High-Risk Multiple Myeloma: Does it Still Exist?

Multiple Myeloma

High-Risk Multiple Myeloma: Does it Still Exist? Sascha A. Tuchman,1 Sagar Lonial2 Abstract Major improvement milestones in the treatment of patients with multiple myeloma (MM) include the introduction of the melphalan/prednisone combination in the 1960s, high-dose chemotherapy supported by autologous stem cell transplant in the 1980s, and the more recent introduction of the novel agents thalidomide, lenalidomide, and bortezomib. Historically, age and eligibility for autologous stem cell transplantation were the primary basis for treatment selection, but, from a biologic standpoint, MM therapy was “one size fits all,” in that therapy was not tailored based on molecular or other features that define subtypes of MM. Recently, novel therapies have extended overall survival for the broad spectrum of patients with myeloma. Moreover, newer data demonstrate that novel therapies may ameliorate the prognostic impact of predictors of high risk and poor outcome in MM, which suggests that patients with MM and with high-risk disease should receive novel agents. Such approaches may constitute nascent steps toward individualized therapy, ie, the selection of highly effective therapies based on specific features exhibited by an individual patient’s MM. However, prospective data that demonstrate the validity of these approaches are lacking. Definitive, multi-institutional clinical trials are required before redefining standards of myeloma care based on this approach. Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. S1, S70-6 © 2011 Published by Elsevier Inc. Keywords: Cytogenetics, Diagnosis, Elderly, Multiple myeloma, Prognosis, Renal insufficiency, Risk stratification

Introduction Treatment options for patients with multiple myeloma (MM) in the induction and relapsed setting of their disease have seen unprecedented advances as measured by response rate, progression-free survival (PFS), and overall survival (OS). These advances have occurred in part due to the broad usage of high-dose therapy and autologous transplantation, as well the introduction of the novel agents thalidomide, bortezomib, and lenalidomide.1 Those agents, either alone or in combination with other antimyeloma agents, have provided clinicians and patients with numerous options that often lead to improved clinical outcomes. Some studies now show that even older patients with MM, a group previously not able to benefit from highdose therapy, are now staying in remission and may be living longer with induction therapy than previously.1-3 Despite these advances in clinical care, the prognosis is not the same for all patients with MM. By using new technology, one can now identify subgroups of patients

1 Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 2 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA

Submitted: Jan 19, 2011; Revised: Feb 21, 2011; Accepted: Feb 28, 2011 Address for correspondence: Sagar Lonial, MD, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322 E-mail contact: [email protected]

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likely to have relatively good (eg, hyperdiploid karyotype or low serum beta-2-microglobulin [B2M] level) or poor clinical outcomes (eg, FGFR3 overexpression or p53 deletion), ie, standard- or highrisk MM. This review will focus on contemporary risk assessment in MM and will discuss recent suggestions that novel therapeutic agents may be rendering such risk assessment less relevant than it has been until now.

The Recent History of MM Risk Stratification Staging in MM has always been different than in other diseases; aside from solitary plasmacytoma, MM is disseminated from the outset and thus does not fit the typical oncology staging paradigm, which is grounded in an evaluation of local invasion and metastasis, and which comprises the basis of prognostication in many cancers. In MM, the original Durie-Salmon staging system was created predominantly to identify or delineate some level of tumor burden at the time of diagnosis, but its utility in the setting of prognosis was limited. More recently, Durie-Salmon was supplanted by the International Staging System (ISS) (Table 1). The ISS improves upon previous stratification systems for MM due to its capacity to predict prognosis and its simplicity as a result of its reliance on just two blood tests, namely albumin and B2M.4-6 Furthermore, because of its reproducibility, the ISS facilitates rough comparisons of outcomes from different clinical trials.7,8 However, the ISS has some important limitations.7 It is not very sensitive in detecting genetically high-risk

2152-2650/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clml.2011.02.008

Table 1 Comparison of Durie-Salmon Criteria and International Staging System Criteria72,73 Stage

