Integrating Frailty Screening for Older Patients Diagnosed with Multiple Myeloma

Transcription

1 Integrating Frailty Screening for Older Patients Diagnosed with Multiple Myeloma Target Audience This activity has been designed to meet the educational needs of hematologists, medical oncologists, physician assistants, nurse practitioners, clinical nurse specialists, and oncology nurses involved in the care of older patients with multiple myeloma. Educational Objectives After completing this activity, the participant should be better able to: Recognize new data regarding the screening and management of older patients with MM Employ an electronic screening tool in clinic to evaluate frailty status among older patients newly diagnosed MM or those needing a new line of therapy Provide appropriate care and counsel for patients and their families. Chair/Faculty Tanya M. Wildes, MD, MSCI Washington University School of Medicine Physician Continuing Medical Education Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Carevive Systems, Inc. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Continuing Education Credit Designation This educational activity for 1.0 contact hours is provided by Postgraduate Institute for Medicine. Accreditation Statement Postgraduate Institute for Medicine is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. Faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Tanya M. Wildes, MD, MSCI, hereby states that they or their spouse/ life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, RN, BSN and Jan Schultz, RN, MSN, CHCP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The following Carevive Systems, Inc. planners and managers reported the following: Timothy J. DiChiara, PhD, Consulting Fees, Gilead Sciences; Karen Hammelef, DNP, RN, Speakers Bureau, Novartis Pharmaceuticals Corporation. Method of Participation and Request for Credit There are no fees for participating and receiving CME credit for this activity. During the period February 29, 2016 through February 28, 2017 participants must read the learning objectives and faculty disclosures and study the educational activity. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on com. On the navigation menu, click on Find Post-test/Evaluation by Course and search by course ID Upon registering and successfully completing the post-test with a score of 75% or better and the activity evaluation, your certificate will be made available immediately. Media e-monograph Release date: February 29, 2016 Expiration date: February 28, 2017 Estimated time to complete activity: 1 hour Disclosure of Unlabeled Use This educational activity may contain discussion of published and/ or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Jointly provided by Postgraduate Institute for Medicine and Carevive Systems, Inc. This activity is supported by an independent educational grant from Celgene Pharmaceuticals, and Takeda Oncology.

2 The Use of Frailty Screening in Older Adults with Multiple Myeloma Tanya M. Wildes, MD, MSCI Introduction Multiple myeloma (MM) is a malignancy strongly associated with aging. The median age at diagnosis in the United States is 69 years, with nearly two-thirds of cases being diagnosed in individuals over 65 years. 1 With the aging of the population and the increased incidence of myeloma with age, a 77% increase is expected in the number of older adults with MM by the year 2030; within 20 years, three out of every four people diagnosed with MM will be aged 65 to 84. 2,3 While better therapies and novel agents have improved survival in both younger and older patients, outcomes in older adults remain poorer than in their younger counterparts. 4,5 These significant impending demographic shifts and rapidly changing treatment paradigms warrant a closer look at individualizing care for older adults with myeloma as well as attention to factors associated with aging that may influence treatment toxicity and survival. The evolving treatment paradigm for managing older patients with MM Choice of regimen Traditionally, algorithms for treating myeloma diverged immediately depending on whether the patient was deemed a candidate for high-dose therapy and autologous stem cell transplantation (ASCT). This dichotomization was necessary to avoid exposure to melphalan and consequent compromise of the ability to harvest hematopoietic stem cells. Clinical trials examining the introduction of novel agents to initial therapy in older adults with myeloma largely proceeded by adding the novel agent to a melphalan and prednisone backbone. Numerous randomized trials have examined the addition of thalidomide 6-12, lenalidomide, 13 or bortezomib 14 to melphalan and prednisone. These studies nearly all demonstrated a benefit for the arm with the novel agent in regard to response rate and progression-free survival (PFS), and some demonstrated an overall survival (OS) benefit. In most studies, however, this was at the expense of greater toxicity. One study raised the concern that more is not necessarily better. In a community-based randomized trial, 502 older adults with newly diagnosed MM were randomized to one of three arms: bortezomib and dexamethasone (VD); bortezomib, thalidomide, and dexamethasone (VTD); or bortezomib, melphalan, and prednisone (VMP). 