Management of Relapsed and Refractory Multiple Myeloma · Briefly, relapsed myeloma is ... we discuss management of these often concur- ... normal cytogenetics with 46,XY in 20 cells

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470 JCOM October 2016 Vol. 23, No. 10 www.jcomjournal.com

Relapsed and RefRactoRy Multiple MyeloMa

ABSTRACT• Objective:Toreviewthemanagementconsiderations

in patients with relapsed and refractory multiplemyeloma(RRMM).

• Methods:Reviewoftheliterature.• Results: RRMM is a heterogeneous disease and

numerous treatment regimens have been studied.Despiteimprovementinprogression-freeandoverallsurvival in newly diagnosed multiple myeloma withcurrent therapies, myeloma remains incurable andrepeatedrelapsesareinevitable.Relapsesareoftencharacterized by diminished response to chemo-therapy(refractoriness)anddurationofresponse.

• Conclusion:ManagementofRRMMshouldbe indi-vidualized using both patient- and disease-relatedfactors,givensubstantialheterogeneity inboth.Fur-therresearchregardingtheoptimaltiming,regimen,anddurationoftreatmentiswarranted.

Although advancements in treating multiple myeloma (MM) have resulted in improved me-dian survival from approximately 2 years in

the 1990s to more recent estimates of over 6 years, the disease remains incurable [1–3]. Its overall course is gen-erally defined by a series of increasingly short remissions and treatment-refractory relapses until eventual death due to MM occurs. Objective criteria for defining both relapsed and refractory MM have been published [4]. Briefly, relapsed myeloma is that which has been previ-ously treated with some form of systemic therapy and which has recurred. That recurrence can be clinical (ie, the development of new or worsening signs or symptoms of active MM) and/or biochemical (ie, rising monoclonal MM proteins in the serum or urine). Refractory MM on the other hand refers to MM that is resistant to particular drugs, defined as MM that is nonresponsive to primary or salvage therapy, or MM that progresses within 60 days of the last therapy [4]. At any juncture during the course

of relapsed MM, patients will have disease that is either sensitive or refractory to specific myeloma drugs. In this article, we discuss management of these often concur-rent entities together as relapsed and refractory multiple myeloma (RRMM).

There are numerous treatment options for patients with RRMM—3 new drugs were approved in Novem-ber 2015 alone. The abundance of available drugs leaves treating clinicians with a daunting task of sequenc-ing therapies among several choices. The durability of response to treatment typically lessens with each disease relapse, such that the clinician needs to think of sequenc-ing not just second-line therapy, but third- and fourth-line as well, further complicating the decision. In this review, we aim to help clinicians individualize treatment plans for patients with RRMM.

CASE STUDIESPatient A

A 62-year-old man with IgG-kappa MM was diagnosed 4 years ago during evaluation of a

pathologic humeral fracture. The disease was prognosti-cally standard risk, with revised International Staging System (RISS) stage I disease (beta-2 microglobulin 3.4 mcg/mL, albumin 4.1 g/dL, normal cytogenetics with 46,XY in 20 cells analyzed, and myeloma fluorescent in situ hybridization [FISH] panel showing t(11;14) but no del17p, t(14;16), t(14;20), or t(4;14)) [5], and normal blood counts, organ function, and lactate dehydrogenase (LDH) at diagnosis. He was treated with 5 cycles of standard lenalidomide, bortezomib, and dexamethasone followed by high-dose melphalan with

Management of Relapsed and Refractory Multiple MyelomaBrandi Reeves, MD, and Sascha A. Tuchman, MD, MHS

From the Division of Hematology and Oncology, Univer-sity of North Carolina – Chapel Hill, Chapel Hill, NC (Dr. Reeves), and the Division of Cellular Therapy and Hemato-logical Malignancies, Duke Cancer Institute, Durham, NC (Dr. Tuchman).

