Treatment Considerations for Transplant-Ineligible Multiple Myeloma

OncologyONCOLOGY Vol 35, Issue 4
Pages: 170-182

Radowan A. Elnair, MD, and Sarah A. Holstein, MD, PhD, review literature regarding progress in the management of the transplant-ineligible multiple myeloma in an article published in the journal ONCOLOGY®.

Elnair is a hematology/oncology fellow at University of Nebraska Medical Center in Omaha, Nebraska.

Elnair is a hematology/oncology fellow at University of Nebraska Medical Center in Omaha, Nebraska.

Holstein is an associate professor of internal medicine in the Division of Oncology & Hematology at University of Nebraska Medical Center in Omaha, Nebraska.

Holstein is an associate professor of internal medicine in the Division of Oncology & Hematology at University of Nebraska Medical Center in Omaha, Nebraska.


While significant advances have been made in the treatment of multiple myeloma, the management of the transplant-ineligible (TI) patient population remains challenging. The individuals enrolled in clinical trials for newly diagnosed TI patients, or those with no planned transplant, may not always be reflective of real-world patients, with respect to age, comorbidities, or frailty status. Likewise, results obtained from randomized relapsed/refractory studies also may not be applicable to this generally older and frailer patient population. In this review, we discuss assessment of frailty and focus on treatment options in both the newly diagnosed and relapsed/refractory settings for TI patients. We describe the patient-specific considerations that factor into treatment decisions as well as provide some guidance about management.

Oncology (Williston Park). 2021;35(4):170-182.
DOI: 10.46883/ONC.2021.3504.0170


The significant developments in medicine have contributed to a globally aging population. Between 1959 and 2016, US life expectancy increased from 69.9 to 78.9 years.1 With the multitude of treatment options available for many diseases, this makes it more important than ever for physicians to make treatment decisions that take into account the nature of the disease, the treatment toxicity, and a patient’s fitness and comorbidity profile.

Multiple myeloma (MM) is an embodiment of this challenge. The median age at diagnosis is 69 years,2 and despite the many strides made in the treatment of MM and discovery of agents with novel mechanisms, MM is still considered an incurable disease.3 Nonetheless, the depth of response to treatment—as assessed by minimal residual disease (MRD)—has been shown to correlate with survival, even in TI patients.4 Whether achievement of MRD negativity translates to being able to safely discontinue therapy without increasing risk of relapse remains to be determined. The goal is to give each patient the best chance of achieving the best possible response, while not conferring excessive toxicity with treatment that is not curative. When making those treatment decisions, there is no one-size-fits-all approach; therefore, the patient’s fitness can play a significant role in determining the appropriate therapy. In this review, we discuss treatment options for newly diagnosed (ND) and relapsed/refractory (R/R) MM in the context of the generally older and/or frail transplant-ineligible (TI) patient population. It is important to note that transplant eligibility can be in the eye of the beholder; there is no strict age cut-off. Multiple groups have documented the safety and efficacy of transplant in the older population.5-7 However, with advancing age and/or increasing comorbidities, the benefit-to-risk ratio may change, and thus a multidisciplinary approach, including geriatric evaluation, is recommended to optimally determine transplant candidacy.8,9 As discussed in greater detail below, there is increasing overlap between induction regimens in transplant-eligible (TE) and TI groups. However, identifying those patients who are TE remains important, given the progression-free survival (PFS) benefit obtained from an upfront autologous stem cell transplant (ASCT) approach.10,11

Assessment of Frailty in MM

Association of a patient’s ECOG performance status (PS) with survival and outcomes has been documented in patients with cancer.12-14 However, in an older cancer population, methods such as Karnofsky PS (KPS) or ECOG PS have limitations in reflecting a patient’s frailty or comorbidities.15 Therefore, objectively assessing a patient’s fitness for treatment is important, and a number of tools have been developed to provide this objective insight. One such tool is the International Myeloma Working Group (IMWG) frailty score. The score was developed from a cohort of 869 ND TI patients from 3 prospective multicenter trials.16 The median age in this cohort was 74 years, with 46% of patients aged more than 75 years. The score encompasses patient age, the Katz Activity of Daily Living score, the Lawton Instrumental Activities of Daily Living score, and the Charlson Comorbidity Index (CCI) score; it then stratifies patients into 3 groups: fit, intermediate-fit, and frail. The score predicted overall survival (OS) as well as risk of toxicity in this population. While patients aged more than 80 years made up 47% of the frail group, only 19% of patients in this category were frail due to age alone, reflecting the limitation of age as a single data point in defining frailty. The scoring system has been externally validated.17