15 Each arm included induction for 24 weeks followed by 25 weeks of bortezomib maintenance. Of note, the bortezomib in this trial was administered twice weekly intravenously (IV). The median age was 73 years, 19% had two or more comorbid medical conditions, and about 10% of patients had a Karnofsky performance status <70%. Overall, there was no difference in PFS or OS between the groups. The VTD arm was associated with a slightly higher overall response rate (80% vs. 73% with VD and 70% with VMP), but toxicity resulted in more discontinuations due to adverse events and patients receiving fewer cycles of VTD overall. The authors pointed out that the antimyeloma efficacy of treatments must be balanced with increased risk of toxicity of therapy and the risk of decreased quality of life (QoL). Duration of initial treatment Recent studies have demonstrated the superiority of continuous treatment in older adults with newly diagnosed MM. In the Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide (FIRST) trial, 1,623 transplant-ineligible patients with newly diagnosed MM were randomized to one of three arms. 16 In the standard arm, 547 patients received 72 weeks of therapy with melphalan (0.25 mg/kg daily on Days 1-4, q 42 days), prednisone (2 mg/kg daily on Days 1-4 q 42 days) and thalidomide (200 mg daily) (MPT). In the second arm, 541 patients received lenalidomide (25 mg daily on Days 1-21 q ) and dexamethasone (40 mg weekly) for the same duration of time 72 weeks. Finally, in the continuous therapy arm, 535 patients received lenalidomide (25 mg daily on Days 1-21 q ) and dexamethasone (40 mg weekly) continuously until progression. The median age was 73 years, ranging from 40 to 92. Most patients (78%) had an ECOG performance status of 0 to 1. Continuous lenalidomide and dexamethasone were associated with significantly improved PFS compared with MPT [hazard ratio (HR) 0.72 (95% confidence intervals [CIs] )] and the fixed-duration lenalidomide and dexamethasone [HR 0.70 (95% CIs )]. While continuous lenalidomide and dexamethasone were associated with reduction in the risk of death compared with MPT [HR 0.78 (95% CIs , P = 0.02)], this did not meet the prespecified superiority boundary (P < ). Overall, the rates of grade 3-4 adverse events were similar across the arms, though the specific toxicities differed. In the MPT arm, grade 3-4 neutropenia occurred in 45% of patients compared with 28% people in the continuous lenalidomide and dexamethasone arm, and 26% in the fixed-duration lenalidomide and dexamethasone arm. The rates of grade 3-4 infection were 29% with continuous lenalidomide and dexamethasone, 22% with fixed-duration lenalidomide and dexamethasone, and 17% with MPT. The rates of venous thromboembolic events were 8% with continuous lenalidomide and dexamethasone, 6% with fixed-duration lenalidomide and dexamethasone, and 5% with MPT. Peripheral neuropathy rate was 9% with MPT compared with 1% or less with lenalidomide and dexamethasone. Formal QoL measures favored lenalidomide and dexamethasone over MPT in regard to side effects of treatment domains and reductions in pain and overall lower symptoms 17, demonstrating that improved disease control with continuous lenalidomide and dexamethasone did not come at the expense of greater toxicity or poorer QoL. In another study examining continuous versus fixed-duration therapy, Palumbo and colleagues performed a meta-analysis of three phase III trials in which patients with newly diagnosed MM were assigned to novel agents on a continuous basis versus fixed duration. 18 Two of the included studies were

