Survival for patients with multiple myeloma (MM) has markedly improved owing to recent progress in treatment strategies . Nonetheless, MM remains incurable for most patients, and a significant proportion of patients with MM experience relapses that require further treatment. The introduction of next-generation immunomodulating agents (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs) has widened treatment options; however, management of patients with relapsed and refractory MM (RRMM) requires a systematic approach. This review summarizes the published results of major clinical trials, as well as patient and disease-related factors, to help guide appropriate drug combinations and sequencing of therapy using currently available drugs.
Patients with RRMM present with three different disease patterns: 1) relapsed but not refractory, 2) relapsed and refractory, and; 3) primary refractory RRMM.
In 2008, the American Society of Hematology and the United States (US) Food and Drug Administration (FDA) Workshop established a uniform consensus on the definition of RRMM , and in 2016, the International Myeloma Working Group (IMWG) published a revised definition of relapsed MM .
Relapsed disease is defined as progressive disease after acquisition of a response to prior therapy that requires salvage therapy, but which does not meet the criteria for “primary refractory” or “relapsed and refractory” disease categories, based on laboratory and radiologic evidence, as follows:
≥25% increase from the lowest confirmed response of the monoclonal protein (M-protein) in the serum (absolute increase, ≥0.5 g/dL) or in the urine (absolute increase, ≥200 mg/d)
≥25% increase from the lowest confirmed response between involved and uninvolved serum-free light chains (absolute increase, >10 mg/dL)
≥10% increase of the absolute percentage of bone marrow (BM) plasma cells
New soft tissue plasmacytomas or bone lesions
≥50% (and ≥1 cm) increase in existing plasmacytomas or bone lesions, as measured serially according to the sum of the products of the maximal perpendicular diameters (SPD) of the measured lesions
Direct indicators of increasing disease and/or end organ dysfunction such as hypercalcemia, renal failure, anemia, and bone lesion (CRAB) features related to the underlying clonal plasma-cell proliferative disorder
Serum calcium concentration>11 mg/dL
Serum creatinine level≥2 mg/dL (from the start of the therapy and attributable to myeloma)
Decreased hemoglobin level by ≥2 g/dL (not related to therapy or other non-myeloma-related conditions)
Hyperviscosity related to serum paraprotein level
The term “relapse and refractory” designates disease in patients who achieve a minor response (MR) or better, and who then either become non-responsive while undergoing salvage therapy or who progress within 60 days of the last therapy.
The term primary refractory designates refractory disease in patients who have never achieved an MR with any therapy. These include patients who never achieve an MR or better, for whom there is no significant change in the M-protein concentration and no evidence of clinical progression.
Several diagnostic procedures should be undertaken for patients with RRMM, including serum and urine protein electrophoresis and immunofixation, urine total protein, serum-free light chain, serum beta-2-microglobulin, and serum lactate dehydrogenase (LDH) tests. A peripheral blood smear test to detect circulating plasma cells is beneficial to discriminate high-risk patients. A bone marrow examination is mandatory, particularly for patients with non-secretory MM accompanied with fluorescent in situ hybridization (FISH) on monoclonal myeloma cells, and for patients who have not previously been identified with high-risk cytogenetics. Skeletal or extramedullary plasmacytoma evaluations using conventional x-ray, computed tomography, magnetic resonance imaging, or positron emission tomography may be required for patients with suspected MM [4, 5].
The introduction of new agents has been reported to have prolonged survival in elderly patients . Although age itself is not an obstacle for treatment, very elderly and frail patients are prone to experiencing treatment-related adverse events, leading to shorter survival . Various frailty assessment tools, including the IMWG geriatric assessment tool, have been developed to predict outcomes concerning frail patients . In one Korean study, scores used to predict poor overall survival (OS) for frail patients involved those related to age (≥80 yr), the Eastern Cooperative Group performance status (ECOG PS) 3–4, the estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m2), and the presence of comorbidities (≥2 comorbidities involving the heart, lung, or liver, cerebrovascular disease, and/or diabetes mellitus) . The treatment goal for elderly and frail patients may focus more on symptom relief and the prevention of new myeloma–associated symptoms. Drug dose reductions and the selection of less intense regimens (such as doublet instead of triplet combinations) could be options more applicable to this patient group.