www.jcomjournal.com Vol. 23, No. 10 October 2016 JCOM 471

autologous stem cell transplantation (ASCT) and then lenalidomide continuous maintenance. He achieved a stringent complete response (ie, complete disappearance of myeloma-derived monoclonal proteins in the serum and urine, a normal serum free light chain ratio, and undetectable monoclonal plasma cells on a bone mar-row aspirate and biopsy) [4]. His MM was monitored every 2 to 3 months for disease progression and medica-tion toxicity. At month 38, a monoclonal protein spike (M-spike) on serum protein electrophoresis (SPEP) remained undetectable, but serum kappa free light chain levels increased from 1.98 mg/dL to 8 mg/dL with stable lambda serum free light chains and a ratio that rose to 16, consistent with low-level biochemical recurrence. He had no evidence of end-organ damage and therefore was maintained on lenalidomide mainte-nance for the time being. Over the next 12 months, his kappa serum free light chain level continued to slowly rise, reaching 24 mg/dL, while the ratio rose to 50. There was still no detectable M-spike. He developed mild anemia during this time, with his hemoglobin dropping from a prior value of approximately 11 g/dL to 9.8 g/dL, though kidney function remained normal. A repeat bone marrow aspirate and biopsy revealed 20% kappa-restricted plasma cells.

Patient BA 75-year-old woman with IgA-kappa MM was diag-nosed after laboratory testing by her primary care physi-cian incidentally showed an elevated serum total protein level. The MM was intermediate risk, with RISS stage II disease, and with mild renal impairment resulting in an estimated creatinine clearance of 45 mL/min that was felt to be due to MM. She was initially treated with bort-ezomib and dexamethasone but received only 2 cycles because she developed painful peripheral neuropathy secondary to bortezomib. Bortezomib was stopped and she was then treated with lenalidomide and dexametha-sone for 4 cycles. She achieved a complete response and elected to stop treatment due to fatigue. Her fatigue did not improve off treatment. Six months after stopping therapy, an M-spike was detectable at 0.1 g/dL and she developed a new painful lytic lesion in the left humerus.

Patient C A 59-year-old man with lambda free light chain MM was diagnosed when he presented with acute renal failure requiring dialysis. The disease was RISS-III at diagnosis

(high risk), with the t(4;14) genetic abnormality in his MM cells detected on bone marrow aspirate, an abnor-mality that has been associated with poor prognosis MM [6–8]. The patient was treated with cyclophosphamide, bortezomib, and dexamethasone [9] for 6 cycles, at which point his disease was in a very good partial re-sponse (>90% reduction in M-spike) [4], and his renal function had recovered to a new baseline creatinine clearance of 45 mL/min. He then underwent ASCT after melphalan conditioning followed by bortezomib maintenance therapy every 2 weeks. Eight months after ASCT, his lambda free light chain level increased from 1.25 mg/dL to 45 mg/dL and the ratio increased from 4 to 22. Renal function was unchanged and there was stable anemia, with hemoglobin of 10.1 g/dL.

• WhenshouldtreatmentforRRMMcommence?

Patients with MM in remission are closely monitored, with clinical and laboratory examinations generally conducted every 1 to 3 months. The history is focused on MM-related symptoms such as increasing bone pain or weight loss, and symptoms of therapy-related toxic-ity such as fatigue, gastrointestinal distress, or periph-eral neuropathy. Laboratory assessment typically includes blood counts and chemistry measurements, as well as measurements of MM-derived monoclonal proteins: SPEP, serum immunofixation (IFE), serum immuno-globulin free light chain measurements, and urine pro-tein electrophoresis and immunofixation (UPEP/urine IFE) [10]. Progressive disease biochemically is defined as a 25% increase in M-spike (at least 0.5 g/dL if the M-spike is in serum or > 200 mg/24 hours if in urine), and/or a rise of greater than 10 mg/dL difference between the involved and uninvolved serum free light chains. Clinically progressive disease is denoted as new evidence of end-organ damage such as a new plasma-cytoma, unexplained hypercalcemia, or worsening anemia due to MM [4]. Many, if not most, patients will have biochemical recurrence identified by laboratory measure-ments ofmonoclonal proteins before clinical recurrence transpires.