Another tool that was shown to be predictive of OS is the Revised Myeloma Comorbidity Index (R-MCI), which categorizes patients into fit, intermediate-fit, and frail.18 This model incorporates age, renal function, lung function, KPS, frailty (as determined by the Fried definition),19 and disease cytogenetics. Calculating the IMWG frailty score requires a time-consuming evaluation, so the R-MCI was proposed as a more clinically applicable scoring system.18 The R-MCI was subsequently validated in a multicenter MM trial conducted by a German study group.20 Of note, there has not been systematic utilization of these scoring systems in prospective clinical trials, making it difficult to gauge frailty of enrolled patients.

After assessing a patient’s fitness, other factors that should be taken into account include the route of administration of the drugs included in a regimen; the frequency of infusion visits; the adverse effect (AE) profile of each medication in a particular regimen and its potential for that to overlap with the patient’s baseline comorbidities; and financial toxicity.21,22

Historical Perspective of Evolution of Induction Therapy for TI MM

Induction regimens for TI patients over the past 20 years have evolved, primarily because of the incorporation (or replacement) of immunomodulatory drugs (IMiDs)23-25 or proteasome inhibitors (PIs)26,27 into the alkylating regimen of melphalan/prednisone.28 In addition, the field has not only moved away from alkylator-based therapy to lenalidomide/dexamethasone (Rd)-based therapy,29-32 but also away from a fixed number of cycles to continuous therapy. More recently, monoclonal antibody (mAb) therapy has been incorporated into the upfront setting.33-35 This evolution is summarized in Figure 1. In this article, we review some of these key studies and discuss how the choice of initial therapy affects subsequent sequencing of therapies in the R/R setting.

Several points must be made about this patient population:

  • The TI designation encompasses an inherently heterogeneous group of patients, because reasons for their transplant ineligibility vary. The reason for transplant ineligibility is typically an irreversible factor that plays into treatment decisions along the patient’s journey.
  • Several of the studies investigating treatment of ND TI MM used an age cut-off of 65 years as a criterion. This differs significantly from the real-life practice in the United States, in which the age cut-off differs by center. Further, evidence suggests that even patients aged more than 70 years derive similar antimyeloma benefit from transplant as younger patients.5-7 We thus recommend that all ND patients be evaluated by a MM specialist at the nearest referral transplant center.
  • As we highlight below, a limited number of patients with high-risk cytogenetics —primarily defined as deletion (del) (17p), translocation (t)(4;14), or t(14;16)—were included in many of these studies. The definition of high risk is evolving, however.36

Agents under development and phase 1 studies are beyond the scope of this review.

FIGURE 1. Evolution of Induction Regimens for Transplant-Ineligible (TI) Multiple Myeloma Tested in Phase 2 or 3 Clinical Trials

FIGURE 1. Evolution of Induction Regimens for Transplant-Ineligible (TI) Multiple Myeloma Tested in Phase 2 or 3 Clinical Trials

Induction Regimens for Patients With TI ND MM:

Lenalidomide/PI combinations: Evidence for bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) as an induction regimen comes from the SWOG S0777 study, which enrolled patients with ND MM who were not necessarily TI but rather had no intent to proceed with upfront ASCT.30 Patients were randomized to 6 months of induction with either VRd (eight 21-day cycles) or lenalidomide and dexamethasone (Rd; six 28-day cycles), followed by Rd maintenance. Patients 65 years or older comprised 43% of the study population. The study showed significant PFS and OS advantages for the triplet arm, with median PFS of 41 months vs 29 months for Rd (HR, 0.74; 96% Wald CI, 0.594-0.928; P = .003) and median OS not yet reached (> 84 months) versus 69 months for Rd (HR, 0.7; 96% Wald CI, 0.543-0.926).37 The high-risk cytogenetic subgroup (~33%) did have a trend toward better outcomes with the triplet, but this was not statistically significant.