Durie-Salmon Staging System

International Staging System

All of the following: hemoglobin value ⬎10 g/100 mL; serum calcium value normal (ⱕ12 mg/100 mL; x-ray film, showing normal bone structure (scale 0) or solitary bone plasmacytomas only; low monoclonal-component production rates; immunoglobulin (Ig) G value ⬍5 g/100 mL; IgA value ⬍3 g/100 mL; urine light chain monoclonal-component on electrophoresis ⬍ 4 g/24 h

Serum ␤2-microglobulin ⬍ 3.5 mg/L Serum albumin ⱖ 3.5 g/dL

II

Not stage I or stage III

Not stage I or stage III

III

One or more of the following: hemoglobin value ⬍8.5 g/100 mL; serum calcium value ⬎12 mg/100 mL; advanced lytic bone lesions (scale 3); high monoclonal-component production rates; IgG value ⬎7 g/100 mL; IgA value ⬎5 g/100 mL; urine light chain monoclonal-component on electrophoresis ⬎ 12 g/24 h

Serum ␤2-microglobulin ⱖ 5.5 mg/L

Subclassification

Two categories for any stage: A ⫽ relative normal renal function (serum creatinine value ⬍ 2.0 mg/100 mL); B ⫽ Abnormal renal function (serum creatinine value ⱖ 2.0 mg/100 mL)

Two categories for stage II; serum ␤2-microglobulin ⬍ 3.5 mg/L but serum albumin ⬍ 3.5 g/dL; serum ␤2-microglobulin 3.5 to ⬍ 5.5 mg/L, irrespective of serum albumin level

I

MM unless that MM is highly proliferative.5 Moreover, Hari et al9 recently demonstrated that the ISS did not improve prediction of posttransplantation outcomes compared with the Durie-Salmon staging system. The incorporation of age, renal impairment, cytogenetics, serumfree light chains, gene expression profiling, and radiography has been explored as possible additions to ISS to refine MM risk stratification. We will discuss age, renal impairment, and cytogenetics at length later in this article. The serum-free light chain assay, which measures ␬ and ␭ immunoglobulin light chains,10 predicts survival in patients with MM,11 and available data suggest that the serum-free light chain assay adds to prognostic information gleaned from ISS staging.12,13 Regarding imaging, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) probably also contribute meaningfully to prognostication. For instance, analyses of large cohorts of available patients enrolled in trials at the University of Arkansas who underwent baseline FDGPET and/or MRI revealed that ⬎7 focal lesions on MRI of the axial skeleton14 or ⬎3 lesions on full-body FDG-PET predicted poor outcomes, whereas resolution of such radiologic abnormalities after therapy predicted improved survival. These findings appeared to be independent of B2M, but complete independence from ISS was not reported.15

Molecular Predictors of Outcome Significant recent developments in MM risk stratification come from the realm of molecular biology and may enhance predictions of outcome based on traditional markers. Chromosomal abnormalities detected either by conventional metaphase cytogenetics or fluorescence in situ hybridization are common, highly variable (Table 2), and long-established predictors of outcome in MM. For instance, del(13) and del(17p) are commonly associated with short PFS and OS,16,17 whereas t(11;14) appears to confer a good prognosis in some studies.16,18 Even aggressive therapy in the form of allogeneic stem cell transplantation appears not to mitigate the prognostic implications of some of these high-risk features; MM, primarily with del(13) on metaphase cytogenetics, was associated with higher re-

Table 2 Frequency of Cytogenetic Abnormalities in Patients With Newly Diagnosed Multiple Myeloma16 Genomic Aberration

% Incidence (No. Patients Analyzed)

del(13)

48 (936)

t(11;14)(q13;q32)

21 (746)

t(4;14)(p16;q32)

14 (716)

Hyperdiploidy

39 (657)

MYC Translocations

13 (571)

del(17p)