The velocity of relapse can help guide decisions about when to reinitiate therapy. High-velocity disease relapse, meaning rapid rise in monoclonal proteins, is an indica-tor of more aggressive disease, and treatment should be

Case-based review



initiated promptly before development of symptoms [11]. Conversely, low-level, indolent recurrence can often be followed with a “watch and wait” approach to determine how the myeloma will progress over time. Expert guide-lines suggest that a monoclonal protein doubling time of 2 months may be an appropriate cutoff for determining high versus low velocity [12], although 2 months is not a firm rule and the decision of when to restart treatment for any given patient with asymptomatic biochemical re-currence should be individualized. Importantly, it is not clear that changing therapy at the time of biochemical recurrence, prior to clinical disease progression, improves outcomes, but clinicians are often nonetheless hesitant to hold therapy in the face of biochemically recurrent MM given the potential for complications, such as a patho-logic fracture. In patients with biochemically recurrent MM for whom re-initiation of systemic anti-myeloma therapy is being deferred, one can consider re-initiation of zoledronic acid therapy, since in a randomized con-trolled trial, zoledronic acid commenced at the time of biochemical relapse resulted in fewer skeletal events as compared to placebo [13].

• What disease factors should be considered inchoosingtreatmentforRRMM?

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 reg-imens, 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 (plasmacyto-mas 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 tomogra-phy/computed tomography (PET-CT), or magnetic reso-nance 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.

• Whatpatient factors shouldbe considered inchoosingtreatment?

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 toler-ability 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 bet-ter than lenalidomide [23].

Patient age and functional status are important con-siderations 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.

As part of therapy selection in RRMM, the clinician needs to consider if the patient is a candidate for ASCT. For patients who did not undergo ASCT as part of initial treatment, ASCT can be considered at the time of relapse. Ideally, all patients who could eventually undergo ASCT should have hematopoietic stem cells collected and stored at the time of first induction; however, collection after re-induction chemotherapy has been shown to be fea-sible [28,29]. ASCT for RRMM appears to be effective, although rigorous randomized comparisons of ASCT versus treatment purely with novel drugs are lacking [30–32]. For patients who did receive ASCT consolida-tion in the frontline, if a response is sustained for 18 months or greater, existing guidelines suggest that a sec-ond ASCT is likely worthwhile [29]. Whether the rou-tine usage of maintenance therapies (low-dose, usually single drugs used to prolong duration of remission once remission is achieved) should change that 18-month cut-off is unclear, however, since maintenance “artificially” makes ASCT appear more effective by prolonging post-ASCT duration of remission. The “is it worth it” discus-sion is also largely subjective and hinges heavily on the patient’s experience with the first ASCT. In our practice, we often use 3 years as the cutoff for considering repeat ASCT in patients on maintenance therapy, meaning that if a patient underwent ASCT and received maintenance,

a remission lasting more than 3 years means we consider ASCT as part of therapy for relapse.

Allogeneic stem cell transplantation (allo-SCT) is a treatment option for RRMM generally reserved for fit patients younger than 65 years [22,33]. The timing of allo-SCT is also controversial, with some reserving it as a last option given a historically high transplant-related mortality and improved progression-free survival but not necessarily overall survival benefit. A recent con-sensus statement has suggested allo-SCT be considered (preferentially in a clinical trial) for eligible patients with high-risk disease who relapse after primary treatment that included ASCT [29]. With the abundance of new treatment options in RRMM with reasonable toxicity profiles, it is not clear for whom and when allo-SCT is best considered.

Table 1 summarizes some of the considerations dis-cussed for selecting therapy for RRMM.

• Whichregimenshouldbeusedtotreatafirstrelapse?