The open-label, phase 3 ENDURANCE trial compared VRd with carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) in patients who had no intention for immediate transplant.31 This study, then, enrolled a mixed population of patients, including fit TI patients as well as TE patients choosing not to undergo upfront ASCT. The median age of the study population was 65 years, with roughly 31% of patients in both arms 70 years or older. This study did not enroll patients with high-risk disease defined as t(14;16), t(14;20), or del (17p), but it did not exclude t(4;14). Enrolled patients received 36 weeks of induction followed by a second randomization to lenalidomide maintenance (2 years fixed duration vs until progression). At an interim analysis with a median follow-up of 9 months (interquartile range [IQR], 5-23), treatment with KRd did not improve PFS (34.6 months vs 34.4 months in the VRd arm) but did result in more toxicity as assessed by a composite of grade 3 to 5 cardiac, pulmonary, and renal treatment-emergent AEs (TEAEs) (16%, KRd, vs 5%, VRd; P <.0001).31 Not surprisingly, higher rates of peripheral neuropathy were observed in the VRd arm (8% grade ≥3 for VRd vs <1% for KRd). Results from the second randomization have not yet been reported. Given the caveats of primarily standard risk and mixed population of TE/TI patients, it is difficult to extrapolate these results to a frail TI patient population; however, the observed AE profiles of the 2 arms could be used to guide treatment decisions.

The phase 3 TOURMALINE-MM2 study enrolled TI MM patients to treatment with either ixazomib (Ninlaro), lenalidomide, and dexamethasone (IRd) or placebo plus Rd. Patients 75 years or older made up roughly 43% of both treatment arms, and approximately 40% of the study population had high-risk cytogenetics. The median PFS was 35.3 months for IRd vs 21.8 months for Rd (HR, 0.83; 95% CI, 0.676-1.018; P = .73).32 The most common AEs in the triplet arm (vs doublet) were diarrhea (61.0% vs 46.1%, respectively), rash (56.2% vs 37.2%) and peripheral edema (48.6% vs 33.5%).32 This study may serve as an example of a result that is clinically significant (ie, improvement in median PFS of 13.5 months) but not statistically significant. As such, the IRD regimen could be an option for frail/unfit patients who are unable to travel for infusion appointments.

The “conventional” VRd regimen with twice-weekly bortezomib has a range of AEs, including thrombocytopenia and neutropenia, constitutional symptoms, infection, and neurologic effects.31,37 In real-world practice, dose adjustments are often needed in TI patients. The RVd-lite regimen was proposed to mitigate the toxicity seen with the conventional VRd regimen; it consists of 35-day cycles with lenalidomide (15 mg on days 1-21), weekly subcutaneous bortezomib, and dexamethasone. A phase 2 study of RVd-lite, in which TI ND patients received 9 cycles of RVd followed by 6 cycles of Rd, showed an overall response rate (ORR) of 86%. The median PFS was 41.9 months, and the median OS was not reached at 61 months follow-up.38,39 Although peripheral neuropathy was common (reported in 62% of patients), only 1 of 31 patients (3.2%) reported grade 3 symptoms. As comparators, the rates of grade 3 or greater neuropathy in the SWOG S0777 and ENDURANCE studies in the VRd arms were 33% and 8%, respectively.30,31 Patients with high-risk cytogenetics constituted a minority of the patients enrolled (12%).

In our practice, VRd is one of our preferred induction regimens for TI patients, with the caveat that once-weekly bortezomib/dexamethasone dosing is used. In addition, lenalidomide dosing is commonly reduced as well. With these modifications, we have found that even frail patients can tolerate this triplet therapy. We reserve KRd for fit patients who have significant baseline neuropathy without significant cardiovascular comorbidities. IRd may be a reasonable option for select patients, particularly those with transportation issues. As noted above, the various studies have included disparate numbers of cycles of induction therapy. Our approach is to have the goal of continuous therapy (ie, treatment until progression), with dose reductions or drug discontinuations based on patient- and disease-specific factors, including toxicity, cytogenetic risk, and disease response.