Cardiac diseases (myocardial infarction, heart failure, and arrhythmias), renal impairment, peripheral neuropathy, diabetes mellitus, and thrombosis may be present at the time of MM diagnosis or as a consequence of previous antimyeloma therapies. Drugs likely to aggravate underlying diseases or residual toxicities that require monitoring for organ-specific complications are as follows: anthracyclines and carfilzomib (cardiotoxicities); lenalidomide and ixazomib, which require dose reductions for patients with impaired renal function; thalidomide, bortezomib, and vincristine (peripheral neuropathy); corticosteroids (glucose intolerance), and; IMiDs (thrombosis).
Several parameters have been proposed as poor prognostic factors in RRMM. Extramedullary disease has been observed in approximately 14% of patients at relapse of MM and is usually associated with high-risk cytogenetic abnormalities affecting poor OS [10, 11]. An elevated LDH level , a peripheral blood plasma cell count that does not fulfill the criteria for plasma cell leukemia (a peripheral blood plasma cell count of >20% of the total white blood cell count, and an absolute count of ≥2,000/μL) , and a high plasma cell proliferative index at post-autologous stem-cell transplantation (post-auto-SCT) D+100  are indicators for short survival. Several studies have recommended that the rapid onset of disease-related organ damage (hypercalcemia, renal failure, and bony complications), as well as the above listed factors predictive of rapid disease progression, be defined as “aggressive disease” that requires treatment intervention using the most effective regimens [4, 5, 15].
The effect of high-risk cytogenetics defined using del(17p), t(4;14), and t(14;16) on the aggressive disease evolution is not straightforward. Different studies involving salvage lenalidomide-dexamethasone (Rd) have reported controversial outcomes regarding del(17p) and t(4;14) [16, 17]. Some of the currently available combination therapies, such as pomalidomide-dexamethasone (Pd, MM-003) , carfilzomib-dexamethasone (Kd, ENDEAVOR) , ixazomib-Rd (IRd, TOURMALINE MM-1) , and daratumumab-bortezomib-dexamethasone (Dara-Vd) (CASTOR) , have significantly improved the poor outcomes of high-risk disease. Further, studies on Rd with or without carfilzomib (ASPIRE) , elotuzumab (ELOQUENT-2) , and daratumumab (POLLUX)  have reported that these drugs improve progression-free survival (PFS) but not significantly. A summary of each trial concerning these high-risk cytogenetics affecting PFS is listed in Table. However, these results should not be compared directly due to the inconsistency of FISH methods and cut-offs in the different studies. Results of the major clinical trials in the experimental arm and in the high-risk cytogenetics group are summarized in Tables 1 and 2.
The objective of treatment in the relapse setting is to alleviate symptoms, prevent progressive organ damage, and re-attain long-lasting disease remission. Indications to initiate therapy are clinical relapse, defined according to the CRAB criteria, or a significant increase of biochemical relapse in 2 consecutive measurements within 2 months apart that meets the IMWG criteria for the definition of progressive disease . Relapses with acute onset and rapid progression of symptoms require a prompt initiation of treatment.
Asymptomatic biochemical relapses could be monitored every 1–2 months with careful observation of symptoms. However, for high-risk disease features indicative of a poor response and a short OS, such as “aggressive disease” at relapse, a treatment-free interval of <12 months with a suboptimal response to prior therapy and unfavorable risk cytogenetics [t(4;14), t(14;16), and del(17p)], treatment should be started immediately. A recent subgroup analysis of patients in the ENDEAVOR study, which compared the results of asymptomatic biochemical and symptomatic relapse in Kd and Vd groups, demonstrated a better median PFS and OS in patients who commenced treatment at the time of asymptomatic biochemical relapse rather than at clinical relapse in both groups . This result indicates that therapeutic intervention at biochemical relapse before (re)appearance of clinical symptoms might be of benefit to patients in terms of PFS and OS.