Entry into a well-designed clinical trial for patients with RRMM should be considered for every patient since

Case-based review

Table 1.ConsiderationsforTreatmentattheTimeofDiseaseRelapse

Diseasecharacteristics

AdversecytogeneticsorFISH,extramedullarydisease,elevatedLDH,progressiontoplasmacellleukemia,freelightchainescape

Durationofresponsetorecenttreatment

Priortreatmenthistory

End-organdamage

Patientcharacteristics

Age

Fitnesslevel

Organfunction

Comorbidities

Toxicityfrompriortreatment

Financialtoxicity

Patientpreference

Goaloftreatment

FISH = fluorescent in situ hybridization; LDH = lactate dehydro-genase.



there is a lack of evidence to guide the best sequenc-ing of chemotherapies [11]. Beyond that, the choice of therapy is based upon 2 main factors: the disease itself (eg, indolent, asymptomatic biochemical recurrence ver-sus aggressive clinical recurrence with new fractures or extramedullary plasmacytomas), and the patient’s preferences and characteristics, such as age, performance status, comorbidities, and toxicities from prior thera-pies. In looking for the “best” re-induction regimen, it is tempting to compare the efficacy of regimens across trials, but such efforts are fraught given the significant heterogeneity of the patient populations between trials. As an example, comparing daratumumab + pomalid-omide + dexamethasone (DPd) to daratumumab + lenalidomide + dexamethasone (DRd), one may conclude that DRd is superior, given an overall response rate of 88% in DRd versus 58% in DPd. However, the DPd trial included patients who were refractory to lenalidomide and bortezomib, while the DRd study required only treatment with one prior therapy [34,35].

For patients who enjoyed a long remission after any particular chemotherapy regimen with good toler-ability and with indolent features at the time of relapse, re-treating with the same regimen can be considered, although nowadays with so many new and highly potent agents available such “backtracking” is less common and some studies suggest that employing new agents may be beneficial. As an example, in the randomized ENDEAVOR study of bortezomib + dexamethasone versus carfilzomib + dexamethasone in RRMM, 54% of patients had been exposed to bortezomib whereas virtu-ally none had received carfilzomib prior to study enroll-ment. Among those patients with prior bortezomib exposure, median progression-free survival was 15.6 versus 8.1 months (hazard ratio 0.56, [95% confidence interval 0.44 to 0.73]) for carfilzomib versus bortezo-mib, respectively. Follow-up was too immature for defin-itive conclusions to be drawn about overall survival, but the substantial difference in progression-free survival provides a compelling argument for using carfilzomib instead of going back to bortezomib for patients with prior bortezomib exposure [36].

Managing RRMM is by necessity highly individual-ized and so it is difficult in an article to summarize an algorithm. Data from some of the most relevant trials are presented in Table 2 [11,35–51]. In general, therapy for relapse is dictated largely by what drugs a patient has been treated with before. At the time of first relapse,

most patients have been treated previously with some combination of bortezomib and/or lenalidomide, and many patients are on one if not both drugs as maintenance.

For patients who are fit and not very old, we gener-ally employ triplet re-induction. For the large number of these patients who were previously exposed to both le-nalidomide and bortezomib, including as part of a main-tenance strategy, outside of clinical trials we routinely use carfilzomib + pomalidomide + dexamethasone [41]. For patients who are lenalidomide-naïve but bortezomib-exposed, we often employ carfilzomib + lenalidomide + dexamethasone based on the phase 3 ASPIRE trial, which showed a significantly improved progression-free survival with carfilzomib + lenalidomide + dexa-methasone versus lenalidomide + dexamethasone [47]. For patients who have previously received lenalidomide but not bortezomib, we consider pomalidomide + bort-ezomib + dexamethasone [52]. These regimens take advantage of the arguably most potent, most proven drugs in treating RRMM, namely proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (lenalidomide and pomalidomide).

For patients who are more vulnerable to toxicity due to advanced age or comorbidities, we consider less intensive regimens, including dose-reduced triplets or doublets. Patients who had received lenalidomide-based combinations but not bortezomib are considered for a bortezomib-based re-induction, including bortezomib + dexamethasone alone. In the case of someone who had initially received a bortezomib-based combination but no lenalidomide, the new drugs are viable options: ixazomib [53] or elotuzumab [43] can both be added to standard lenalidomide + dexamethasone, with expectations of increasing response rates and progression-free survival and an acceptably low increased risk of severe toxicity. Ixazomib + lenalidomide + dexamethasone also has the benefit of being all-oral. For patients with bortezomib- and lenalidomide-exposed RRMM, using carfilzo-mib [54] or pomalidomide [55] with dexamethasone is reasonable.

