Therapy for Relapsed Multiple Myeloma

REVIEW

Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy David Dingli, MD, PhD; Sikander Ailawadhi, MD; P. Leif Bergsagel, MD; Francis K. Buadi, MD; Angela Dispenzieri, MD; Rafael Fonseca, MD; Morie A. Gertz, MD; Wilson I. Gonsalves, MD; Susan R. Hayman, MD; Prashant Kapoor, MD; Taxiarchis Kourelis, MD; Shaji K. Kumar, MD; Robert A. Kyle, MD; Martha Q. Lacy, MD; Nelson Leung, MD; Yi Lin, MD, PhD; John A. Lust, MD, PhD; Joseph R. Mikhael, MD; Craig B. Reeder, MD; Vivek Roy, MD; Stephen J. Russell, MD, PhD; Taimur Sher, MD; A. Keith Stewart, MBChB; Rahma Warsame, MD; Stephen R. Zeldenrust, MD, PhD; S. Vincent Rajkumar, MD; and Asher A. Chanan Khan, MD Abstract Life expectancy in patients with multiple myeloma is increasing because of the availability of an increasing number of novel agents with various mechanisms of action against the disease. However, the disease remains incurable in most patients because of the emergence of resistant clones, leading to repeated relapses of the disease. In 2015, 5 novel agents were approved for therapy for relapsed multiple myeloma. This surfeit of novel agents renders management of relapsed multiple myeloma more complex because of the occurrence of multiple relapses, the risk of cumulative and emergent toxicity from previous therapies, as well as evolution of the disease during therapy. A group of physicians at Mayo Clinic with expertise in the care of patients with multiple myeloma regularly evaluates the evolving literature on the biology and therapy for multiple myeloma and issues guidelines on the optimal care of patients with this disease. In this article, the latest recommendations on the diagnostic evaluation of relapsed multiple myeloma and decision trees on how to treat patients at various stages of their relapse (off study) are provided together with the evidence to support them. ª 2017 Mayo Foundation for Medical Education and Research

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ultiple myeloma, a malignant disorder of clonal plasma cells, remains incurable in most patients despite the development of novel therapies that have improved the depth and duration of responses and prolonged survival for many patients with this disease.1,2 Advances in our understanding of the biology of the disease aided by novel technologies such as next-generation sequencing show that genetically, the disease is highly heterogeneous,3-7 although it is possible to stratify patients into different disease risk groups, an approach that can have a meaningful effect on the choice of therapy and clinical outcomes.8,9 In parallel with this

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understanding, the field has witnessed a sea change with the development of many novel therapeutic agents, including immunomodulatory drugs (IMiDs) such as lenalidomide10 and pomalidomide11,12; proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib13,14; monoclonal antibodies (MAbs) including daratumumab15 and elotuzumab16; and histone deacetylase inhibitors such as panobinostat17 that have continued to improve overall survival in patients with this disease. The availability of so many novel agents has led to the development of a multitude of viable treatment options that have also altered the paradigm of therapy. Concomitantly, the

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From the Division of Hematology (D.D., F.K.B., A.D., M.A.G., W.I.G., S.R.H., P.K., T.K., S.K.K., R.A.K., M.Q.L., Y.L., J.A.L., S.J.R., R.W., S.R.Z., S.V.R.) and Division of Nephrology (N.L.), Department of Internal Medicine, Mayo Clinic, Rochester, MN; Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL (S.A., V.R., T.S., A.A.C.K.); and Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ (P.L.B, R.F., J.R.M., C.B.R., A.K.S.).

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not possible, then we follow these guidelines, taking into account the patient’s comorbidities23,24 and wishes after a discussion of various treatment options, the expected toxicity, and potential outcomes. Given that this article relates only to therapy for relapsed multiple myeloma, we will not discuss the diagnosis and initial management of the disease. The reader is referred to various guidelines that have been published by our group in this regard.20-22

ARTICLE HIGHLIGHTS d

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d

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Major advances have occurred in the therapy of multiple myeloma with several new classes of agents approved in 2015. Therapy of relapsed multiple myeloma is becoming more complex due to the development of such novel agents. Restaging of myeloma and evaluation for disease evolution is important at the time of relapse. Combination therapy that incorporates novel agents such as monoclonal antibodies is recommended.

d

Patients should be considered for stem cell transplant at time of relapse.

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The disease can evolve to secondary plasma cell leukemia or extramedullary myeloma at any time. Guidelines for therapy of first, second, or third relapse of the disease are provided.

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application of tools that reliably assess the “frailty” of patients with myeloma is also helping with decision making, given that many patients with myeloma are elderly and often have significant comorbidities.18,19 More than 25 Mayo Clinic physicians with a special interest in the care of patients with multiple myeloma have developed guidelines for therapy for this disease that are based on consensus after a careful review of the current literature. This led to the development of the Mayo Stratification for Myeloma and RiskAdapted Therapy. The group has published guidelines for newly diagnosed myeloma in 2007, 2009, and 2013.20-22 These guidelines, which are available online at http://www. msmart.org, are updated regularly as new data become available. Given the recent developments in therapy, Mayo Clinic physicians have updated their consensus opinion on optimal therapy for relapsed multiple myeloma, and these guidelines and their justification are presented. Emphasis is based on the outcomes from randomized controlled trials, but if such data do not exist, the guidelines are based on consensus within the group. We used a standard system for rating the evidence and grading of recommendations as outlined in Table 1. It should be stressed from the outset that it is always preferable to enroll patients in well-designed clinical trials, but if this is 2

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DRUGS APPROVED FOR THERAPY FOR MULTIPLE MYELOMA Currently, there are 6 classes of medications that are used for therapy for relapsed multiple myeloma: (1) IMiDs, (2) PIs, (3) histone deacetylase inhibitors, (4) MAbs, (5) DNA alkylating agents, and (6) glucocorticosteroids. Other agents such as doxorubicin, cisplatin, and etoposide are also often used in combination chemotherapy for multiple myeloma. Although many of these have single agent activity, when used alone the duration of response is limited and the depth of response achieved is often poor. However, when agents from these various classes are used in combination, they are highly active and lead to responses of considerable duration, especially when used in synergistic combinations that also reduce the risk of toxicity. Many of these agents have been used in combination therapy, and we provide a list of randomized studies of therapies for relapsed multiple myeloma in Table 2. Immunomodulatory Drugs The prototype IMiD was thalidomide,39,40 although it is not often used in the United States because of the neurotoxicity, fatigue, constipation, and cost. However, it may still be a useful agent, especially in patients with renal insufficiency or cytopenias, in whom it can be safely used and even combined with other agents such as alkylating agents,41-45 dexamethasone, and PIs with good effect.29,43,46,47 Lenalidomide is a second-generation IMiD that is more potent and generally has a better safety profile than does thalidomide. Lenalidomide is approved for initial therapy for myeloma and for relapsed disease. The

