Personalized Approach Is Needed for Transplant-Ineligible Multiple Myeloma

Smith Giri, MD, MHS

To effectively tailor treatment for transplant-ineligible patients with multiple myeloma in the frontline setting, factors such as frailty status must be taken into consideration, according to Smith Giri, MD, MHS.

“Often, improving efficacy comes at a risk of excess toxicity, so the decision should be individualized at the end of the day,” said Giri, a member of the Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham (UAB). “We need to learn more about how to adapt some of the treatment options available based on the different frailty status of each unique patient. There is a lot to be done in terms of personalization of treatment in transplant-ineligible patients.”

In an interview with OncLive during the 2020 International Perspectives in Cancer webinar on Multiple Myeloma, Giri, who is also an assistant professor in the Department of Medicine of the Division of Hematology/Oncology at UAB, discussed the options available for transplant-ineligible patients with myeloma, the factors to consider to personalize treatment, and future directions in the field.

OncLive: What factors should be considered when determining whether a patient is eligible for transplant?

Giri: Transplant eligibility has been historically defined by some of the early trials testing the role of autologous stem cell transplant in patients with multiple myeloma based on an age cutoff of 65 years or younger or those with limited comorbidities. However, in the United States and in many other countries, the age cutoff of 65 years is almost never followed. In fact, data from many single-institution studies, as well as the Center for International Blood and Marrow Transplant Research, suggest that patients well into their 70s routinely undergo transplant with very good outcomes and extremely low toxicity, particularly early treatment-related mortality.

The most recent ASCO guidelines recommend no clear age cutoff for transplant. Generally, though, in our institution and elsewhere, a patient who is older 75 years of age is generally considered ineligible. Again, it is important to acknowledge that there are very limited data [regarding] the right age cutoff.

It is also important to recognize that transplant eligibility remains subjective and it's really up to the patient and the transplant physician to decide [whether or not transplant is the best option]. This process usually includes a physical exam and assessment of organ function, including pulmonary function tests and echocardiogram, as well as a subjective estimate of their performance status or their frailty.

How do you determine the frailty of patients in practice?

Generally, in myeloma, frailty is a relatively novel concept. There is no universally agreed criteria to define frailty; however, frailty typically [focuses on the] treatment-related tolerability of any older individual to withstand and to safely undergo a treatment without excess toxicity. Two fundamental approaches are used to measure frailty: the so-called Fried phenotypic approach and the Rockwood Accumulation of Deficits approach.

The International Myeloma Working Group (IMWG), led by Antonio Palumbo, MD, of the University of Torino, combined age, the Charlson Comorbidity Index, and the Activities of Daily Living and Instrumental Activities of Daily Living into a cumulative score, which categorized patients into fit, unfit, and frail. A paper that came out in 2014 really laid out the foundation of how we could define frailty. The authors nicely showed that [this score] predicts not just survival, but also treatment-related toxicity.

Several other frailty scores have been proposed by other authors. For example, we have seen a revised Myeloma Comorbidity Index and a frailty approximate using ECOG performance status, age, and comorbidity.

[One] important area that needs further work in patients with multiple myeloma is narrowing down and widely validating a simple, easy-to-use, frailty index that can be quickly adopted in our routine clinical practice. Having said that, at UAB we do a comprehensive frailty evaluation [using] a deficit accumulation approach. We do both the IMWG frailty index, but we also capture a lot more. We have prepared our own deficit accumulation–based frailty index prepared in the context of an ongoing longitudinal study. We are collecting more data than the IMWG to try to identify and refine these indexes in the future.

How do you approach the up-front treatment for patients who are considered to be ineligible for transplant?

More than 1 option is available for our transplant-ineligible patients. Historically speaking, the first trial that compared lenalidomide (Revlimid)/dexamethasone doublet therapy with the traditional melphalan flufenamide (Melflufen)–based triplet established the superiority [of the former approach]. The MPT regimen—comprised of melphalan, prednisone, and thalidomide (Thalomid)—was widely accepted as an important benchmark and an important treatment for transplant-ineligible [patients].