Once MM has progressed beyond the arguable “core drugs” of early-stage MM, namely lenalidomide, bortezomib, carfilzomib, and pomalidomide, off pro-tocol we favor daratumumab monotherapy [56,57]. Other options include panobinostat (given usually with bortezomib) [58] and bendamustine [59], among others.


Case-based review

Table 2.TrialsofDrugsforTreatingRelapsedandRefractoryMultipleMyeloma

Agent

In Patients Who Have Received/Are Refractory to

ORR,%

PFS, mo

Considerations

Pomalidomide[37] Bortezomibandlenalidomide 15% Alloral,avoidssteroid

Pomalidomide+dexamethasone[37]

Bortezomibandlenalidomide 34% Alloral

Pomalidomide+cyclophosphamide+dexamethasone[38]

Lenalidomide+2priorlinesoftreatment

65% 9.2 Alloral

Lenalidomide+ixazomib+dexamethasone[39]

1–3lines;couldbeprimaryrefractorydisease

78.3% 20.6 Alloraloption.Thrombocytopenia.27%peripheralneuropathy.Mediantimetoresponseof1.1months.

Ixazomib+panobinostat+dexamethasone[40]

Heavilypre-treated;allrefractorytolenalidomide,mosttobortezomib,carfilzomib,andalkylators

27% Alloral.Phase2studyplanned.

Pomalidomide+carfilzomib+dexamethasone[41]

Refractorytolenalidomide;mostwerealsobortezomibrefractory

50% 7.2 Carfilzomibgivenondays1,2,8,9,15,16ofa28-daycycle

Daratumumab+pomalidomide+dexamethasone[35]

≥2linesincludinglenalidomide+bortezomib

58.5% Daratumumabisalonginfusiongiveninitiallyweekly,thenevery2weeks,thenmonthly

Daratumumab+lenalidomide+dexamethasone[36]

≥1priorline 88% NR At12monthsoffollow-up,themedianPFShadnotbeenreached

Daratumumab+bortezomib+dexamethasone[42]

≥1linesoftherapy,66%hadpriorbortezomib,33%IMiD-refractory

83% NR Daratumumabsignificantlyim-provedORRversusbortezomib+dexamethasonealone(83%vs63%),withsimilarside-effectprofile

Lenalidomide+elotuzumab+dexamethasone[43]

1–3priortreatments 79% 20 Elotuzumabinfusiongivenweeklyfor2months,thenevery2weeks

Lenalidomide+bendamustine+dexamethasone[44,45]

≥1priortreatment 49% 11.8 Neutropenia,thrombocytopenia,anemia,fatigue

Carfilzomib[46] 5linesincludingIMiDandPI 23% 7.8

Carfilzomib+lenalidomide+dexamethasone[47]

1–3priorlines;NOTrefractorytolenalidomideorbortezomib

87% 26.3 Mediantimetoresponse1.6months.Slightcardiacsignalascomparedtolenalidomidealone,with6.4%cardiacfailureofanygradeand5.9%ischemicheartdiseaseofanygrade.Noperipheralneuropathyseen.

Panobinostat+bortezomib+dexamethasone[11,48]

1–3priorlines 61% 11 Diarrhea,fatigue,thrombocytopenia.Responsesseeneveninthosewhohadreceivedpriorbortezomib

Panobinostat+carfilzomib+dexamethasone[49]

≥1priorline;median5lines 67% 7.7

VDT-PACE[50] ≥1priorline 63% 7 67%ORRevenforthoserefractorytoproteasomeinhibition.59%ofpatientsrequiredadosereductionofpanobinostat.

Ixazomib+pomalidomide+dexamethasone[51]

DoublerefractorytolenalidomideandPI

62% Grade3-4neutropenia56%.Inpatientregimen.BestgivenasabridgingtreatmentgivenshortPFS.Oftenusedwhenquickcontrolisneeded

IMid=immunomodulatory;ORR=overallresponserate;PFS=progression-freesurvival;PI=proteasomeinhibitors;VDT-PACE=bort-ezomib,dexamethasone,thalidomide,cisplatin,doxorubicin,cyclophosphamide,andetoposide..