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combination of lenalidomide and dexamethasone (Rd) has been the standard of care for relapsed multiple myeloma according to 2 large international randomized trials (MM-009 and MM-010).26,27 It can also be combined with PI,33,36,48,49 alkylating agents,45,50 and MAbs,34,38,51 leading to high response rates (Table 2). The main toxicities related to lenalidomide are cytopenias, fatigue, and diarrhea. Lenalidomide-induced diarrhea is often due to bile acid malabsorption and can be effectively treated with bile acid sequestrants such as cholestyramine and colesevelam.52 Patients who are experiencing an indolent relapse of the myeloma while taking maintenance lenalidomide may respond when the dose is increased or the drug is combined with other agents such as bortezomib or cyclophosphamide. More recently, pomalidomide was approved by the Food and Drug Administration for therapy for relapsed multiple myeloma in combination with dexamethasone.31,53 It is an even more potent IMiD and seems to induce responses even in patients who are lenalidomide resistant or refractory.11,31,53,54 Pomalidomide can be combined with cyclophosphamide,55,56 carfilzomib,57 or bortezomib,58,59 and clarithromycin. The combination of pomalidomide, bortezomib, and dexamethasone is associated with a response rate of 65% and 80% in patients who are refractory to lenalidomide, even with previous exposure to a PI.58,59 One potential adverse effect shared by all IMiDs is the risk of thrombosis. Unless there is a contraindication, patients should be receiving some form of thromboprophylaxis while taking these agents.60 Although aspirin may be adequate for thromboprophylaxis for the patient at an average risk of deep venous thrombosis, low-molecularweight heparin or oral vitamin K antagonists may be needed for patients at higher risk of thrombosis.60-62 Proteasome Inhibitors Bortezomib was a first-in-class, reversible PI that is given parenterally.25 The subcutaneous route is equally effective as the intravenous route and associated with a considerably lower risk of peripheral neuropathy.63-66 Bortezomib, together with dexamethasone, can be combined with cyclophosphamide,67 Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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TABLE 1. Classification System for Levels of Evidence and Grades of Recommendations Type of evidence Level I

II

III

IV V

Type of evidence Evidence obtained from a meta-analysis of multiple, well-designed, controlled studies. Randomized trials with low false-positive and low false-negative errors (high power) Evidence obtained from at least 1 well-designed experimental study. Randomized trials with high false-positive and/or false-negative errors (low power) Evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, time series, or matched case-control series Evidence from well-designed, nonexperimental studies, such as comparative and correlational descriptive and case studies Evidence from case reports and clinical examples Grade of recommendation

Grade A B C D

Type of evidence Evidence of type I or consistent findings from multiple studies of type II, III, or IV Evidence of type II, III, or IV, and findings are generally consistent Evidence of type II, III, or IV, but findings are inconsistent Minimal or no systematic empirical evidence

thalidomide,68 and lenalidomide,69 resulting in highly active regimens for relapsed multiple myeloma. The risk of neuropathy is increased when bortezomib is combined with thalidomide.70 Patients treated with bortezomib or other PI should be taking acyclovir or valacyclovir to suppress herpes virus reactivation. Proteasome inhibitors are considered critical components of any regimen that is used to treat patients with high-risk myeloma or patients with renal failure. Carfilzomib is a novel epoxy-ketone tetrapeptide that irreversibly binds and inhibits the proteasome. It is given intravenously and was approved for relapsed and refractory multiple myeloma in 2013 for patients who have been previously treated with lenalidomide and bortezomib.71 The main adverse effects of carfilzomib are fatigue, anemia, nausea, thrombocytopenia, and hypertension.35 Carfilzomib and dexamethasone (Kd) can be combined with lenalidomide,33 cyclophosphamide,43 or pomalidomide57 and such combinations are associated with high response rates in the relapsed setting. The incidence of neuropathy with carfilzomib is low, and therefore, carfilzomib is an attractive agent in patients with preexisting neuropathy

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TABLE 2. Phase 3 Trials on Relapsed Multiple Myeloma Reference, year

Regimen

No. of patients

ASCT (%)

ORR (%)


VGPR (%)

PFS (mo)

HR

Richardson et al,25 2005

Vd D Rd D Rd D V-PLD V VTD TD VþVori V Pd D PanoVD Vd KRd Rd ERd Rd Kd Vd IRd Rd DVd Vd DRd Rd

333 336 176 175 177 176 324 322 135 134 317 320 302 153 387 381 396 396 321 325 464 465 360 362 251 247 286 283

67.0 68.0 61.9 28.4 66.1 19.4 57.0 54.0 53.0 53.0 36.0 36.0 71.0 69.0 56.0 59.0 54.8 57.8 52.0 57.0 37.2 49.6 59.0 55.0 62.2 60.3 62.9 63.6

38 18 60.2 24.0 61.0 19.1 44.0 41.0 87.0 72.0 56.2 40.6 31.0 10.0 60.7 54.6 87.1 66.7 79.0 66.0 77.0 63.0 78.0 72.0 82.9 63.2 92.9 76.4

7 1 24.4 5.1 24.3 1.7 27.0 19.0 56.0 35.0

7.0 5.6 11.3 4.7 11.1 4.7 9.3 6.5 19.5 13.8 7.6 6.8 4.0 1.9 11.99 8.08 26.3 17.6 19.4 14.9 18.7 9.4 20.6 14.7 NR 7.2 NR 18.4

0.55

Dimopoulos et al,26 2007 Weber et al,27 2007 Orlowski et al,28 2007 Garderet et al,29 2012 Dimopoulos et al,30 2013 San Miguel et al,31 2013 San Miguel et al,32 2014 Stewart et al,33 2015 Lonial et al,34 2015 Dimopoulos et al,35 2016 Moreau et al,36 2016 Palumbo et al,37 2016 Dimopoulos et al,38 2016

6.0 <1.0 27.6 16.0 69.9 40.4 33.0 28.0 54.0 29.0 48.0 39.0 59.2 29.1 75.8 44.2

0.65 0.35 0.55 0.59 0.77 0.48 0.63 0.69 0.70 0.53 0.74 0.39 0.37

ASCT ¼ autologous stem cell transplant; D ¼ dexamethasone; DRd ¼ daratumumab, lenalidomide, and dexamethasone; DVd ¼ daratumumab, bortezomib, and dexamethasone; ERd ¼ elotuzumab, lenalidomide, and dexamethasone; HR ¼ hazard ratio; IRd ¼ ixazomib, lenalidomide, and dexamethasone; Kd ¼ carfilzomib and dexamethasone; KRd ¼ carfilzomib, lenalidomide, and dexamethasone; NR ¼ not reached; ORR ¼ overall response rate; PanoVD ¼ panobinostat, bortezomib, and dexamethasone; Pd ¼ pomalidomide and dexamethasone; PFS ¼ progression-free survival; Rd ¼ lenalidomide and dexamethasone; TD ¼ thalidomide and dexamethasone; V ¼ bortezomib; Vd ¼ bortezomib and dexamethasone; VGPR ¼ very good partial response; V-PLD ¼ bortezomib, pegylated liposomal doxorubicin, and dexamethasone; VTD ¼ bortezomib, thalidomide, and dexamethasone; VþVori ¼ bortezomib and vorinostat.

and in whom therapy with a PI is considered important. There are rare reports of thrombotic microangiopathy with PI, and therefore clinicians need to be aware of this problem, especially in patients who develop hypertension and thrombocytopenia during therapy.72 Proteasome inhibitors may be associated with an increased risk of cardiotoxicity, and this potential complication has to be kept in mind when patients present with symptoms of congestive heart failure.73 Ixazomib is the first oral PI that was approved by the Food and Drug Administration in 2015 for therapy for relapsed 4

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multiple myeloma in combination with lenalidomide and dexamethasone (IRd).36 Although the risk of peripheral neuropathy associated with ixazomib is lower than with bortezomib, it is associated with a higher incidence of gastrointestinal toxicity (nausea, vomiting, and diarrhea) as well as a rash, although the latter is uncommon. Ixazomib is also active when combined with cyclophosphamide and dexamethasone (ICd). Therefore, IRd and ICd provide convenient “all oral” regimens that may be particularly attractive to patients with indolent relapse of their disease.