PI/Alkylator combinations: The phase 3 CLARION study randomized 955 patients with ND MM who were TI to carfilzomib, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP; 9 cycles).27 The median age in both treatment arms was 72 years, with more than 30% of patients in both arms 75 years or older. Patients with higher-risk cytogenetics constituted a minority in both the KMP (11.3%) and VMP arms (14.0%). No statistically significant difference was observed in median PFS (22.3 vs 22.1 months for KMP and VMP, respectively; HR, 0.9; 95% CI, 0.746-1.101; P = .159). This trial highlighted the differences in the toxicity profiles of bortezomib vs carfilzomib, with peripheral neuropathy of any grade more common with bortezomib (13.6% vs 1.7%, respectively), while both cardiovascular complications (hypertension, cardiac failure) of any grade and acute kidney injury (AKI) were more common in the KMP arm (hypertension, 21.9% vs 6.8%; cardiac failure, 6.5% vs 2.1%; AKI, 6.3% vs 2.8%). In the United States, the use of oral melphalan remains uncommon, thus this study was not practice-changing. However, this study, in conjunction with the ENDURANCE study, provides evidence that carfilzomib is not superior to bortezomib, at least in the ND nontransplant setting, and that the 2 agents have a notably different AE profile, which could impact the decision to recommend one regimen over the other for specific patients.

As noted, oral melphalan is rarely used in the United States, in part due to concerns related to stem cell toxicity.40 VCD—bortezomib, cyclophosphamide, dexamethasone—substitutes cyclophosphamide for melphalan; however, evidence for the use of this combination in the TI setting is limited to retrospective reports and phase 2 studies. The phase 2 EVOLUTION study showed an ORR of 63% for VCD and 82% for VCD-modified (mod; in which an additional dose of cyclophosphamide was added at day 15).41 The corresponding 1-year PFS was 93% and 100%, respectively. The major grade 3 or greater AE was neutropenia (30%, VCD; 24%, VCD-mod); however, AEs leading to discontinuation of treatment were 12% for the VCD arm and 6% for the VCD-mod arm. Patients were enrolled in this study regardless of their transplant eligibility.41 Similarly high response rates were seen in a retrospective multicenter analysis42 and in a smaller phase 2 study of patients who proceeded to transplant.43 This regimen can be a reasonable option in frail patients with unstable renal dysfunction or in patients who have an absolute contraindication to anticoagulation and therefore cannot receive lenalidomide.

Daratumumab-containing induction regimens: The anti-CD38 mAb daratumumab has found widespread use in the R/R setting; subsequently, investigators have begun to incorporate this agent into the ND setting. In the phase 3 ALCYONE trial, TI patients were randomized to VMP with daratumumab (Darzalex; D-VMP) or without.35,44 The median age was 71 years; 38% were aged at least 75 years. Patients received 9 cycles of induction followed by either observation (VMP arm) or single-agent daratumumab (D-VMP). The quadruplet resulted in a significant PFS advantage (HR, 0.42; 95% CI, 0.34-051; P = .0001) and OS advantage (HR, 0.6; 95% CI, 0.46-0.80; P = .003).44 The high-risk cytogenetics subgroup comprised 14% of the study population. While an ORR benefit was observed in the quadruplet arm in this subgroup (odds ratio, 4.45; 95% CI, 1.32-15.01; P = .0111), there was not an OS advantage (HR, 0.91 95% CI, 0.5-1.65). Pneumonia was the most common grade 3 or 4 AE (11%, D-VMP vs 4.2%, VMP). Given the uncommon use of melphalan as part of an induction regimen in the United States, the results of this study were not practice-changing. However, this study is noteworthy as it provides some insight into the potential benefit of single-agent daratumumab maintenance post induction in the nontransplant setting.