• Can agents to which the MM was previouslyrefractorybereused?

With the understanding that MM is not a disease defined by a single molecular mutation, but rather clones and subclones, it is reasonable to think that even treat-ments that have previously failed may be beneficial to patients if they have been off those treatments for some length of time and sensitive subclones reemerge. Addi-tionally, combining the “failed” agent with a new drug may overcome the previously seen refractoriness, as in the case of panobinostat + bortezomib [48]. That said, given the multitude of new treatment options for RRMM and data from such trials as ENDEAVOR as mentioned, revisiting previously used drugs is probably best reserved for second or greater relapses.

• What should be the duration of therapy forRRMM?

There is no evidence to guide duration of therapy in RRMM. Most patients with relapsed disease will be con-sidered for continuous treatment until disease progres-sion, which usually means treatment for 6 to 12 months with full-dose induction, often to maximal response, followed by transition to some form of lower-dose main-tenance in which parts of a multi-drug regimen may be eliminated and/or the doses for the remaining drugs may be reduced. Patients with a slow-velocity relapse and no markers of high-risk disease may be suitable candidates for a defined course of treatment without maintenance therapy [11], but most patients nowadays remain on some form of maintenance for RRMM after achieving remission.

• WhatsupportivecareisneededinRRMM?

BoneHealthSkeletal-related events, namely fractures, can be dev-astating in MM. Bisphosphonates have been shown to decrease such events in MM and zoledronic acid has shown a trend toward improved survival, perhaps re-

lated to its impact on the bone marrow microenviron-ment or direct toxicity to myeloma cells [60,61]. It is unclear whether bisphosphonates improve overall survival in the relapsed setting, although zoledronic acid has shown decreased skeletal-related events in the setting of biochemical-only disease progression [13,62]. In active RRMM, our general practice is to resume par-enteral bisphosphonate therapy (either zoledronic acid or pamidronate in our U.S. practices) usually every 3 to 4 weeks, depending on the length of the chemotherapy cycle.

SupportiveCareRRMM is a complex disease in which patients often expe-rience a multitude of symptoms and other complications as a result of the disease itself as well as therapy. Aggressive supportive care is of paramount importance. As examples, zoster prophylaxis is required for virtually all patients on proteasome inhibitors, anticoagulation/antiplatelet thera-pies should be considered for venous thrombotic event prophylaxis, and proton pump inhibitors may be appropri-ate for these patients who often have a real risk of peptic ulcer disease due to the use of corticosteroids, nonsteroidal anti-inflammatory drugs, and/or aspirin prophylaxis. Attention to dental health is important for patients on bisphosphonates to minimize the risk of osteonecrosis of the jaw. Nutritional problems should be monitored and can arise due to anorexia, dysgeusia, diarrhea, or constipa-tion. Peripheral neuropathy is extremely common and sup-port should be offered in the form of adjusting therapy to minimize risk of worsening it, analgesics if needed, assis-tive devices to aid in ambulation, and/or physical therapy. Depression and anxiety are understandably prevalent in patients with RRMM, who face an incurable disease that provides constant reminders of its presence due to symp-toms, the need for daily pills, or frequent clinic visits for treatment and/or blood product transfusions [63]. Sup-porting a patient’s emotional health is a vital component of enhancing quality of life in RRMM.

CaseStudiesContinuedPatient A was noted to have biochemical pro-gression initially, with relapse detectable only

in serum free light chains. Treatment commenced at the time of worsening anemia. Notably, his disease origi-nally secreted IgG-kappa and at relapse secreted kappa free light chain only; that is, he developed “light chain escape,” which signifies a high-risk disease and likely


heralds clonal evolution [64]. He had excellent caregiver support and lived within 20 minutes of a treatment center. His performance status remained good at the time of relapse and he had normal organ function. He was treated with carfilzomib + pomalidomide + dexa-methasone for 4 cycles, achieving a very good partial response. He then received a second ASCT with melpha-lan conditioning and again achieved stringent complete response. Indefinite maintenance therapy commenced with pomalidomide, and at 16 months post-ASCT he was doing well and still in remission.