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Histone Deacetylase Inhibitors Panobinostat is a pan-histone deacetylase inhibitor that was approved by the Food and Drug Administration in 2015 for the treatment of patients with multiple myeloma who have received at least 2 previous therapies that include bortezomib and an IMiD.32 Panobinostat inhibits the aggresome pathway in myeloma cells that can be used to bypass the proteasome and result in PI resistance. Therefore, in principle, the combination of panobinostat and PIs should be synergistic.74 The major quality-of-lifeeaffecting adverse effects of panobinostat are significant (grade 3 or 4) diarrhea and fatigue that can occur in approximately 25% of patients.

Monoclonal Antibodies Daratumumab is an MAb directed at CD38, an antigen that is highly expressed by malignant plasma cells. The antibody has single agent activity in the setting of relapsed multiple myeloma that approaches 30%75 and even higher activity when combined with PIs or IMiDs (CASTOR37 and POLLUX38 trials, respectively). It was approved in 2015 for therapy for relapsed multiple myeloma in patients who have received at least 3 previous therapies including PIs and IMiDs or who are considered to have disease that is double refractory to a PI/IMiD combination. Daratumumab kills myeloma cells via a number of mechanisms including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and by interfering with the enzyme activity of CD38.76,77 The antibody is given by a slow intravenous infusion and is generally well tolerated: reactions tend to occur mainly during the administration of the first dose. It is an IgG1 kappa antibody, and its presence in the circulation can interfere with the interpretation of the results of serum protein electrophoresis and immunofixation (if the patient’s myeloma cells also produce an IgG kappa). Similarly, it can interfere with the monitoring of minimal residual disease by multicolor flow cytometry. Because erythrocytes express CD38, daratumumab therapy can interfere with cross-matching techniques.78,79 Therefore, it is recommended that a comprehensive red cell antigen screen is performed by the blood bank before the initiation of therapy with this agent. Moreover, Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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dithiothreitol treatment of reagent erythrocytes used for antibody screening appears to reliably eliminate the confounding effect of daratumumab in the patient’s serum.80 The only caveat is that dithiothreitol therapy removes the Kell antigen from the erythrocytes, and so patients must be transfused with Kell negative blood. With the increasing use of mass spectrometry to identify serum monoclonal proteins, the potential problem of interpretation of serum protein electrophoresis and immunofixation results will be resolved because the peak due to daratumumab will be reliably identified as distinct from the plasma cellerelated monoclonal protein.81 Elotuzumab is an MAb that targets the signaling lymphocyte activation molecule F7 that is expressed on myeloma cells and, to a lesser extent, on natural killer cells. Most myeloma cells express the signaling lymphocyte activation molecule F7 that is independent of the underlying cytogenetic abnormality driving the disease. Elotuzumab kills myeloma cells via 2 mechanisms: (1) it directly activates natural killer cells and (2) it kills via antibody-dependent cellular cytotoxicity.82 It was the first MAb approved for therapy for relapsed multiple myeloma in 2015. Although elotuzumab has no single agent activity against multiple myeloma, it appears to be synergistic with Rd in the relapsed myeloma setting with an improvement in progression-free survival (PFS) compared with Rd alone (ELOQUENT-2 study34). Elotuzumab infusions are well tolerated and, in general, are of shorter duration than daratumumab infusions. Therefore, elotuzumab may be a particularly suitable agent in combination with Rd for frail patients with indolent relapse of their multiple myeloma who have disease that is not refractory to lenalidomide.

Alkylating Agents Cyclophosphamide is an alkylating agent that has single agent activity against myeloma. It is used in combination therapy with thalidomide,44,83 lenalidomide,84,85 pomalidomide,56 bortezomib,86,87 carfilzomib, or ixazomib43,88 and sometimes even as single agent for maintenance therapy after autologous stem cell transplant (ASCT).89 Prolonged use of this

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agent can lead to myelodysplastic syndrome and secondary acute leukemia. Melphalan has been available for therapy for multiple myeloma for more than 50 years. Apart from its established use as the conditioning agent of choice before ASCT, it has been studied in combination with IMiDs45,90-92 and PIs46,93,94 both for induction of newly diagnosed myeloma and in the relapsed setting, the latter in combination with panobinostat.95 It is reserved for patients who are not candidates for ASCT. Prolonged use of this agent can increase the risk of myelodysplasia as well as acute myeloid leukemia.96 Bendamustine is a multifunctional alkylating agent that is often used to treat lymphoid malignant neoplasms. It has single agent activity in multiple myeloma, but it is generally used in combination with dexamethasone and IMiDs97,98 or bortezomib99-102 for therapy for relapsed disease. The major adverse effects of bendamustine are fatigue, rash, headache, constipation, and cytopenias. Cytopenias may be prolonged, especially in heavily treated patients, and this may limit the extended use of bendamustine combinations in patients with relapsed disease. Several additional agents are being studied in clinical trials and show promise in relapsed multiple myeloma. These include the oral PI oprozomib103 that is related to carfilzomib and marizomib104; dinaciclib,105 an oral cyclin-dependent kinase inhibitor; selinexor,106 a selective inhibitor of exportin 1; venetoclax,107 a selective inhibitor of bcl-2, and isatuximab,108 a novel MAb that also targets CD38 and may have a more favorable pharmacological profile than does daratumumab. Other agents in early clinical trials include immune checkpoint inhibitors (pembrolizumab and nivolumab) and chimeric antigen receptor T cells. EVALUATION OF DISEASE RELAPSE Before the initiation of therapy for relapsed multiple myeloma, a full history, physical examination, and restaging of the disease are essential to determine whether this is simply a biochemical relapse (that is to be expected in most patients) or a more aggressive relapse. In addition, full staging provides an opportunity to consider the patient for specific clinical trials that increasingly target patients with 6