Phase III clinical trials evaluating Dara in combination with a fixed duration of Vd (CASTOR)  and with continuous Rd (POLLUX)  have proven their synergistic efficacy compared with a comparator arm. The POLLUX trial reported prolonged PFS (median not reached vs. 17.5 mo) and a better ORR (92.9% vs. 76.4%) in the Dara-Rd arm compared with Rd at 25.4 months follow-up. A PFS benefit in the Dara-Rd arm was observed across age subgroups and ISS stage . In the 19.4 months of updated analysis from the CASTOR trial, 8 cycles of Dara-Vd followed by Dara maintenance improved PFS (16.7 vs. 7.1 mo) and ORR (83.8% vs. 63.2%) compared with Vd only. Dara-Vd was effective regardless of age, ISS stage, renal failure, and cytogenetic risk . In the POLLUX and CASTOR trials, a significant rate of MRD negativity was achieved across both high and standard cytogenetic risk patients . Phase III studies comparing Dara (intravenous or subcutaneous)-Pd with Pd (APOLLO, NCT 03180736), Dara-Kd with Kd (CANDOR, NCT 03158688), and Dara intravenous versus subcutaneous administrations (COLUMBA, NCT 03277105) are currently ongoing.
A second autoSCT with high-dose therapy may be an option in transplant-eligible patients if sufficient stem cells have been collected . Previous retrospective analyses have shown patients who relapsed >18-24 months after the first autoSCT may benefit from autoSCT after re-induction therapy [76, 77]. Matched-pair analysis from the Korean myeloma registry has reported significantly longer OS (55.5 vs. 25.4 mo) for salvage autoSCT compared with systemic chemotherapy alone in patients who relapsed after upfront autoSCT . A poor outcome could be predicted for patients who relapsed <18 months after their first autoSCT and ISS III. The only phase III German trial comparing re-induction Rd followed by salvage autoSCT and maintenance Rd with continuous Rd did not prove the efficacy of autoSCT as a salvage treatment in terms of ORR, PFS, and OS; however, patients with high-risk cytogenetics experienced improved survival after salvage autoSCT (HR, 2.71 for PFS and 4.22 for OS;
Although no established guideline exists for the most optimal treatment of RRMM, practical treatment algorithms based on currently available study results and from Korean settings can be suggested (Fig. 1). Biochemical relapse not fulfilling the IMWG criteria for progressive disease may be followed up every 2 months, with close monitoring for the appearance of myeloma-related symptoms. Biochemical relapse that has met the IMWG criteria and clinical relapses should proceed to treatment. Aggressive biology (rapid onset of hypercalcemia, renal insufficiency and skeletal events, newly appearing extramedullary plasmacytoma, doubling of M-protein concentration, elevated LDH levels, elevated peripheral blood plasma cell counts, and a high plasma cell proliferation index) may be better treated with at least triplet combinations of novel agents, which are able to elicit a rapid and deep response. Patients in deep and durable responses, such as those with a response duration of >24 months to frontline therapy, from 18 to 24 months after autoSCT without maintenance, and from 36 to 48 months after autoSCT with maintenance, can be retreated with previously prescribed drugs or undergo salvage HDT with autologous stem cell support . Drugs that were previously refractory should be avoided. Patients refractory to bortezomib should receive lenalidomide-backbone triplets or doublets (KRd, IRd, DRd, Elo-Rd, and Rd) or Kd, while lenalidomide-refractory patients should be treated with Kd or Vd with or without daratumumab. Double-refractory patients to IMiDs and PIs can benefit from pomalidomide-based doublet or triplet therapies (Pd or PCd) and daratumumab monotherapy.
Owing to the recent approval of new agents by the Health Insurance Review & Assessment (HIRA) Service in the Republic of Korea, the outcome concerning MM has markedly improved. Real-world clinical experience using the approved drugs and their combinations in Korea have shown similar efficacy and toxicity profiles compared with results from the clinical trials. Well-organized long-term observational studies are needed to confirm the beneficial effect of novel agents, and efforts to develop newer treatment modalities are required to prolong survival for patients with MM.
No potential conflicts of interest relevant to this article were reported.