11 (532)

lapse and death rates in certain allogeneic transplantation trials.19,20 That said, especially the poor-prognosis groups appear to be quite heterogeneous. In one study, del(13), in the absence of t(4;14) or del(17p), had outcomes that were similar to those of MM that lacked del(13).16 In a separate work, patients with t(4;14) MM could be divided into markedly different risk strata with respect to OS when using B2M and hemoglobin.21 In terms of using chromosomal markers to build on existing ISS-based prognostication, a study of 9897 patients by the International Myeloma Working Group (IMWG) revealed that probing for t(4;14) allowed investigators to dissect ISS stages into more precise risk strata. For instance, patients with ISS stage I and with t(4;14) MM demonstrated 4-year OS of 22 months vs. 81 months in patients with ISS stage I and without t(4;14). This pattern persisted across all ISS stages (P ⬍ .0001).22 In recent years, investigators have developed microarray profiling in an effort to more broadly survey gene expression patterns in MM in high throughput fashion. Anguiano et al23 reported on the use of genomic approaches to elucidate the deregulation of key oncogenic pathways in MM. They then used that approach to retrospectively dissect ISS stages into potentially meaningful prognostic subgroups. Earlier studies, by Bergsagel et al,24 exploited different genomic methods to devise a prognostically relevant classification system for MM rooted in the identification of specific chromosomal translocations and abnormalities in cyclin D genes. Several other gene expres-

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High-Risk MM sion– based models have been described more recently in the literature, including an extensive, ongoing body of work by the Arkansas group,25-27 in addition to other studies.28 A full discussion of genomically based prognostication goes well beyond the scope of this review, but it is hardly surprising that, as a result of the significant advances in this burgeoning field, the IMWG now advocates comprehensive gene-expression profiling at the time of diagnosis in clinical trials so these techniques can be further validated in correlative studies.29

Risk Stratification in the Era of Novel Therapies As we evolve into an era marked by an increasingly potent armamentarium of MM therapies, the relevance of many of the high-risk disease markers described above is coming under debate. Nonetheless, we believe that these markers retain prognostic significance and may also pave the way to future individualization of MM therapy.

Age Age is historically a powerful predictor of survival in MM that also significantly impacts therapeutic decision making. In a large study by the IMWG, the investigators retrospectively analyzed outcomes from patients treated before the widespread introduction of newer therapies for MM. Younger patients (defined in this study as ⬍50 years old) had a median OS of 5.2 years vs. 3.7 years in older patients (P ⬍ .001). Autologous stem cell transplantation (ASCT) failed to mitigate those differences as compared to older patients who survived, on average, 5.7 years after ASCT in contrast to 7.2 years in younger patients (P ⫽ .04). These findings were independent of ISS stage.30 Earlier, smaller studies that involved conventional therapy, mainly without ASCT, provide further evidence for this trend.31-33 As relates to the capacity of newer agents to mitigate divergent survival between elderly and younger patients with MM, studies aimed at establishing the efficacy of bortezomib and the immunomodulatory (IMiD) agents thalidomide and lenalidomide in older patients are few, but available data are mixed. Regarding thalidomide, the most mature and largest body of evidence relates to the melphalan, prednisone, thalidomide (MPT) regimen. Despite a meta-analysis of major trials that shows prolongation of PFS and a trend toward an OS benefit for MPT instead of standard melphalan and prednisone (MP) in patients who were elderly and/or not ASCT candidates,3 it remains unclear whether thalidomide severs the correlation between advanced age and poor prognosis. Facon et al,34 eg, described the IFM 99-06 trial in which MPT extended OS compared with MP or ASCT, yet the investigators also note that, despite thalidomide, the elderly still had inferior OS as compared to the young. In the GIMEMA study, Palumbo et al35 reported a PFS benefit for patients on MPT vs. MP but no change in OS. Notably the improvement in PFS was present in the subgroup of patients older than 75 years of age (hazard ratio, 0.53 [95% confidence interval, 0.310.91]), although outcomes for specifically younger vs. older patients are not discussed. The HOVON trial also revealed a PFS benefit to MPT vs. MP but no OS benefit and, germane to this discussion, is their multivariate analysis in which age remained predictive of OS but not EFS after adjustment for randomization to thalidomide or placebo. Taken together, these data suggest that, when added to MP, thalidomide extends at least PFS for patients with MM in general and

