Management of Relapsed and Refractory Multiple Myeloma

• What disease factors should be considered in choosing treatment for RRMM?

MM exhibits genetic complexity, and prior treatments may result in clonal evolution of and selection for an initially nondominant, treatment-resistant clone [14,15]. This heterogeneity and selection pressure may explain why 3-drug regimens often outperform 1- or 2-drug regimens, why each remission is generally shorter than the last, and why patients who have enjoyed a long duration of response to one therapy and been off it for some length of time may again have a good response when re-treated with the same therapy at time of MM relapse. So how does one know if a new clone has emerged? While there is no standard for monitoring intra-clonal heterogeneity presently, changes in clinical phenotype likely correlate with evolving clones. Some such changes include free light chain escape (ie, MM that initially secreted an intact M-spike and then only secretes free light chain at relapse), new development of extramedullary disease (plasmacytomas outside of bone) in patients who previously had MM only in the bone marrow, and resistance of some sites to treatment while others respond (a mixed response). The former 2 phenotypes in particular portend poor prognosis and unsurprisingly they can be seen together [16–19]. Restaging, meaning a complete reassessment of MM disease status at the time of relapse, including bone marrow aspirate and biopsy, is beneficial to help guide therapy, as those with high-risk features including high ISS stage [20], high-risk cytogenetics, increased LDH, and extramedullary disease should be treated with triplet therapy when possible [11]. Repeat imaging should also be considered as a new baseline comparator. This can be done with standard x-rays, positron-emission tomography/computed tomography (PET-CT), or magnetic resonance imaging. PET-CT offers the advantage of showing active disease sites and the presence of extramedullary disease, although it exposes the patient to more radiation than the other methods.

In terms of using genetics to guide therapy decisions in RRMM, the presence of the del(17p) abnormality either by karyotyping or FISH portends high risk and pomalidomide in one study was shown to mitigate that risk [21]. How genetics and prognostic markers should dictate therapy selection in RRMM otherwise, however, is unclear and an area of active research efforts.

• What patient factors should be considered in choosing treatment?

Given the relatively large selection of possible regimens for the treatment of RRMM, patient preference can be incorporated into regimen selection. Patients who have long commutes or who are trying to work may not be ideal candidates to receive carfilzomib-based regimens given the twice-per-week infusion schedule (though a once-a-week dosing schedule is being tested) [22]. Patients who have poor venous access may be good candidates for all-oral regimens. Prior treatment tolerability and side effects should also be considered. Patients who experienced significant peripheral neuropathy with bortezomib may have less neuropathy with carfilzomib. Those with renal failure may tolerate pomalidomide better than lenalidomide [23].

Patient age and functional status are important considerations in choosing a treatment regimen for RRMM. Very old patients (a subjective categorization to include patients > 80 years by chronologic or physiologic age), those with functional dependence, or patients harboring substantial medical comorbidities are at risk for therapy toxicity and so often warrant less intensive approaches [24]. Deciding which patients empirically warrant less dose-intensive approaches can be challenging, especially with the growing recognition that fit seniors can often tolerate and enjoy the benefits of full-dose approaches, including sometimes even ASCT. Geriatric assessment instruments that interrogate a variety of geriatric-relevant domains, such as number of falls, independence in activities of daily living, and polypharmacy, are being investigated as toxicity predictors and may help make those decisions in the future. Such instruments have been shown to predict chemotherapy toxicity in solid tumors [25,26] and preliminarily in MM [27], but they remain investigational. While no validated geriatric assessment instruments are currently available for routine clinical employment in MM, clinicians should consider the geriatric domains that these instruments assess when choosing among treatment options. Clinically, that often translates to choosing gentler regimens with likely better tolerability, albeit perhaps with less efficacy, for patients judged to be vulnerable to toxicity.