after transplant and maintenance therapy. The non-randomized, [phase 2] BMTCTN1902 trial [NCT05032820] is looking at [the use of] consolidation CAR T-cell therapy in [patients] who have very good partial responses or worse after transplant and maintenance therapy. [We] hope that we [can] deepen patient response with more naive lymphocytes [in] patients who haven’t been treated as aggressively before. [However,] there are long-term toxicities [associated with] CAR T-cell therapy [such as] immunosuppression and immune cytopenia. This trial will inform [us on] the efficacy of this approach, and the [frequency] and severity [of CAR T-related toxicities] in these patients.

[The phase 3] SWOG 1803 study [NCT04071457] is also looking at [the use of] minimal residual disease [MRD] to [direct] maintenance therapy intensification.

The frontline, [phase 2] MASTER-2 trial [(NCT05231629) will be] opening soon. The trial has [several] different treatment arms based on [a patient’s] MRD status after a quadruplet induction. More and more data [have shown] that quadruplet inductions using standard bortezomib, lenalidomide and dexamethasone [VRd], [plus] daratumumab have deeper up-front responses. At the 2022 ASH Annual Meeting, some data [showed] that the quadruplet regimen improved quality of life faster than VRd because [it provides] better disease control. The MASTER-2 trial uses that quadruplet as a backbone [in several of the treatment arms]. [Achieving] deep responses early on, when the cancer is most drug naive, [will hopefully] lead to longer overall survival.

Reference

National Comprehensive Cancer Network. Multiple Myeloma (Version 3.2023). https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed January 31, 2023