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restricted characteristics (eg, venetoclax for myeloma cells that have the t(11;14) or chimeric antigen receptor T cells therapy for patients with myeloma cells that express B cell maturation antigen). Given that many patients are now receiving maintenance therapy, it is expected that they are followed on a regular basis. We routinely monitor patients with monoclonal protein studies in the serum and urine, complete blood cell count, calcium and creatinine levels, at least every quarter. In addition, we recommend that skeletal imaging is performed yearly even in the absence of symptoms to detect evidence of early radiological progression. Our preferred surveillance imaging modality is low-dose skeletal computed tomography (CT). However, depending on the symptoms, we proceed with other imaging studies such as magnetic resonance imaging (MRI), positron emission tomography (PET)/CT, or PET/ MRI. One has to keep in mind that myeloma evolves,109,110 and patients with standardrisk disease may acquire new mutations such as 17p deletion, which leads to a loss of TP53 and other genes111; 1q amplification112; 1p deletion5,113,114; or MYC rearrangement.115,116 Acquisition of these secondary mutations alters the patient’s risk stratification and has an additional effect on prognosis.117 Moreover, the disease may progress because of the development of extramedullary plasmacytomas (suggestive of independence from the bone marrow microenvironment) or evolve into secondary plasma cell leukemia.118 Therefore, a bone marrow biopsy with fluorescence in situ hybridization (FISH) studies and imaging studies such as PET/CT or PET/MRI are useful if relapse or progression of multiple myeloma is suspected.119,120 In patients with known cytogenetic or FISH abnormalities, a more limited panel that evaluates for the development of high-risk abnormalities that can be acquired with disease evolution may be adequate. We routinely determine the fraction of clonal plasma cells that are in the “S” phase of the cell cycle because a high fraction (>3%) is associated with a short duration of response.121,122 If indicated, gene expression profiling may be performed to further understand the behavior of the disease and guide therapy,123 although this is not always necessary. We also routinely determine whether

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TABLE 3. Prognostic Factors in Relapsed Multiple Myeloma Tumor cell related Ploidy (hyperdiploidy vs hypodiploidy) Translocations t(4;14) t(6;14) t(11;14) t(14;16) t(14;20) Monosomy 13 (by cytogenetics) 17p deletion (or loss of TP53) 1q amplification 1pComplex karyotypes Lactate dehydrogenase (above normal) Circulating plasma cells (any number) Plasma cell growth rate (>3% by flow cytometry) Gene expression profile (various platforms) Tumor burden Durie-Salmon stage International Staging System Extramedullary disease Patient related Age Performance status Renal failure Frailty (IMWG guidelines) IMWG ¼ International Myeloma Working Group.

there are circulating clonal plasma cells by flow cytometry because this is more sensitive than morphological evaluation by the blood smear. The presence of circulating clonal plasma cells also suggests active, and generally more aggressive, disease and has an effect on prognosis.122,124,125 A summary of prognostic factors relevant to patients with relapsed multiple myeloma is provided in Table 3. On the basis of these studies, patients are stratified into low-, intermediate-, and highrisk disease,20-22,114,123,126-132 similar to the newly diagnosed setting (Figure 1) but with the difference that patients who previously had standard- or intermediate-risk disease may subsequently be reclassified into the high-risk group because of the acquisition of additional mutational events as discussed above. Patients who progress while receiving therapy, or within the first year of diagnosis, also have a poor prognosis. These patients should be considered to have high-risk disease Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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regardless of their cytogenetic or FISH abnormalities.133 Similarly, the duration of the interval between the last therapy and biochemical or clinical relapse is also critically important. A slow biochemical relapse years after ASCT or last therapy suggests an indolent form of the disease. In contrast, relapse soon after discontinuing therapy or within 18 months of ASCT,134 or while receiving maintenance therapy or the development of hypercalcemia or extramedullary plasmacytomas suggests more aggressive disease. Apart from the clinical examination, estimation of the N-terminal prohormone of brain natriuretic peptide level can provide a simple strategy to determine whether a patient is frail135 or otherwise fit to withstand the rigors of therapy for relapsed multiple myeloma.136 Our approach is to attempt treating patients with high-risk disease continuously because PFS in such patients is generally short, and keeping the disease burden as low as possible theoretically reduces the risk or rate of acquisition of additional mutations, leading to subsequent therapeutic failures and progression of the disease. Recommendation: All patients should undergo full staging and risk stratification at the time of relapse to determine whether they have aggressive vs indolent relapse and standard-, intermediate-, or high-risk relapsed multiple myeloma. Level of evidence: II Grade: A THERAPY FOR PATIENTS IN FIRST RELAPSE Patients may experience relapse of their disease either while receiving maintenance therapy (eg, lenalidomide or bortezomib after ASCT137,138) or continuous therapy (in ASCT-ineligible patients), or after induction therapy139,140 or while being observed expectantly in the absence of therapy (Figure 2). The major determinants of the best therapeutic options are (1) the general state of health of the patient; (2) the nature of the relapsedwhether it is indolent or aggressive; (3) the agents used for previous therapy as well as the quality (depth) and duration of the response to that therapy; and (4) FISH data on the relapsed bone marrow. Information about previous adverse effects related to each drug used is also important

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Classification of relapsed multiple myeloma

High risk

• Primary refractory disease • Relapse <12 months from ASCT • Progression within the first year of diagnosis • FISH • Deletion 17p • t(14;16) • t(14;20) • High risk GEP

Intermediate risk

• FISH • t(4;14) • 1q amp • High "S" phase

Standard risk

All others including • Trisomies • t(11;14) • t(6;14)

FIGURE 1. MSMART risk stratification in relapsed multiple myeloma. ASCT ¼ autologous stem cell transplant; FISH ¼ fluorescence in situ hybridization; GEP ¼ gene expression profiling; MSMART ¼ Mayo Stratification for Myeloma and Risk-Adapted Therapy.

to help in the selection of therapy for relapsed disease. There is increasing evidence that deeper responses are associated with better PFS if not overall survival.141-143 Therefore, it is our approach to try and achieve as deep a response as possible after the first relapse in an attempt to favorably affect overall survival, keeping in mind the presence of comorbidities, the quality of life of the patient, including the need for frequent and perhaps lengthy clinical visits, and the expense of therapy. Given the superiority of triple combination therapy for both newly diagnosed144,145 and relapsed multiple myeloma,29,33 we also generally prefer triple combination therapy for relapsed disease, as long as the patient can tolerate the therapy. However, therapy with doublets such as Rd, pomalidomide and dexamethasone (Pd), bortezomib and dexamethasone (Vd), or Kd is acceptable for patients with significant comorbidities. We do not routinely escalate therapy in patients who have their disease in control and are tolerating therapy well. The duration of therapy in patients with relapsed multiple myeloma is not well defined. It may be reasonable to treat until a plateau is reached in patients who have indolent relapse and then observe carefully in the absence of therapy in an attempt to minimize the risk of toxicity. However, most patients continue the therapy until they 8

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relapse or progress on second-line therapy or they develop significant toxicity. In the latter scenario, it is reasonable to adjust the dose of the offending agent in an attempt to reduce toxicity before eliminating that agent or substituting it with a complementary drug that has a lower risk of inducing the same toxicity (eg, substituting bortezomib with carfilzomib if neuropathy becomes significant and if the use of a PI is considered to be important, especially in high-risk patients). We often try to reduce the dose of dexamethasone after the maximal response is achieved to improve the quality of life and reduce the risk of metabolic adverse effects and immunosuppression that are inherent to long-term glucocorticosteroid use. Patients who are fit or are experiencing an indolent relapse should be considered for a salvage ASCT.146-149 Moreover, patients who already had ASCT can be considered for a second ASCT if they are clinically eligible and had a meaningful response to the first transplant with either a response that lasted at least 18 months in the absence of maintenance therapy or a response that lasted more than 36 months while receiving maintenance therapy.89,147,148,150-152 In the NRCI Myeloma X Relapse [Intensive trial], 174 patients with relapsed multiple myeloma received reinduction with bortezomib, doxorubicin, and dexamethasone and then randomized to a second ASCT or oral cyclophosphamide (400 mg/m2 weekly for 12 weeks). The median time to progression for the ASCT arm was 19 months compared with 11 months for controls (P<.0001).89 Moreover, overall survival for patients randomized to a second ASCT was higher than for controls (67 months vs 52 months; P¼.0169).153 Given that these patients did not receive any maintenance therapy after their second ASCT, the duration of the response is acceptable. There is increasing evidence of benefit of ASCT even in the older population, and therefore patients should be referred for evaluation to a transplant center because ASCT can have a positive effect on survival in this population.154-156 Relapse in Patients Receiving Maintenance Therapy Our general approach for patients who relapse while receiving maintenance with either