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may benefit elderly as much as younger patients with MM, but it appears that advanced age remains predictive of a poorer outcome and thalidomide does not nullify advanced age as a high-risk prognostic marker in MM. Fewer data are available for the other newer agents. In the pivotal APEX trial bortezomib was administered to patients with relapsed or refractory MM (RRMM), and 1-year OS was 79% in patients older than 65 years compared with 81% in younger patients, with similar rates of adverse events.2 In the recent study described by Cavo et al36 in which bortezomib, thalidomide and dexamethasone (VTD) was demonstrated to prolong PFS over thalidomide and dexamethasone (TD), advanced age was a univariate predictor of OS but dropped out in multivariate analysis. As for lenalidomide, long-term follow-up of the British MM-009 and MM-010 phase III trials did not demonstrate age to be a significant predictor of survival in patients treated with lenalidomide and dexamethasone in a post hoc comparison.37 The latter 2 studies suggest that both bortezomib and lenalidomide may attenuate age-related differences in outcomes. Difference in therapy selection for the young vs. the elderly confounds this subject. This point is highlighted in a large populationbased study by Brenner et al,38 which showed significant, age-related differences in outcome over 2-year periods, 1990-1992 and 20022004, but that retrospective database study lacked information regarding therapy, so therapy-related differences in outcome cannot be excluded. The aforementioned IMWG study provides further evidence of this confounder; older patients in their study were far less likely to undergo high-dose therapy with ASCT.30 Porer outcomes in the elderly with MM compared with the young hence may stem from a combination of intrinsic differences in MM itself as well as more conservative approaches to aggressive forms of therapy such as ASCT. Whatever the reason, it, nonetheless, can be stated that advanced age is historically a marker for high risk in MM, and whether novel agents are now closing the gap between young and old is uncertain. The evidence discussed here shows that bortezomib in particular may indeed accomplish that aim, in that reported data show that the young and old seem to have similar PFS and OS when administered bortezomib on protocol. Thalidomide, although effective in the elderly, still results in age-based survival discrepancies. Early, promising data regarding lenalidomide is as yet too scanty for drawing definitive conclusions. Given that available evidence most strongly supports bortezomib for ameliorating advanced age as a high-risk marker in MM, we believe that bortezomib should generally be included when designing therapy regimens for the elderly. Prospective trials designed to examine this subject further are necessary.

Renal Insufficiency Renal insufficiency (RI) is a common manifestation of MM at presentation. To date, it has been a harbinger of poor outcomes,39,40 with one large retrospective study of patients treated with conventional chemotherapy that demonstrates that patients with a normal plasma creatinine concentration had a median OS of 36 months in contrast to patients with severe RI, whose median OS was 13 months.39 Another study, by Kleber et al,41 showed that severe renal impairment, measured as a glomerular filtration rate (GFR) ⬍30 mL/min, and age ⬎59 years were the strongest predictors of death

