Defining relapsed and refractory MM: the challenges and controversies

Patients with relapsed/refractory multiple myeloma (RRMM) are a diverse group. Three distinct subgroups can be identified within this category:

• Patients who relapsed while not on active treatment

• Patients who relapsed while on active treatment and became refractory

• Patients with primary refractory MM

In addition, RRMM can refer to patients who relapse early after first-line treatment, as well as to patients who relapse after several lines of therapy or after a long duration of remission. This makes patients with RRMM a very heterogeneous group to treat. Furthermore, new therapies added to the treatment armamentarium in recent years increases the complexity of selecting and sequencing treatments for each patient.¹

In clinical trials, it is important to have a homogenous group of patients, which in turn requires clear definitions to be used in the selection criteria of what constitutes a patient experiencing a relapse or becoming refractory to a specific agent. Some studies can use vague terms such as “exposure”, which does not specify the dose or duration of treatment. This can lead to enrollment of a mixed patient population and the need for subgroup analyses, making the interpretation of results and their application into practice more difficult. These definitions are also important for drug approvals to accurately identify the population that can be treated with a specific agent.¹

Defining relapsed and refractory MM

The International Myeloma Working Group (IMWG), European Hematology Association (EHA) and European Society for Medical Oncology (ESMO), American Society of Hematology, and the U.S. Food and Drug Administration (FDA) Workshop reached a consensus on certain key definitions, a summary of which can be found in Figure 1.

Figure 1. Key definitions in multiple myeloma

BM, bone marrow; CRAB, calcium, renal, anemia, bone disease; FLC, free light chain; MR, minimal response; MRD, measurable residual disease; NGF, next-generation flow; NGS, next-generation sequencing; SPD, sum of the products of the maximal perpendicular diameters of measured lesions.
*Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.
^†MR: ≥25% but ≤49% reduction of serum M protein and reduction in 24-hour urine M protein by 50–89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD^†) of soft tissue plasmacytomas is also required.

Current challenges with the definitions in clinical research

A number of clinical trials use the inclusion criteria of progressive disease rather than clinical relapse, which encompasses patients showing signs of early biological/biochemical progression, as well as patients in clinical relapse (Figure 1). These two groups may have very different prognoses and outcomes; thus, trial results may depend on the proportion of patients in each group in addition to the treatment intervention being examined.⁶

Not all clinical trials use clear definitions; for example, as shown in Table 1, patients in which ≥3 lines of therapy “failed” are included in the DREAMM-2 trial.⁷ This could encompass patients who are intolerant to treatment due to adverse events, who have relapsed on treatment/become refractory, or who have discontinued due to non-compliance.

Table 1. Examples of clinical trial variability in definitions for relapsed/refractory MM in inclusion criteria

A similar problem occurs with definitions of the term “refractory” especially when a patient is refractory to more than one agent. With the advent of so many novel agents, the different combinations can be numerous, and patients must be defined as refractory to a specific agent, not double refractory alone. Looking at the literature, multiple definitions can be found for double refractory, ranging from “MM that is relapsed and/or refractory to bortezomib and lenalidomide”¹¹ to “MM refractory to both proteasome inhibitors and immunomodulatory agents”¹².

Conclusion

While the IMWG and EHA-ESMO guidelines have advanced how we categorize patients with RRMM, further work in standardization needs to be done. Refractoriness definitions naturally evolve with the changes in standard of care and the approval of new agents, but still, care must be taken when comparing patient groups between trials as this shows that double or even triple refractory patients may have different definitions between studies. Ongoing trials in advanced disease show that this field will gain more and more layers of complexity since the selection criteria now include definitions for quad- and penta-refractory MM. Inclusion criteria need to be specific to ensure a homogenous group of patients; however, some consensus is urgently needed, for example, to narrow down whether patients in biochemical relapse should be included along with those in clinical relapse under the heading of progressive disease.