Patient B was symptomatic at the time of disease pro-gression. As her primary complaint was that of a painful humeral lytic lesion, she first underwent a course of pal-liative radiation, which alleviated her pain. She did not wish to restart systemic treatment and instead elected to watch her MM closely with her oncologist on a monthly basis. By 3 months, her M-spike had reached 0.6 g/dL and her serum creatinine had increased slightly, result-ing in a creatinine clearance of 34 mL/min. She lived approximately 90 minutes from the closest treatment facility and found it difficult to come for visits more than once monthly. Her Eastern College Oncology Group (ECOG) performance status was 2. With her advanced age and frailty, she was not considered to be a good can-didate for ASCT. She requested to go back on lenalido-mide and decided with her oncologist to try ixazomib + lenalidomide + dexamethasone, with which she achieved a very good partial response. She had difficulty with myelosuppression with lenalidomide, which was dropped after 4 cycles, and she is planned for ixazomib mainte-nance until disease progression or drug intolerance. She receives monthly zoledronic acid to reduce the risk of fractures.

Patient C has high-risk disease as indicated by R-ISS III stage disease at diagnosis and progression only 8 months after ASCT and while on bortezomib mainte-nance therapy. Although he currently only has evidence of biochemical relapse, prompt initiation of treatment was warranted to prevent further renal compromise such as during his initial presentation [65]. Further, PET-CT showed the presence of extramedullary soft tissue dis-ease, another high-risk feature. He was a robust patient with good social support and received carfilzomib + pomalidomide + dexamethasone re-induction. He was not considered for a second ASCT given his short dura-tion of response. With his high-risk features of early re-lapse after ASCT, R-ISS III, and extramedullary disease,

it was recommended that he continue triplet drug ther-apy until disease relapse or drug intolerance.

OngoingandFutureTrialsThe management of RRMM will continue to evolve as paradigms for treating MM change and new treatment options become available. In particular, immunothera-pies (ie, approaches that harness the immune system’s ability to fight cancer) are under exploration and some such drugs that are already FDA-approved in other diseases are being tested in MM. Chimeric antigen receptor-T cells (CAR-T), a form of cell-based immuno-therapy, have generated tremendous excitement in acute lymphocytic leukemia [66] and are being tested in MM [67]. New analogs of old drugs may offer more effective, less toxic ways to control MM. The role of ASCT is being explored in randomized trials investigating whether ASCT should be pursued early or late in a patient’s MM course. These studies will no doubt further augment the armamentarium of anti-myeloma drugs that have already resulted in the increasingly longer survival we see today in this disease [3,68]. That said, MM remains incurable, and almost all patients who live long enough eventu-ally relapse and die of MM. Hence, further research and progress are critical.

SummaryA well-designed clinical trial should be considered for all patients with RRMM, and in lieu of an available trial, regimen selection should be tailored upon disease and patient characteristics. Carfilzomib-based regimens are among the most popular at the time of first relapse cur-rently based upon their efficacy in bortezomib-refractory cases and tolerability. Pomalidomide shows activity in lenalidomide-refractory patients. Due to intra-clonal het-erogeneity, triplet regimens are preferred for fit patients, reserving doublet or monotherapy for those patients who are frail or who have an indolent disease relapse. Ongoing research will undoubtedly improve outcomes for RRMM, a disease for which the prognosis is far bet-ter than it formerly was, but which still has quite a bit of room for improvement.

Corresponding author: Brandi Reeves, MD, University of North Carolina – Chapel Hill, 170 Manning Dr., Physi-cians’ Office Building, CB 7305, Chapel Hill, NC 27599, [email protected].

Financial disclosures: Dr. Tuchman reports the following:

Case-based review



speakers’ bureau: Celgene, Takeda; consulting: Celgene, Takeda; research support: Celgene, Takeda, Novartis, Onyx.

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