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lenalidomide or bortezomib is to initiate triple combination therapy with at least 1 new class of agents and/or a change to a next-generation agent from the same class because of a higher probability of a response.54,157 Therefore, we recommend a combination of carfilzomib, pomalidomide, and dexamethasone (KPd)57 or daratumumab, bortezomib, and dexamethasone (DVd)37 for fit patients who relapse while receiving, or soon after discontinuing, lenalidomide maintenance. In contrast, for patients who relapse while receiving maintenance therapy with bortezomib or soon after discontinuing bortezomib maintenance, we recommend therapy with daratumumab, lenalidomide, and dexamethasone (DRd).38,51 It should be noted that disease progression while taking a specific agent does not necessarily imply that such an agent cannot be used again in the future. The tumor group is composed of various subpopulations that may have differing sensitivities to the various agents available to treat multiple myeloma. A change in therapy may suppress one clone, whereas another clone that may be sensitive to other agents may emerge leading to “clonal tides.”7 Such clonal selection has been well documented158 and will likely become more important in the future as technology to determine drug sensitivity becomes available. In a phase 1 trial of patients who were lenalidomide refractory (100%) and mostly bortezomib refractory (91%), the combination of KPd (carfilzomib 20/27 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16; pomalidomide 4 mg daily on days 1-21; and dexamethasone 40 mg orally weekly) was generally safe and well tolerated. The main adverse effects were hematologic, with grade 3 or higher anemia observed in 34% of patients. In this cohort of heavily pretreated patients (median of 6 previous regimens), the overall response rate was 50%, with 16% achieving a very good partial response (VGPR) and a median PFS of 7.2 months. In a small number of patients with 17p deletion, the PFS at 12 months was 60% and overall survival was 80% at 12 months.57 In a phase 1/2 trial of the single agent daratumumab in patients with relapsed, heavily treated multiple myeloma, the overall response rate approached 40%.159 Recently, the results of the CASTOR trial37 were reported. In this Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

n

Therapy at first relapse (off study)

Receiving maintenancea

Fit patient

Indolent relapse or frail patient

• Receiving lenalidomidea • KPd • DVd

• Receiving lenalidomidea • DVd • ICd

• Receiving bortezomiba • DRd

• Receiving bortezomiba • IRd • DRd

a

Discontinued therapy/unmaintaineda

Fit patient

• KRda • DRda

Indolent relapse or frail patient • IRda • ERda

ASCT is an option for select patients.

FIGURE 2. Therapy for multiple myeloma at first relapse. The approach depends on the biology of the relapse (indolent vs aggressive), the performance status of the patient, molecular features of the disease, and the therapeutic history. ASCT ¼ autologous stem cell transplant; DRd ¼ daratumumab, lenalidomide, and dexamethasone; DVd ¼ daratumumab, bortezomib, and dexamethasone; ERd ¼ elotuzumab, lenalidomide, and dexamethasone; ICd ¼ ixazomib, cyclophosphamide, and dexamethasone; IRd ¼ ixazomib, lenalidomide, and dexamethasone; KPd ¼ carfilzomib, pomalidomide, and dexamethasone; KRd ¼ carfilzomib, lenalidomide, and dexamethasone.

trial, 498 patients with relapsed multiple myeloma were randomized in a 1:1 ratio to 8 cycles of bortezomib and dexamethasone (bortezomib 1.3 mg/m2 subcutaneously on days 1,4, 8, and 11 and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) with or without daratumumab (16 mg/kg intravenously weekly for the first 3 cycles, day 1 of cycles 4 to 8, and then every 4 weeks). Patients had received a median of 2 (range, 1-10) previous lines of therapy, with 66% having been exposed to bortezomib, 76% to an IMiD, and 48% to both a PI and an IMiD. One-third of the patients were considered to be refractory to IMiDs, and 32% were refractory to their last line of therapy at the time of enrollment in the study. Although the median follow-up is short (7.4 months), the addition of daratumumab significantly increased the overall response rate (83% vs 63%) and doubled the depth of response (VGPR: 59% vs 29%; complete response [CR]: 19% vs 9%; P<.001). The

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improved responses translated into better PFS (not reached vs 7.14 months; P<.0001), with a 61% reduction in the risk of progression or death from multiple myeloma. The time to progression was also not reached compared with 7.29 months for patients taking Vd alone, giving a 70% reduction in the risk of progression. The most common toxicity related to daratumumab was infusion related and mostly restricted to the first dose. Thrombocytopenia (54%) and peripheral neuropathy (47%) were also common.37 In the POLLUX study,38 569 patients with relapsed multiple myeloma (at least 1 previous line of therapy) were randomized to Rd (lenalidomide 25 mg orally on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22 with therapy repeated every 28 days) with or without daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks until progression). The median number of previous therapies was 1 (range, 1-11): 86% had been treated with a PI, 55% with an IMiD, and 44% with a PI/ IMiD combination. Twenty-seven percent of the patients enrolled were refractory to their last line of therapy. The median follow-up at the time of reporting was 13.5 months. The addition of daratumumab (DRd) improved all outcomes including overall response rate (93% vs 76%), depth of response (
VGPR: 76% vs 44%;
CR: 43% vs 19%; P<.001), PFS (not reached vs 18.4 months; P<.0001), and time to progression (not reached vs 18.4 months; P<.0001). Daratumumab reduced the risk of progression by 66% and the risk of death by 63% (P<.0001), and the effect is independent of the presence of cytogenetic risk groups. The addition of daratumumab was associated with an increased risk of neutropenia and thrombocytopenia as well as upper respiratory tract infections. Infusionrelated reactions to daratumumab were experienced only with the first infusion in 92% of patients.38 Patients who experience an indolent relapse of their disease while receiving lenalidomide maintenance, or soon after discontinuing maintenance with lenalidomide, or are considered frail160 can be treated using several regimens including DVd37 or ICd.161 The latter is an all-oral triple combination therapy that has the convenience of less frequent 10

