The Moving Target of When to Treat on the Myeloma Spectrum

Myeloma is consistently preceded by a precursor state that is characterized by a paraprotein — an excess of a monoclonal immunoglobulin or light chain in the serum. The clinical spectrum of this plasma cell disorder extends from asymptomatic monoclonal gammopathy of undetermined significance (MGUS) at one end, to symptomatic myeloma at the other, characterized by hypercalcemia, renal failure, anemia, and bone lesions. This pathological spectrum can be divided further into two groups — above and below a bone marrow plasma cell burden of 10 percent (and/or > 3 g/dL monoclonal serum protein); when above that burden, myeloma becomes clinically apparent. In the absence of symptoms, this state is classified as smoldering multiple myeloma (SMM) to reflect the propensity of the condition to ignite into active, symptomatic myeloma.¹  SMM may be further subdivided into groups at high and low risk of progression.²  The current standard of care is to monitor for the development of myeloma-defining events when the balance of risk of drug toxicity is outweighed by the benefits of therapy. Although pragmatic, this approach may feel unsatisfactory to clinicians and patients alike, with some arguing that intervention should take place before organ damage has occurred, but not so early as to expose patients to adverse effects unnecessarily?

The first major trial to assess intervention in SMM was performed by the PETHEMA group and published in 2013.³  A treatment arm of lenalidomide and dexamethasone was compared to observation alone in a cohort of patients considered to be at high risk of progression to myeloma. Results demonstrated a two-year progression-free survival (PFS) of 92 percent in the treatment arm compared to 30 percent in the observation arm. This was perhaps not surprising given the effectiveness of lenalidomide and dexamethasone as treatment. Additionally, however, overall survival (OS) increased from 76 percent in the observation arm to 93 percent with treatment during the reported follow-up period. For the first time, researchers showed that the natural history of precursor states to myeloma could be modified by starting therapy prior to the onset of end-organ damage. However, the study has not altered mainstream practice for numerous reasons. As suggested by the approximate one in four mortality rates in the observation arm, the trial may in part reflect high-risk disease close to active myeloma, obscuring the effect on treating lower-risk SMM.

To address these concerns, Dr. Sagar Lonial and colleagues⁴  performed a randomized, open-label, multicenter phase III trial that compared oral lenalidomide (25 mg) to observation across all risk groups of progression in SMM. The design of the trial made use of current diagnostic criteria for myeloma, and the primary end point was PFS, which was defined as time from random assignment to symptomatic myeloma. Lenalidomide therapy seemed to be safe but was not always well-tolerated. Twenty-nine of 88 patients discontinued therapy owing to adverse events or patient preference. By three years of follow-up, PFS was 91 percent in the lenalidomide arm compared to 66 percent in the observation arm. , This equates to a cumulative incidence of myeloma of 7 percent in the lenalidomide arm versus 32 percent in the observation arm at three years from random assignment. In terms of OS, no benefit was observed, in contrast to the earlier trial. This may be expected, as the trial recruited patients with lower-risk SMM, as demonstrated by the greater PFS in the observation arm.

The data presented by Dr. Lonial and colleagues build on earlier observations to show that the natural history of myeloma can be altered by early intervention. The evidence from this randomized trial may be used in the clinic to counsel patients who are presented with the challenging diagnosis of SMM. The trial by Dr. Lonial and colleagues clearly demonstrates, in a well-characterized group of patients with SMM, that the progression to active disease may be delayed as well as avoiding some end-organ damage. The effect on OS remains uncertain to date.

However, many questions remain to be answered before we change our standard of practice to treat patients with high-risk SMM. It is unknown whether therapy with single-agent lenalidomide drives the selection of insensitive subclones of malignant plasma cells and if so, what the effect on OS might be. Another question is whether response rate and minimal residual disease are critical as end points in SMM. In the study by Dr. María-Victoria Mateos and colleagues, PFS correlates with response, but the study by Dr. Lonial and colleagues indicates that lenalidomide as a single agent without dexamethasone may be acting as immunotherapy that controls the disease burden and improves PFS in the absence of a deep response. It opens the question as to whether immunotherapy should be the ultimate therapy in this group of patients. Furthermore, both studies used very different inclusion criteria for SMM, and we need better clinical-genomic markers that can predict more accurately the rate of progression in SMM.

Although these two large randomized studies have changed the concept of watch-and-wait by moving the needle towards early therapeutic intervention, they have not definitively proved that lenalidomide with or without dexamethasone are the best therapeutic approaches for a patient with high-risk SMM. Until a more successful approach is shown in clinical trials, the current standard of care in SMM remains observation with initiation of therapy at the earliest opportunity with triplets or possibly quadruplets of drugs.

The future of prevention of progression of SMM is likely to require an entirely novel approach. This should include 1) better prognostic markers that truly identify patients at high risk, 2) precision intervention with approaches according to the different biological and immune subtypes of SMM, 3) immunotherapeutic approaches that could restore immune surveillance to help long-term control of the malignant clone, 4) non-toxic and non-continuous therapies that do not lead to clonal selection and long term toxicity, and 5) a potential to eradicate the clone at its earliest progenitor state. Such approaches may indeed lead to a potential cure in MM by an earlier therapeutic intervention. Adequately powered trials of targeted interventions are required to answer these questions for patients.