The phase 3 MAIA trial randomized ND TI patients (based on age [≥65 years] or presence of comorbidities) to daratumumab, lenalidomide, and dexamethasone (DRd) vs Rd.33 Treatment was continued until disease progression or unacceptable toxicity. With a median follow-up of 28 months, the triplet arm vs the doublet had a significantly longer PFS (median PFS, not reached vs 31.9 months, respectively; HR, 0.56; 95% CI, 0.43-0.73; P <.001), a higher ORR (92.9% vs 81.3%; P <.001), and a higher depth of response based on MRD negativity (24.2% vs 7.3% [10-5 using next-generation sequencing]; P <.001). The most common AE of any grade was infection (86.3% vs 73.4%, respectively), and grade 3 or 4 neutropenia was seen in 50.0% of patients in the triplet arm vs 35.3% in the doublet arm. Approximately 15% of patients had high-risk cytogenetics and the PFS benefit in the triplet arm was not statistically significant in this subgroup (HR, 0.85; 95% CI, 0.44-1.65). Of note, intravenous daratumumab was used in this study. In real-world practice, subcutaneous daratumumab has now become the default option given the similar efficacy, shorter administration time, and lower incidence of infusion reactions when compared with the intravenous formulation (13% vs 34%, respectively).45

We find the DRd regimen useful in patients with preexisting neuropathy where the use of bortezomib is of concern. The use of the DRd regimen in patients who are at a significantly higher risk of pneumonia or infections (eg, due to underlying chronic lung disease) should be coupled with caution, given the higher incidence of pneumonia and neutropenia. When compared with the SWOG S0777 trial, the MAIA trial had a significantly older population, with 99% of patients aged more than 65 years and 44% 75 years or older. Furthermore, a recent report46 of patient-reported outcomes (PROs) for patients in the MAIA trial from enrollment through cycle 12 showed that DRd resulted in faster and clinically meaningful improvements in PROs regardless of age or depth of treatment response, with a greater proportion of patients showing improvement in fatigue and physical functioning, and greater reductions in pain, compared with Rd. We thus consider this an appropriate option even in patients who are frail. The other daratumumab combinations (daratumumab plus bortezomib, thalidomide, and dexamethasone [dara-VTD]47 and dara-VRd48) were studied in the TE population, and we thus restrict the use of daratumumab in the upfront treatment of TI population to the DRd regimen.

Very few studies have specifically focused on the unfit or frail patient population. The phase 2 HOVON 143 study evaluated the combination of daratumumab, ixazomib, and dexamethasone in patients with ND MM who were unfit or frail per the IMWG frailty index.34 Patients received 9 cycles of therapy followed by maintenance with daratumumab-ixazomib for up to 2 years. The combination showed an ORR of 87% in unfit patients and 78% in frail patients, with a 9-month PFS rate of 78% and 61%, respectively, based on the data reported from the first 23 patients enrolled to each group.49 Hematologic toxicity was mainly in the form of neutropenia (grade 4, 4% in unfit and 13% in frail) and thrombocytopenia (grade 4, 0% in unfit and 4% in frail). The main nonhematologic toxicity reported was grade 3 infections occurring in 9% of both unfit and frail patients. Early death rate (in 3 months or less) was 0% in the unfit arm and 12% in the frail arm. As the data for this combination come only from a phase 2 study, this regimen should be considered for treatment of ND TI MM patients only in scenarios where DRd or VRd are contraindicated.

Maintenance Post Induction

Lenalidomide: While maintenance therapy has been shown to prolong PFS and OS in the posttransplant setting,50 only a PFS benefit has thus far been shown in the TI setting.51 The randomized phase 3 Myeloma XI trial had an adaptive design with 3 potential randomizations: induction treatment with allocation by transplant eligibility; intensification treatment with allocation by response to induction; and maintenance treatment.51 Maintenance was continued until progressive disease or development of unacceptable toxicity. In the TI patients, lenalidomide maintenance significantly improved PFS vs observation (median, 26 vs 11 months; HR, 0.44; 95% CI, 0.37-0.53; P <.0001) but not OS (3-year OS, 66.8% vs 69.8%; HR, 1.02; 95% CI, 0.80-1.29; P = .88). For the entire study population, the median duration of lenalidomide maintenance therapy was 18 cycles (IQR, 6-30) and 69% of patients required dose modifications. Overall in the study, the most common grade 3/4 hematological AEs associated with lenalidomide maintenance were neutropenia (33%) and thrombocytopenia (7%), but information was not provided for the TI subgroup specifically.