Sascha A. Tuchman, Sagar Lonial independent of other clinical markers. Similarly, one large European study showed median OS of 24 and 61 months in patients with GFR ⬍30 and ⱖ30 mL/min, respectively, after treatment with mainly conventional agents plus ASCT in some patients (P ⫽ .0002). This finding has been further confirmed in at least one other smaller series.42 Emerging data highlight bortezomib’s capacity to potentially mitigate RI’s association with poorer outcomes. Data from the APEX trial in RRMM showed that a creatinine clearance of ⱕ50 mL/min affected neither time to progression nor OS for patients randomized to bortezomib, whereas patients with RI who received dexamethasone fared worse by both outcome measurements than patients without RI (P ⫽ .003).43 Conversely, in the VISTA clinical trial, in which MP was tested against bortezomib, melphalan, and prednisone (VMP) in newly diagnosed MM (NDMM), patients with RI tended to have worse outcomes regardless of treatment arm, although the study was not powered to investigate that endpoint, and that finding did not reach statistical significance.44 With regard to the IMiDs, Tosi et al,45 reported that thalidomide and dexamethasone can even be administered as induction therapy before tandem ASCT in select patients with RI with manageable toxicity, yet data are lacking regarding the specific issue under discussion. Moreover, given reported associations between thalidomide and bradycardia46,47 or other arrhythmias,48,49 and at least one case series of thalidomide-associated hyperkalemia in patients with RI,50 it is prudent to consider thalidomide in RI with caution. Lastly, regarding lenalidomide, which notably undergoes primarily renal clearance and requires dose adjustment in RI,51 in one retrospective study of 167 patients treated with lenalidomide and either high- or low-dose dexamethasone, Klein et al52 observed that median OS was similar for subgroups with varying degrees of RI but response rate and time to progression were both worse in patients with RI. Further supporting persistently shorter survival in patients with RI despite lenalidomide are data from patients randomized to receive both lenalidomide and dexamethasone as part of the MM-009 and MM010 trials that showed similar response rates among patients with differing degrees of renal function, but median OS was shorter in moderate-to-severe RI, and toxicity also was significantly greater in that group. Perhaps most importantly, it is clear that, in patients presenting with any degree of MM-induced RI, successful MM therapy can feasibly be given with manageable toxicity, and even conventional agents alone often induce at least partial restoration of renal function.39,40,53 Nonetheless, Greek investigators have shown that novel therapies may be of special importance in this setting and report an improvement in RI according to standardized criteria in 59% of patients who received conventional regimens in contrast to 79% of patients who received IMiDs and 94% of those on bortezomib (P ⫽ .02).54,55 Many of the aforementioned larger studies described already confirm this finding; recent reports that focused on RI in the VISTA44 and the MM-009 and MM-01052 studies also show that novel therapies induce a higher rate of RI reversal than conventional therapies. In summary, like advanced age, RI historically comprises a marker of high risk in MM. In terms of how effectively specific drugs can nullify RI’s poor-prognosis associations and equalize outcomes for

patients with MM and with and without RI, little evidence supports thalidomide for patients with RI despite its conveniently nonrenal clearance. Moreover, available data regarding lenalidomide show increased toxicity and poorer OS in patients with RI and on lenalidomide compared with patients without RI, which indicate that any unique efficacy for lenalidomide in RI may be offset by toxicity despite dose adjustment. However, bortezomib undergoes non-renal clearance, it is fairly well tolerated in patients with RI, and the APEX trial in particular, which showed that bortezomib but not dexamethasone equalized outcomes for patients with RI and those without RI implies that bortezomib may at least partially abrogate RI’s high-risk implications in MM. We, therefore, generally prefer bortezomibbased regimens for patients with MM and with RI, although prospective trials should study this issue. We also would point readers to the recent consensus statement by the IMWG, which discusses the issue of MM-related RI in depth.56

Genetics and Genomics The importance of molecular prognostic markers in MM is evolving in the modern era of MM therapy. For example, in light of data emerging from large, randomized trials, the relevance of genetic markers of high-risk MM such as del(13) or t(4;14) has recently become unclear. Regarding bortezomib, analysis of nonrandomized data initially suggested that it overcomes prognostic implications of del(13q).57-59 The French Myeloma Intergroup demonstrated in the IFM 2005-01 trial that bortezomib plus dexamethasone induction therapy (VD) equalized the risk of progression in NDMM for biologically high- and standard-risk disease; PFS was statistically equivalent for both groups, when high risk was defined as t(4;14), del(17p), or ISS stages II or III.60 The Italian group similarly reported no difference in PFS between high- and standard-risk MM defined either molecularly or by ISS, when patients were administered VMP and were randomized, in addition, to receive either nothing or thalidomide given both with induction and with bortezomib maintenance (VMPT-VT).61 One of the most mature and pivotal studies of novel agents, namely VISTA, revealed statistically equivalent event-free survival62 and OS as of the last update for patients with high-risk cytogenetics (del[17p] or del[13q]).63 Most recently, Cavo et al36 reported results from their trial of VTD vs. TD induction and noted that the presence of t(4;14) was an adverse risk factor in the TD treatment arm (37% vs. 63% 3-year EFS for patients with t(4;14)-MM vs. those with non-t(4;14)-MM; P ⫽ .0131), as opposed to patients who were receiving VTD, for whom t(4;14) lost its prognostic capacity. Regarding lenalidomide, in one trial lenalidomide given with melphalan and prednisone as consolidation after lenalidomide/dexamethasone induction demonstrated no difference in PFS in patients with abnormal cytogenetics or ISS stage III disease.64 This ample evidence lends support to the concept that bortezomib mitigates the poor-prognosis clinical phenotype associated with certain classically high-risk molecular markers, particularly t(4; 14). Much more limited data demonstrate that lenalidomide may achieve this effect as well. Conversely, results from other trials suggest that molecular markers of risk remain prognostically relevant. In the single-arm APEX trial, bortezomib therapy for RRMM resulted in median OS at 1 year of 72% for patients with ISS stage II/III disease in contrast to 91% in