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clinical visits and is generally well tolerated. The main adverse effects of ixazomib are rash, thrombocytopenia, and upper and lower gastrointestinal toxicity. The combination has excellent response rates in the newly diagnosed setting. Patients who have received bortezomib maintenance can therefore be treated with IRd36 or DRd.38,51 The IRd regimen has shown promising activity in phase 1/2 studies.14 More recently, Moreau et al36 reported on the efficacy of IRd in a phase 3 trial (TOURMALINE MM-1 trial) involving 722 patients with relapsed, refractory, or relapsed and refractory multiple myeloma. Patients were randomized (1:1) to oral ixazomib (4 mg) or placebo on days 1, 8, and 15 together with lenalidomide (25 mg) on days 1 to 21 and dexamethasone (40 mg) on days 1, 8, 15, and 22. Those patients with an estimated GFR of 60 mL or higher received 10 mg of lenalidomide, and therapy was repeated in 28-day cycles, with therapy continued until progression or the development of unacceptable toxicities. Patients were stratified on the basis of the International Staging System and previous exposure to a PI. With a median follow-up of 14.8 months, the PFS was 20.6 months for IRd vs 14.7 months for placebo Rd (P¼.01), with a 26% reduction in the risk of progression or death due to myeloma. The IRd regimen was active across all risk groups of myeloma, including those with high-risk cytogenetic abnormalities, International Staging System’s stage 3, and age above 75 years. A VGPR or better response was observed in 48% vs 39% of patients (P¼.01), and the responses were durable. Transient thrombocytopenia was common (31%), and peripheral neuropathy (mostly grades 1 and 2) was seen in 27% of patients in the ixazomib arm of the study. The PFS for patients with 17p deletion (w10% of the patients enrolled) was 21.4 months for those taking ixazomib vs 9.7 months for those taking placebo. Recommendation: Patients who relapse while receiving therapy should be treated with a 3-drug regimen. Fit patients should be treated with a daratumumab- or carfilzomibbased regimen. Frail patients should be treated with a daratumumab- or ixazomibbased regimen. Patients may also be considered for a salvage or second ASCT if they are eligible.

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A comprehensive red blood cell antigen typing must be performed before the initiation of daratumumab therapy. Level of evidence: I to III Grade: B Relapse in Patients After Discontinuing Therapy Although maintenance therapy is now commonly used either after ASCT137,138,140,162 or after induction therapy, there are still many patients who elect not to undergo maintenance after achieving a deep response and/or plateau or who have to discontinue therapy because of toxicity or intolerance. When such patients relapse after discontinuing therapy, carfilzomib, lenalidomide, and dexamethasone (KRd)33 or DRd38,51 may be administered, especially if they do not have significant comorbidities. In the pivotal ASPIRE trial, 792 patients with relapsed multiple myeloma were randomized to KRd vs Rddat the time considered the standard of care for relapsed disease.26,27 Carfilzomib was given intravenously (20/27 mg/m2 on days 1, 2, 8, 9, 15, and 16 for cycles 1-12 and on days 1, 2, 15, and 16 for cycles 13-18), with lenalidomide (25 mg orally on days 1-21) and dexamethasone (40 mg on days 1, 8, 15, and 22). Patients in the Rd arm received lenalidomide (25 mg on days 1 to 21) and dexamethasone (40 mg weekly). After 18 cycles, both cohorts continued receiving Rd therapy until progression. The KRd regimen was associated with an improved PFS (26.3 months vs 17.6 months) irrespective of prespecified subgroups, including previous treatment, the presence of high-risk cytogenetic abnormalities, and staging.33 There was a trend for an improved overall survival in the KRd arm, although the median has not been reached for either cohort. The median duration of therapy in the KRd arm was 88 weeks, and the most common reason for discontinuing therapy in either arm was disease progression. The KRd regimen was also associated with an improved quality of life compared with the Rd regimen. Patients who experience an indolent relapse of their disease while receiving lenalidomide maintenance or soon after discontinuing lenalidomide maintenance or are considered frail160 can be treated with IRd36 or elotuzumab, lenalidomide, and Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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dexamethasone (ERd). Given the promising activity of ERd in phase 1/2 studies,163 the phase 3 ELOQUENT-2 study34 was designed, in which patients with relapsed or refractory multiple myeloma were randomized to the ERd or Rd arm. Elotuzumab was given at 10 mg/kg intravenously on days 1, 8, 15, and 22 for the first 2 cycles and on days 1 and 15 for subsequent cycles. Lenalidomide was given at a dose of 25 mg orally from day 1 through 21 with dexamethasone 40 mg weekly. Patients randomized to the ERd arm received dexamethasone 8 mg intravenously before elotuzumab and 28 mg orally on the day of elotuzumab administration. All patients received thromboprophylaxis, and those receiving elotuzumab were premedicated with diphenhydramine, ranitidine, and acetaminophen 30 to 90 minutes before the initiation of elotuzumab infusion. The overall response rate was 79%, with 11% achieving CR and 33% VGPR. The PFS was 19.4 months. Patients responded across all group stratifications including patients with high-risk cytogenetic abnormalities. Grade 3 or 4 neutropenia was observed in 34% of patients, but there was no increase in risk of infections compared to Rd. Infusion reactions were observed in 10% of patients, and most of them were mild (grade 1 or 2) and experienced only with the first infusion. We prefer the use of ERd in frail patients or those with indolent relapse because of its favorable characteristics with respect to infusion times and tolerance during infusion that may lead to a better quality of life in the frail patient. The combination of pomalidomide and dexamethasone is also a viable option for frail patients. The addition of cyclophosphamide to pomalidomide and dexamethasone is also possible and is associated with improved outcomes without any increase in toxicity.56 The STRATUS (MM-010) trial53 was a phase 3b study of 682 patients with relapsed and refractory multiple myeloma treated with pomalidomide 4 mg on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15, and 22 (the dose was reduced to 20 mg for patients older than 75 years) until progression or unacceptable toxicity. In this heavily treated population (median of 5 previous regimens), with 80% of patients refractory to lenalidomide

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and bortezomib, the overall response rate was 32.6%. The median duration of the response was 7.4 months, and the median overall survival was 11.9 months. Most of the toxicity was hematologic (neutropenia in 49.7%, anemia in 33%, and thrombocytopenia in 24.1%), whereas pneumonia (10.9%) and fatigue (5.9%) were the most common nonhematologic adverse effects. Thromboembolism and peripheral neuropathy were both uncommon (1.6%). Recommendation: Patients who have relapsing disease without therapy or without maintenance can be treated with triple combinations. Fit patients should be treated with a carfilzomib- or daratumumab-based regimen. Patients who are frail or experiencing an indolent relapse may be treated with IRd or ERd. Patients should also be considered for a salvage or second ASCT if they are eligible. Level of evidence: II Grade: B

Second or Later Relapse Despite the efficacy of novel agents in multiple myeloma, the disease almost invariably progresses or relapses, generally while receiving therapy. The decision on the next best therapy becomes more complex because of the possible accumulation of toxicity from the use of previous agents and the emergence of new comorbidities that may be independent of the multiple myeloma or its therapy (Figures 35). The details of previous antimyeloma therapy, tolerance to therapy, and duration of response become crucial. Consideration should be given to ASCT as a salvage approach especially in patients who had a good response to previous ASCT and who are eligible, particularly if the relapse is indolent.89,147,148,150-152 Although currently the use of triple combination therapy is more the norm than the exception, it is possible that there are patients who may relapse while receiving dual therapy such as Rd,26,27 Pd,164 Vd, or Kd.35 We

Second or later replase (off study)

Not secondary plasma cell leukemia or extramedullary disease

SINGLE REFRACTORYa

DUAL REFRACTORYa

IMiD or PI but not both

Lenalidomide and Bortezomib/lxazomib

• IMiD refractory • DVdb • PI refractory • DRdb

• Pomalidomide based • DPdb • DPCdb • Carfilzomib based • KPd • KRd

a b

TRIPLE REFRACTORYa Lenalidomide Bortezomib/lxazomib Carfilzomib

TRIPLE REFRACTORYa Bortezomib/lxazomib Lenalidomide Pomalidomide

• Pomalidomide based • DPdb • DPCdb

• Daratumumab basedb • Alkylator based • PI and Panobinostat

ASCT is an option for select patients. Patients who are refractory to daratumumab can be treated with elotuzumab.