The SWOG S0777 study incorporated maintenance Rd; however, the study population was not truly TI—as reviewed above—and the same limitation applies to the ENDURANCE trial, in which lenalidomide maintenance is being evaluated for 2 years vs indefinitely. In patients who start VRd and later develop neuropathy, it is reasonable to continue lenalidomide (with or without dexamethasone) for as long as it is tolerated or effective. The above-mentioned studies do not address the scenario of initiating lenalidomide maintenance following induction that lacks an IMiD, and we would not recommend that approach. Instead, for patients who did not receive lenalidomide with induction, we would recommend a lenalidomide-containing regimen at the time of relapse (as discussed in greater detail below).

Ixazomib: The phase 3 Tourmaline MM4 study randomized TI patients who had achieved a partial response or better, after standard induction therapy lasting 6 to 12 months, to receive either ixazomib or placebo for a total of 24 months. Approximately 60% of patients had received an induction regimen containing bortezomib (VMP, VCD, or VTd). The median age was 72 years; more than 37% of patients in the ixazomib arm were 75 years or older. Ixazomib maintenance resulted in a 34% reduced risk of progression or death compared with placebo (median PFS, 17.8 vs 9.8 months; HR, 0.659; 95% CI, 0.54-0.80; P <.001). A PFS benefit was also observed in a prespecified subgroup analysis of patients 75 years or older. Approximately 30% of patients in the ixazomib arm developed a TEAE requiring dose reduction.52 Ixazomib offers the advantage of an oral agent that can be given once weekly for defined period of 24 months, but whether maintenance beyond 24 months provides additional benefit is unknown.

Daratumumab: Data from the ALCYONE trial showed the activity of single-agent daratumumab as a maintenance strategy post induction with VMP.35,44 Evaluation of the PFS curves from this study reveals that while there is separation of the curves (in favor of the daratumumab-containing arm) during induction (12-month PFS, 87% vs 76%),35 the separation widened during the daratumumab-vs-observation portion of the study (36-month PFS, 51% vs 19%).44 The most common grade 3/4 AEs reported during daratumumab maintenance included anemia (4%), pneumonia (4%), hypertension (3%), and neutropenia (2%).44 However, extrapolation from that study to use of single-agent daratumumab maintenance following other daratumumab-containing regimens is not routinely recommended at this time. For patients who initiated DRd induction and subsequently become intolerant to lenalidomide, it may be reasonable to continue daratumumab (with or without dexamethasone) until time of progression.

Relapsed/Refractory Disease

More than a third of patients with MM never receive a second-line therapy,53 and even when they do, shorter durations of response are seen with subsequent lines of therapy.54,55 Factors that should be kept in mind when selecting a treatment strategy in the subsequent lines of therapy include the context of the relapse/progression, the patient’s fitness and comorbidities, tolerance to previous agents, and the potential for overlapping toxicities with agents in prior lines of therapy. For patients with an asymptomatic biochemical relapse and in the absence of extramedullary disease, a watch-and-wait approach can be reasonable and is in line with recommendations from the IMWG, provided that the rise in paraprotein level is slow.56 While several phase 3 studies conducted over the past decade have established the superiority of (primarily) triplet combinations over doublets in the R/R setting, it is rare for studies to focus specifically on the TI population. Thus, modifications to dosing/schedule may be required to ensure tolerability of these multiagent regimens in unfit/frail patients; such modifications have unknown consequences on efficacy. Below, we discuss some general concepts related to sequencing in the R/R setting as well as some of the recent studies that have reported outcomes based on frailty.

In TI patients in the United States, similar to the TE population, it is becoming increasingly common for their disease to be lenalidomide-refractory at the time of first relapse. As noted above, the majority of the commonly used induction regimens include lenalidomide. Thus, while several randomized phase 3 studies have demonstrated the superiority of lenalidomide-containing triplets over Rd in early lines of relapse (summarized in the Table), these studies are not relevant for patients progressing on lenalidomide. In that context, regimens containing PIs or pomalidomide (Pomalyst) should be considered (Figure 2). However, multiple options exist, and aside from trying to perform cross-trial comparisons, it is not possible with the existing data to determine which option should be prioritized. Instead, we recommend an individualized approach which encompasses the induction (plus/minus maintenance) regimen previously received; the patient’s disease characteristics (eg, if rapid progression on lenalidomide, would favor a PI-based combination over pomalidomide-based); comorbidities (eg, if severe cardiac disease, would prefer not to use carfilzomib; if severe neuropathy, would prefer not to use a bortezomib-containing regimen); and other factors such as route/administration schedule. If a patient did not receive lenalidomide with induction, or has been off lenalidomide for an extended period of time prior to progression (eg, 6 months), then it would be reasonable to choose a lenalidomide-based combination. Likewise, the choice of third-line therapy will be dictated in large part by the decisions regarding first-line and second-line treatments. Further, in the older/unfit/frail patient population, comorbidities along with TEAEs may be more of an issue, preventing the consistent delivery of combination therapies.