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High-Risk MM Figure 1 Working Scenario for the Impact of Novel Therapies on Historically High-risk Multiple Myeloma (MM). The Propensity of Newer Agents to at Least Attenuate, If Not Eliminate, the Poor-prognosis Clinical Phenotype Exhibited by MM Characterized by Historically High-risk Markers (eg, del[13]) Suggests That the Net Benefit of These Agents in High-risk MM (B) is Even Greater Than That Seen in Unselected MM Patients (A). Visually, This Additional “High-risk Survival Benefit” is Depicted By the Green Shaded Area in (B).

All MM

Proportion of Patients

Risk-in

depend

ent Surv

ival Ben

efit

Conventional Therapy Novel Therapy

Duration of Overall Survival

stage I disease.2 In work by Reece et al,65 lenalidomide given with high- or low-dose dexamethasone, was unable to equalize risk of death between RRMM with del(17p13) and RRMM without del(17p13), although, to the contrary, t(4;14)-positive RRMM patients fared as well as patients with t(4;14)-negative RRMM. In a separate trial that evaluated the lenalidomide/dexamethasone combination in NDMM, outcomes were improved overall with lenalidomide but a persistently worse prognosis was observed in patients who harbor MM with high-risk as opposed to standard-risk molecular characteristics (PFS of 18.5 month vs. 36.5 months, P ⬍ .001).66 When using VD vs. vincristine, doxorubicin, and dexamethasone as pre-ASCT induction therapy, the IFM reported that, despite global improvements in OS with VD administration, the patients with MM characterized by either t(4;14) or del(17p) still fared worse than patients who lacked those features, by both EFS and OS.67 In contrast, when those patients who were receiving VD induction and ASCT were then administered lenalidomide maintenance as part of the IFM 2005-02 trial, t(4;14) dropped out as a prognostic indicator, which indicates that lenalidomide maintenance may have been key.60 Newer regimens that combine novel agents provide further data but perhaps also complicate this issue more. In one prospective study, bortezomib, lenalidomide, and dexamethasone given together overcame the adverse prognostic impact of del(13) but not del(17p) on time to progression.17 Recent results published by the DanaFarber group regarding their phase I/II trial of the RVD regimen (lenalidomide, bortezomib, and dexamethasone given in a different dosing regimen than the previously discussed study), show that 18month estimated PFS for patients with del(13), del(13q), del(17p), or t(4;14) was comparable to patients who lack those genetic aberrancies, yet ISS in that study retained its prognostic significance; the patients with ISS stage I disease had an estimated 18-month PFS of 89% vs. 65% in patients with MM of higher ISS stages in post hoc comparison.68 Lastly, analyses of outcomes from the Arkansas Total

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High-risk MM

B

Proportion of Patients

A

Additio nal Hig h-risk Ris Surviva k-in l Benefi dep t end ent Sur viva l Be nef it

Conventional Therapy Novel Therapy

Duration of Overall Survival

Therapy 3 trial, which built on a highly aggressive, mult-chemotherapy- and ASCT-based therapy regimen by adding both thalidomide and bortezomib, demonstrated that ISS stage III disease, the presence of any cytogenetic abnormality, and designation of high-risk MM by using a genomic model for high-risk MM previously described by that group,25 all were significant univariate predictors of both EFS and OS, which indicates that these markers remained prognostic despite aggressive therapy including two novel agents.69