FIGURE 3. Therapy for second or subsequent relapse of multiple myeloma. The decision on which agents to use depends on the therapeutic history and response to previous agents. Triple combination therapy is preferred. ASCT ¼ autologous stem cell transplant; DPCd ¼ daratumumab, pomalidomide, cyclophosphamide, and dexamethasone; DPd ¼ daratumumab, pomalidomide, and dexamethasone; DRd ¼ daratumumab, lenalidomide, and dexamethasone; DVd ¼ daratumumab, bortezomib, and dexamethasone; IMiD ¼ immunomodulatory drug; KPd ¼ carfilzomib, pomalidomide, and dexamethasone; KRd ¼ carfilzomib, lenalidomide, and dexamethasone; PI ¼ proteasome inhibitor.

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recommend that patients who have disease that is considered to be refractory to IMiDs should be treated with DVd,37 and if refractory to PI, they should be treated with DRd.38,51 However, it is highly likely that patients who are experiencing second or subsequent relapses have been exposed to and have disease that is resistant to bortezomib, ixazomib, and lenalidomide (Figure 3). It is reasonable to consider a trial of the same agents used in the past if relapse occurs while the patient is not receiving therapy, but a change in therapy is clearly needed if a patient progresses while receiving therapy with these agents. Our approach in such patients is to switch to a next-generation agent from the same class that may be active (change lenalidomide with pomalidomide or bortezomib with carfilzomib) and introduce a novel class of agents such as MAbs and/or alkylating agents in an effort to maximize the likelihood of a response. Therefore, in such a scenario, we recommend that the patient is treated with a regimen such as daratumumab, pomalidomide, and dexamethasone (DPd),165 with or without cyclophosphamide because there is evidence of synergy between IMiDs and alkylating agents.50,55 If the patient is deemed to be refractory to daratumumab, elotuzumab can be substituted because the combination of elotuzumab with an IMiD and dexamethasone appears synergistic.34 Chari et al165 reported on a phase 1b multicenter study in which 77 patients with relapsed or relapsed refractory multiple myeloma were treated with the combination of DPd. Daratumumab was given at 16 mg/ kg weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks. Pomalidomide was given at 4 mg orally from day 1 through 21 and dexamethasone 40 mg weekly (20 mg weekly for patients 75 years or older). Each cycle was 28 days in length. The median number of previous therapies was 3.5 (range, 2-10), with 65% of the patients enrolled considered to be refractory to bortezomib, 30% refractory to carfilzomib, and 88% refractory to lenalidomide. Overall, 65% of patients were considered refractory to both a PI and an IMiD. In this heavily pretreated group of patients, DPd was associated with a response rate of 58%, including 3 patients with stringent CR, 1 other CR, and 12 with a VGPR. Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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QUADRUPLE REFRACTORY DISEASE (Lenalidomide, Pomalidomide, Bortezomib, and Carfilzomib)

VDT-PACE x 2 cycles Candidate for ASCT?

YES • ASCT • Consolidation • Maintenance

• • • • •

NO Daratumumab-based therapy Panobinostat-based therapy Bendamustine-based therapy Alkylator-containing combination Anthracycline-based therapy

FIGURE 4. Patients with quadruple refractory disease have limited treatment options. If eligible, patients should be considered for ASCT. ASCT ¼ autologous stem cell transplant; VDT-PACE ¼ bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide.

The response was rapid and appears to be sustained, although longer follow-up is needed. The only toxicity observed compared with the typical toxicities reported with Pd were infusion reactions due to daratumumab that were mostly restricted to the first dose.165 Other options for patients who have disease that is refractory to bortezomib or ixazomib and lenalidomide would be KPd57 or KRd33 because there is evidence that either carfilzomib or pomalidomide can lead to responses in patients who have failed bortezomib and lenalidomide.166-168 Patients who are considered to be resistant to all available PIs and lenalidomide (triple refractory disease) may be treated with a combination of DPd165 with or without cyclophosphamide. Patients who have disease that is refractory to bortezomib/ixazomib, lenalidomide, and pomalidomide can be treated with a daratumumab-based regimen such as DPd165 or carfilzomib, cyclophosphamide, and dexamethasone,43 especially if they have never been exposed to an alkylating agent. Another option is the combination of a PI with panobinostat. In the PANORAMA-1 study,32 768 patients with relapsed multiple myeloma were randomized to Vd (bortezomib on days

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Secondary plasma cell leukemia or extensive extramedullary disease VDT-PACE x 2 cyclesa Candidate for ASCT?

YES • ASCT • Consolidation • Maintenance

a

• • • •

NO Daratumumab-based regimen Bendamustine-based therapy Alkylator-based regimen Anthracycline-containing regimen

CVAD or similar regimen can be used in older patients or in those with poor functional status.

FIGURE 5. Therapy for secondary plasma cell leukemia or extramedullary multiple myeloma. Fit patients should receive intensive chemotherapy and consolidation by ASCT. Frail patients can be considered for an anthracycline- or daratumumab-based regimen. ASCT ¼ autologous stem cell transplant; CVAD ¼ cyclophosphamide, vincristine, doxorubicin, and dexamethasone; VDT-PACE ¼ bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide.

1, 4, 8, and 11) with panobinostat (20 mg orally 3 times a week on days 1-14 with therapy repeated every 21 days for cycles 1-8 followed by weekly Vd for cycles 9-12). Patients randomized to the combination of panobinostat and Vd had a PFS of 12 months vs 8.1 for the Vd combination, with a 37% risk reduction of progression and death in favor of panobinostat. Toxicity was higher during therapy repeated every 21 days for cycles 1 to 8 and suggested that panobinostat should be used with weekly Vd to minimize adverse effects. The most common adverse effects of the combination were diarrhea (26%; grade 3 or 4) and thrombocytopenia (67%). A subsequent analysis of the study exhibited that the improved PFS by the addition of panobinostat was regardless of previous exposure to IMiDs or bortezomib (or both) with approximately 7.8-month improvement in PFS compared with Vd alone.169 Patients who have quadruple refractory disease (resistance to lenalidomide, pomalidomide, bortezomib, and carfilzomib) have limited treatment options (Figure 4). Enrollment in a clinical trial is highly recommended if their performance status allows. If rapid 14