3 designed for patients ineligible for high-dose therapy and ASCT. Overall, 827 patients were included in the intent to treat groups, with 410 receiving initial therapy of a fixed duration, and 417 receiving continuous therapy. The median PFS from the start of maintenance was 32 months with continuous therapy compared with 16 months with therapy of fixed-duration [HR 0.47 (95% CIs )]. The median OS was longer with continuous therapy compared with treatment of fixed-duration [HR 0.69 (95% CIs )]. Lessons from clinical trials about toxicity A number of important lessons relevant to the care of older adults with myeloma have emerged from clinical trials. These include the fact that the net benefit of greater antimyeloma effect of a regimen may be negated by excessive toxicity, such that greater response rates will not always translate into improved PFS or OS. Another example is that alterations in administration of some agents may allow for improved tolerability while maintaining dose intensity. The first point is exemplified in two studies in which higher doses of corticosteroids were associated with higher response rates but also with greater toxicity and even mortality. In one trial, 289 newly diagnosed older adults who were ineligible for high-dose therapy and ASCT were randomized to thalidomide and dexamethasone (TD) versus melphalan and prednisone (MP). 19 In this study, TD patients received thalidomide 50 to 400 mg and dexamethasone 40 mg Days 1 to 4 each cycle and Days 15 to 18 in even cycles. In the MP arm, patients received prednisolone 2 mg/kg Days 1 to 4 q 28 to 42 days. Though the response rate was higher in the TD arm (68% vs. 50%, P = 0.002), OS favored the MP arm [1.55 (95% CIs )]. Early deaths were more frequent in the TD arm and were related to infection and cardiac events. Importantly, OS in the subgroup of patients over age 75 was markedly shorter (median 19.8 vs months); on multivariate analysis, older age and poor performance status predicted early nonmyeloma mortality. Another randomized trial directly examined the impact of corticosteroid dose on outcomes. 20 While this study was not exclusively designed to examine treatment in older adults, more than one-half of the enrolled patients were aged 65 or older. In total, 445 patients were randomized to lenalidomide 25 mg with high-dose dexamethasone (40 mg Days 1-4, 9-12, and 17-20) vs. lenalidomide 25 mg with low-dose dexamethasone (40 mg Days 1, 8, 15, and 22). While the overall response rate after four cycles was higher with lenalidomide with high-dose dexamethasone (79% vs. 68.3%, P = 0.008), survival was higher in the lowdose dexamethasone arm (1-year overall survival was 96% with low-dose vs. 87% in the high-dose arm, P= ). Treatment discontinuation traceable to adverse effects, venous thromboembolic events, infection, weakness and early mortality were all more common in the high-dose dexamethasone arm. Thus, low-dose dexamethasone is preferred. In a meta-analysis of four trials of older adults newly diagnosed with myeloma, Bringhen and colleagues examined the association among patient factors, the occurrence of toxicity, and OS. 21 In this analysis of over 1,400 older adults receiving initial therapy, the occurrence of grade 3-4 nonhematological toxicities was associated with an increased risk of death within 6 months of the event [HR 1.82 (95% CIs )]. Specifically, cardiac, infectious or gastrointestinal grade 3-4 adverse events were associated with the greatest risk of death [HR 2.53 (95% CIs )]. Of all the deaths in the study, 24% were attributable to toxicity. Peripheral neuropathy is an especially important adverse effect of therapy in older adults given the potential for causing functional impairment. Studies of these novel agents have sought to balance efficacy with toxicity and to determine the optimal dosing and route of administration to strike that balance. One study performed in older adults with newly diagnosed MM provided particular insight into the dosing strategies for bortezomib. In a randomized trial of bortezomib, melphalan, prednisone, and thalidomide followed by bortezomib-thalidomide maintenance (VMPT- VT) versus bortezomib, melphalan, and prednisone (VMP), the administration of bortezomib was changed from twiceweekly to once-weekly partway through the trial, yielding insight into the risk of toxicity limiting dose intensity. 22 In both arms, the initial protocol specified dosing for bortezomib was 1.3 mg/m 2 IV on Days 1, 4, 8, 11, 22, 25, 29, and 32. After the first 139 patients experienced a 51% rate of grade 3-4 nonhematological toxicities, the protocol was amended to change the bortezomib administration to once a week. With this modification, the rate of total grade 3-4 nonhematological toxicities was reduced to 36%, and the rate of grade 3-4 peripheral neuropathy dropped from 16% to 3%. On the weekly schedule, this lower rate of toxicity allowed patients to receive a similar dose intensity as with twice-weekly administration and to experience similar response rates, PFS and OS. The results of this study were aggregated and presented with two additional randomized trials in which older adults received bortezomib, melphalan, and prednisone. 