Summary and Conclusions Novel therapies have inarguably prolonged survival for patients with MM overall. In some trials, the benefit has been particularly marked for patients with MM who exhibit historically high-risk features, such as advanced ISS stage or del(13q), in that both PFS and OS for patients with MM and with or without those features has equalized. Nonetheless, many trials continue to demonstrate persistently worse outcomes in high-risk MM, especially del(17p). We, therefore, suspect that, although the prognostic implications of such markers in MM may be abrogated partially by new drugs, the persistent, albeit not completely consistent, pattern of poorer outcomes in high-risk groups even in the latest trials implies that high-risk markers remain relevant. In other words, newer drugs indeed improve outcomes for poor-prognosis subtypes of MM but not to the degree that “high-risk MM” is an entity of purely historical interest. If, however, newer agents can even partially equalize prognosis for high- and standard-risk MM, it implies that this generation of MM therapies is particularly effective in high-risk MM, ie, the presence of a high-risk marker heralds a poor prognosis but is also predictive of a greater clinical benefit to be derived from novel therapies (Figure 1). One should note that such a “mixed blessing” is not unprecedented in oncology; HER-2/neu-overexpressing breast cancer often has a clinically aggressive phenotype, yet HER-2/neu overexpression also strongly predicts disease response and even prolongation of OS with trastuzumab therapy.70 Open questions we would pose are the fol-

Sascha A. Tuchman, Sagar Lonial Figure 2 Schema for a Hypothetical Trial Testing Subtypespecific Therapy for Multiple Myeloma (MM). The Patients’ MM is First Classified into Subtypes According to Molecular Features. The Patients are Then Randomized to Standard of Care (clinician’s choice of therapy) or Subtype-specific Therapy, After Which Clinical Outcomes are Compared.

only the regimens that stand the highest chance of inducing response in each patient’s unique subtype of MM. When that concept is realized, then the identification of high-risk MM takes on vital importance for therapy selection. At the same time, high-risk MM may also happily become a purely historical entity from the perspective of predicting prognosis.

Acknowledgments This study was supported by the Deets Fund for Myeloma Research.

MM patients Determination of MM subtype using molecular markers RANDOMIZATION

Disclosures Sagar Lonial, MD, Grant or research support: Millennium, Celgene, Bristol-Myers Squibb, Novartis; Paid consultant: Millennium, Celgene, Bristol-Myers Squibb, Novartis.

References Clinician’s choice of therapy (standard of care)

Subtype-specific therapy

COMPARE OUTCOMES

lowing: Are specific novel therapies particularly effective in specific high-risk subtypes of MM? If so, can we tailor treatment regimens to exploit that subtype-specific efficacy? Data we have discussed hint that, for instance, bortezomib, even as monotherapy, may make advanced age moot as a prognostic factor;2 VTD induction36 or lenalidomide maintenance after VD induction60 may entirely mitigate t(4;14) as a poor-prognosis marker; and RVD triple therapy may attenuate the high-risk phenotype of del(13).17,68 As such, bortezomib alone may constitute optimal therapy for the elderly, VTD or VD plus lenalidomide maintenance may be best for t(4;14)-positive MM, and RVD may be the correct choice for del(13). Aside from these hypotheses, derived mainly from subgroup analyses of select trials, however, questions related to individualizing MM therapy remain largely unanswered. Where to go from here? Given broad evidence that newer agents improve overall survival in unselected patients with MM1 and in at least one large trial, even in the newly diagnosed setting,62 we agree with guidelines that generally recommend giving novel agents whenever possible, at both initial induction and subsequent treatment in the absence of convincing contraindications, particularly for patients with high-risk subtypes of MM such as those associated with advanced age, RI, or certain cytogenetic abnormalities.71 Although, perhaps with the few loose exceptions noted in the prior paragraph, it is premature to recommend specific regimens for specific high-risk subtypes of MM, the concept of subtype-specific therapy warrants further exploration. We depict a conceptual framework for testing subtype-specific efficacy of particular MM therapies in Figure 2, where the aim would be to identify the best pairings of subtype and therapy. If we can thereby succeed in using markers of high risk in MM as predictors of response to particular treatment regimens, we stand to simultaneously augment treatment efficacy and minimize toxicity by individualizing therapy for patients with MM, ie, by using

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