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disease control is needed or perhaps as a bridge to ASCT for suitable candidates, 1 or 2 cycles of VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) may be used as salvage therapy.170 Older patients may be treated with cyclophosphamide, vincristine, doxorubicin, and dexamethasone rather than VDT-PACE.171 Some patients may still benefit from ASCT, especially if they had a durable response to previous high-dose melphalan therapy. Other options would include regimens that contain daratumumab (DPd, DRd, and DVd), bendamustine (eg, bendamustine, lenalidomide, and dexamethasone),98 or an anthracycline-containing regimen such as bortezomib, doxorubicin, and dexamethasone172; lenalidomide, doxorubicin, and dexamethasone173; or bortezomib, pegylated liposomal doxorubicin, and dexamethasone.174 However, these recommendations are all based on small phase 1 or 2 studies, and for this reason alone, enrollment in a clinical trial is highly recommended. Recommendation: Patients experiencing relapse of their disease that is resistant to lenalidomide should be treated with DVd, whereas patients experiencing relapse of the disease that is resistant to bortezomib should be treated with DRd. Patients who fail daratumumab can be considered for elotuzumab-based therapy. Level of Evidence: II Grade: B or C Therapy for Secondary Plasma Cell Leukemia or Extramedullary Myeloma Patients who progress to secondary plasma cell leukemia or who develop extensive extramedullary myeloma have a poor prognosis because the disease would have evolved to be independent of the bone marrow microenvironment.118,175-179 Often patients with plasma cell leukemia have rapidly dividing cells with a high plasma cell labeling index or “S” fraction, and although they respond to therapy, the duration of response is usually short.180 Progression to secondary plasma cell leukemia or development of extramedullary myeloma may occur at any time in the course of the disease and is often associated with the acquisition of novel chromosomal abnormalities such as 17p deletion,181,182 MYC upregulation,181,183 and loss of 1p.184 There

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are no randomized clinical trials to guide therapy in this setting because of the relative rarity of these complications. One randomized clinical trial185 has evaluated therapy for primary plasma cell leukemia, and the study suggested that combination therapy that includes a PI, anthracycline, and an alkylating agent may be useful. Therefore, it is our approach to treat these patients with combination therapy, ideally with agents that the disease is not resistant to (Figure 5). Progression to secondary plasma cell leukemia or the development of extramedullary myeloma can occur at any time in the course of the disease.181 Therefore, determination of the previous therapies administered and response attained with each of the previous regimens is critical. In healthy patients, we favor therapy with 2 cycles of VDT-PACE to achieve disease control, and if possible, the response is consolidated with ASCT or allogeneic stem cell transplant. If the patient is not a candidate for aggressive chemotherapy and transplant, we favor the use of combination therapy with daratumumab-containing regimens (eg, DRd, DVd, and DPd), an alkylator-based therapy if the patient is known not to be refractory to these agents (eg, cyclophosphamide, bortezomib and dexamethasone; carfilzomib, cyclophosphamide, dexamethasone and thalidomide; and bendamustine-containing regimens), or an anthracycline-containing regimen such as bortezomib, doxorubicin, and dexamethasone172; lenalidomide, doxorubicin, and dexamethasone173; or bortezomib, pegylated liposomal doxorubicin, and dexamethasone.174 Fit patients may be referred for consideration of ASCT in an attempt to improve their survival.186-188 Although the procedure is toxic and the disease may relapse, a substantial number of patients may achieve disease control and prolongation of survival that would otherwise be unlikely.189 Recommendation: Fit patients with secondary plasma cell leukemia or extramedullary disease should be treated with VDT-PACE and consolidated with ASCT, if possible. Frail patients with secondary plasma cell leukemia or extramedullary disease should be treated with a daratumumab- or anthracycline-based regimen. Level of Evidence: III Grade: C Mayo Clin Proc. n XXX 2017;nn(n):1-21 www.mayoclinicproceedings.org

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Supportive Care Although not within the scope of the article, it is critical that patients with relapsed multiple myeloma also receive supportive care in the form of antimicrobials (acyclovir or valacyclovir), Pneumocystis jiroveci prophylaxis if they are taking high doses of glucocorticosteroids, bisphosphonates together with calcium and vitamin D supplementation, adequate analgesia, blood transfusion support, and immunizations (especially the seasonal influenza and pneumococcal vaccines). Consideration should be given to vertebroplasty or kyphoplasty in patients with vertebral compression fractures, with prompt referral to interventional radiology for pain control and prevention of further loss of height and for potential functional improvement. CONCLUSION Therapy for multiple myeloma is changing rapidly because of the availability of an everincreasing armamentarium of effective therapeutic agents. Combination therapy with nonecross-resistant and synergistic combinations are leading to deeper and longer responses and translating into improved survival for this disease. Secondary plasma cell leukemia and extramedullary myeloma present difficult therapeutic challenges. Abbreviations and Acronyms: ASCT = autologous stem cell transplant; CR = complete response; CT = computed tomography; DPd = daratumumab, pomalidomide, and dexamethasone; DRd = daratumumab, lenalidomide, and dexamethasone; DVd = daratumumab, bortezomib, and dexamethasone; ERd = elotuzumab, lenalidomide, and dexamethasone; FISH = fluorescence in situ hybridization; ICd = ixazomib, cyclophosphamide, and dexamethasone; IMiD = immunomodulatory drug; IRd = ixazomib, lenalidomide, and dexamethasone; Kd = carfilzomib and dexamethasone; KPd = carfilzomib, pomalidomide, and dexamethasone; KRd = carfilzomib, lenalidomide, and dexamethasone; MAb = monoclonal antibody; MRI = magnetic resonance imaging; Pd = pomalidomide and dexamethasone; PET = positron emission tomography; PFS = progression-free survival; PI = proteasome inhibitor; Rd = lenalidomide and dexamethasone; Vd = bortezomib and dexamethasone; VDT-PACE = bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; VGPR = very good partial response Potential Competing Interests: Dr Dingli has received research funding from Amgen, Millenium/Takeda, and Karyopharm. Dr Ailawadhi has received grants and other

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support from Pharmacyclics, Takeda Oncology, and Amgen, outside the submitted work. Dr Bergsagel has received personal fees from Janssen, Incyte, Juno, and Kesios; grants from Novartis; and nonfinancial support from Millenium, Amgen, Celgene, and E. R. Squibb & Sons, outside the submitted work. Dr Dispenzieri has received grants from Pfizer, Celgene, Takeda, and Alnylam and nonfinancial support from Janssen and Prothena, outside the submitted work. Dr Gertz has received grants from IONIS, Prothena Therapeutics, Annexon Biosciences, Novartis, and Alnylam Pharmaceuticals; personal fees from Celgene, Research To Practice, Med Learning Group, National Cancer Institute at Frederick, Sandoz Inc. (a Novartis Company), GlaxoSmithKline, outside the submitted work. Dr Kapoor has received research funding from Takeda, Celgene, and Amgen. Dr Kumar has received consultancy fees from Merck, Millennium/Takeda, Celgene, Sanofi/Genzyme, Amgen, Janssen and Glycomimetics; speakers’ bureaus fees from Skyline Diagnostics, Noxxon, and Kesios. Dr Lacy has received grants from Celgene, outside the submitted work.

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Grant Support: Supported in part by grant CA186781 from the National Cancer Institute, National Institutes of Health. Correspondence: Address to David Dingli, MD, PhD, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (dingli.david@ mayo.edu).

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