23 Patient-level data on those who received VMP in each study were examined. Patients who received regimens where bortezomib was primarily administered once a week tended to receive similar cumulative dose-intensity compared with those who received twice-weekly bortezomib, with similar overall response rates and OS, yet they enjoyed lower rates of peripheral neuropathy. Several studies also support improved tolerability with subcutaneous (SC) bortezomib with similar efficacy. In a randomized noninferiority study, 222 patients with relapsed myeloma were assigned to IV or SC bortezomib 1.3 mg/ m 2 on Days 1, 4, 8, and 11 every 21 days. 24 While the trial was not specifically designed for a population of older adults, one-half of the enrolled patients were over age 65. Cumulative dose intensity, response rates, time to response, time to progression, PFS, and OS were identical between the two groups, and SC bortezomib was deemed statistically noninferior to IV administration. Patients receiving SC bortezomib had a lower rate of grade 3-4 adverse events

4 (57% vs. 70%) and were less likely to require dose reductions or treatment discontinuation. The rate of grade III peripheral neuropathy fell from 15% with IV bortezomib to 5% with SC bortezomib. In summary, older adults with MM have poorer survival than younger patients, but novel therapies have improved survival over the past 15 years. Optimal dose and administration of the novel agents are evolving as studies reveal opportunities to improve the clinical care of older adults with MM. While a focus on the disease and therapeutics will be an important component of improving outcomes in older adults with MM, attention must also be given to factors outside of the myeloma that influence tolerance to chemotherapy and survival. The following section will explore concepts of geriatrics and their application in older adults with cancer and myeloma in particular. The comprehensive geriatric assessment Geriatric assessment and frailty in noncancer populations Geriatric assessment is a comprehensive, multidimensional appraisal of the health of an older individual; domains of a comprehensive geriatric assessment (CGA) are listed in Table 1. In clinical geriatrics practice, the goal of the CGA is not just to identify problems, but to intervene on nascent issues to prevent future problems, particularly functional decline and mortality. An assessment alone will not impact outcomes, but rather intervention is targeted to areas of concern or vulnerability uncovered in the CGA. Dependence in daily activities and limitations in physical function may be mitigated by referrals to occupational and physical therapy. In addition, the social history is important in determining whether patients and their caregivers are able to compensate for dependence or whether they require additional assistance. For example, if patients require assistance with taking medications, home health nurses may facilitate drug adherence by setting up a pillbox. Medication review is an important component of a CGA. Polypharmacy, which is often defined as taking more than four medications, is associated with increased risk of adverse drug reactions. Consensus guidelines have been established regarding medications that are considered inappropriate in older adults due to an increased risk of adverse effects. 25 The CGA may uncover a history of falls or determine that the patient is at risk for falls through a simple analysis of gait and balance, such as a time of 13.5 seconds on the Timed Up and Go test. 26 Falls are a potentially preventable event. 27 The most effective interventions to eliminate falls are multicomponent activities, tailored to the individual s risk factors. Those who have fallen or are at increased risk for falls should be referred for physical therapy and for a home safety evaluation, often performed by occupational therapists. Medication review with a pharmacist may identify drugs that increase the risk of falls. Deficient or insufficient vitamin D should be supplemented in older adults who experience falls as it impacts skeletal health but is also implicated in muscle weakness. This assessment may also uncover mood disorders or cognitive impairment. Simple screening tools such as the PHQ -928 may aid in establishing a diagnosis of depression, which is underrecognized in older adults. Noting cognitive impairment may allow identification of such treatable conditions as thyroid disorders or