However, more recent data from the SWOG S0777 study led by Brian G. M. Durie, MD, of Cedars-Sinai Medical Center, showed that the triplet VRd regimen can improve both progression-free survival (PFS) and overall survival (OS). As such, this is an option for patients. It is important to note that in that particular study, the criteria for inclusion was intent to transplant and not necessarily eligibility for transplant. Hence, many younger patients were included in the study. The population is perhaps not a clean transplant-ineligible older population. [Still], those are data showing that VRd is superior to Rd [for] an all-comers population who do not get up-front transplant.

The ALCYONE study added daratumumab to bortezomib (Velcade), melphalan, and prednisone (VMP), which is widely used in Europe as a standard of care for transplant-ineligible patients. The addition of daratumumab resulted in improved PFS and OS, based on a recent update published in the Lancet this year; so, that is also an option. VMP is not very popular in the United States. We traditionally use more lenalidomide-based regimens, so Rd is often used more than VMP.

Daratumumab/Rd was compared with an Rd-based doublet in the MAIA study, [which] also showed an improved PFS for patients; the hazard ratio was 0.56, [translating to] a statistically significant improvement in PFS. The OS data are not mature yet, but that is also one of the very effective treatment options for our patients.

I would argue that a relatively fit, transplant-ineligible patient should be getting more than just Rd and [for that patient] VRd or daratumumab/Rd [could serve as potential] options. For slightly less-fit patients, Rd could still be a standard option, particularly for those who are very frail. An additional option is VRd-lite, which is a slightly attenuated regimen rather than a full dose of VRd. It has been shown to be well tolerated in a very frail subset of patients, as well.

Often, improving efficacy comes at a risk of excess toxicity, so the decision should be individualized for each patient at the end of the day. We need to learn more about how to adapt some of these treatment options based on the different frailty status of each unique patient. There is a lot to be done in terms of personalization of treatment in transplant-ineligible patients.

Are there any regimens or combinations in the pipeline that look particularly interesting? Where should future efforts be focused?

As I mentioned before, an important area in this field is to try to personalize therapy for each individual patient. We've been sort of putting every transplant-ineligible patient into 1 basket, but we've learned that very fit patients and less fit patients are in this group. There is certainly room to try to pick a regimen that is individualized to their frailty status. Several ongoing studies are being done in Europe and in Australia, where patients are being treated based on their frailty profile. For example, in the FiTNEss study in Europe, patients are being assigned to treatment pathways based on their frailty status. That is an important future direction to take.

The other important area and where we need additional data [is understanding] the role of these more novel, more recent treatments—particularly with regard to carfilzomib (Kyprolis), and whether it has any role in the up-front treatment of transplant-ineligible patients. The recent data from the ENDURANCE study presented during ASCO showed no difference between KRd and VRd. Carfilzomib potentially may not have a benefit over bortezomib, but that needs to be clarified specifically in this transplant-ineligible subset, as well. Additionally, in the CLARION study, investigators compared carfilzomib, melphalan, and prednisone versus VMP. Results did not show any benefit with carfilzomib over bortezomib in this particular subset.

Some of the more novel therapies, such as carfilzomib and the most recently approved CD38-directed monoclonal antibody isatuximab-irfc (Sarclisa) may have a role there; however, the role of this agent in transplant-ineligible patients still needs to be clarified. There is a lot to be done in this field; this goes beyond picking a personalized treatment approach. We also want to move some of these promising novel therapies to the frontline setting even in the transplant-ineligible population.

Was there anything else that you wanted to highlight?

The treatment of transplant-ineligible patients with multiple myeloma is an evolving field. In the past 2 years, we've seen that the addition of daratumumab to [some of] the standard-of-care regimens has uniformly shown to improve PFS. It seems like that is the way to go for the future, [although it should be] recognized that there is not a one-size-fits-all approach.