TABLE. Summary of Recent Phase 3 Studies in Relapsed/Refractory Multiple Myeloma

TABLE. Summary of Recent Phase 3 Studies in Relapsed/Refractory Multiple Myeloma

FIGURE 2. First- and Second-Line Therapy Choices in the Newly Diagnosed Transplant-Ineligible Setting

FIGURE 2. First- and Second-Line Therapy Choices in the Newly Diagnosed Transplant-Ineligible Setting

Therefore, we cannot recommend a one-size-fits-all approach to this patient population, and that means that it is difficult to devise simple treatment algorithms. Figure 2 outlines several potential pathways from induction to second-line therapy, taking into account that while VRd and DRd may be 2 of the most common induction regimens for TI patients, one can take multiple paths after starting these triplet therapies. While the intent may be to continue all 3 agents until progression, in the real-world situation, this approach may not be possible, and dropping 1 (or 2) agent(s), or even stopping all therapy and monitoring, may be necessary because of toxicities or other emerging health problems. At all treatment decision points, referral to a MM specialist is encouraged; new treatment paradigms are being rapidly developed and clinical trial options may be appropriate.

Analysis of frailty in the R/R setting: A post hoc analysis57 of patients with R/R MM treated with carfilzomib in 3 phase 3 trials—ASPIRE (KRd vs Rd),58 ENDEAVOR (Kd vs Vd),59 and ARROW (once-weekly Kd vs twice-weekly Kd)59—showed overall consistent efficacy and safety profiles across patient subgroups, regardless of frailty status. We thus consider a carfilzomib-containing regimen (such as dara-Kd) to be a reasonable second-line option in patients who are considered lenalidomide refractory (Figure 2). The phase 3 ICARIA-MM study60 enrolled patients with R/R MM who had received 2 or more prior lines of therapy including lenalidomide and a PI. A regimen of isatuximab, pomalidomide, and dexamethasone (isa-Pd) was compared with a control arm of Pd, and treatment was continued until disease progression or unacceptable toxicity. The triplet arm had a superior PFS (median PFS, 11.5 vs 6.5 months for Pd; HR, 0.596; 95% CI, 0.44-0.81; P = .001).60 A post hoc analysis was performed looking at differences in outcomes and toxicity based on patients’ frailty scores according to the modified CCI stratified into fit, intermediate, and frail categories.61 This analysis revealed that patients in the frail group had similar outcomes and AE profiles to the overall study population. Finally, in a recent subgroup analysis of the phase 3 Boston study, which randomized patients to selinexor (Xpovio)/bortezomib/dexamethasone vs bortezomib/dexamethasone, an improvement in ORR and PFS was observed in those aged more than 65 years (60% of the study population) as well as those considered frail (44% of the study population) who received triplet therapy.62


Significant advances have been made in the treatment of MM. Currently, the 2 triplet combinations of choice for ND TI patients are VRd (using weekly bortezomib) and DRd. However, the optimal induction treatment for frail or unfit patients remains to be determined. Particularly in the R/R setting, the results of phase 3 randomized studies may not always be applicable to the TI population, necessitating extrapolation of data obtained from a predominantly younger/TE population, with possibly different disease biology and toxicity profiles.63 In acknowledging our knowledge gaps in this territory, we highlight that the best answer for those patients—whenever available—is enrollment in a clinical trial and consultation with a MM specialist and geriatric oncologist. Furthermore, we advocate for more routine incorporation of geriatric assessment and frailty screening into both the clinical trial and nontrial settings (eg, as recently demonstrated by Nathwani et al64), with the goal of optimizing treatment decisions.

Financial Disclosure: RAE declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. SAH has served as a consultant for Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Oncopeptides, Sanofi, Sorrento, and has received research funding from Oncopeptides.


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