vitamin B 12 deficiency as well as referral for neuropsychological testing. Table 1. Domains of a comprehensive geriatric assessment Domain Functional Status Physical Performance Cognition Comorbidities/Multimorbidity Polypharmacy and Inappropriate Medications Depression Other Geriatric Syndromes Examples of measures/screening tools used Activities of Daily Living: bathing, dressing, toileting, transferring, continence, and feeding Instrumental Activities of Daily Living: using telephone, transportation, shopping, meal preparation, housework, taking medications, and managing money Timed Up and Go Test Short Physical Performance Battery Gait speed assessments Diagnosis of dementia Mini-Mental Status Exam Short Blessed Test Clock Construction Test Medical history Charlson comorbidity index Beers Criteria for Inappropriate Medications STOPP/START criteria Clinical diagnosis of depression Patient-Health Questionnaire-9 Falls, Incontinence, Nutrition, Neglect/Elder Abuse

5 Assessing a patient s social support is an important component of the CGA. If an individual is dependent on daily activities, another person must help the patient meet those needs. Consultation with a social worker may help an older adult access such resources as transportation or chore workers, allowing patients to remain in their home. A social worker may also help ensure that the older adults tangible needs are addressed. A social worker is also an essential resource if concerns arise about elder neglect or abuse. Frailty is a syndrome characterized by increased risk for poor health outcomes, including falls, incident disability, hospitalization, and mortality. 29 Two major approaches to operationalizing frailty are the phenotypic frailty model and an accumulation of deficits model. In the phenotypic frailty model, frailty is defined by the presence of three out of five criteria that include grip strength, low self-reported energy, slow gait speed, low physical activity, and weight loss. 30 The accumulation of deficits model focuses less on specific criteria and more on the total number of deficits present in an individual. 31,32 Each approach has its merits and drawbacks, informing some approaches to studying older adults with cancer and is detailed below. Geriatric assessment and frailty in cancer populations Researchers interested in the intersection of cancer and aging have begun to demonstrate the predictive and prognostic utility of applying the tools of a geriatrician to the care of older cancer patients. In a prospective cohort study of older adults with solid tumor malignancies, 500 of them underwent a brief primarily self-administered geriatric assessment prior to initiation of a course of chemotherapy and were followed for the occurrence of grade 3-4 toxicities. 33 The mean age of participants was 73 years, ranging from 65 to 91. Geriatric syndromes were common: 43% required assistance with one or more Instrumental Activities of Daily Living (IADLs) and 90% had at least one comorbid medical condition. Nearly one in five (18%) had a fall within the prior 6 months. Over one-half of patients (53%) experienced one or more grade 3-5 toxicities during the chemotherapy course. The team developed a predictive model of chemotherapy toxicity (Table 2 and Figure 1) based on risk score. The model is able to distinguish older adults at low (30%), intermediate (52%), and high (83%) risk for grade 3-5 toxicity of chemotherapy. The area under the curve (AUC) of the model was Notably, physician-rated Karnofsky Performance Status performed poorly in predicting chemotherapy toxicity (AUC = 0.53, P = 0.19), demonstrating the utility of an evaluation beyond traditional oncology constructs. In a similar study, the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) trial, separate predictive models were developed of factors predictive of hematological and nonhematological toxicity of chemotherapy. 34 In 518 patients over 70 years of age beginning a course of chemotherapy for solid tumor malignancies, grade IV hematological toxicity occurred in 32% of patients, and grade 3-4 nonhematological toxicity occurred in 56% of patients. Factors predictive of grade 4 hematological toxicity Table 2. Cancer and aging research group model: geriatric assessment factors predictive of chemotherapy toxicity Risk factor The Use of Frailty Screening in Older Adults with Multiple Myeloma Points assigned Aged >/=72 2 Gastrointestinal or genitourinary cancer 2 Standard-dose chemotherapy 2 Combination chemotherapy 2 Hemoglobin <11 g/dl (males); <10 g/dl (females) 3 Creatinine clearance <34 ml/min 3 Hearing--fair or worse 2 One or more falls in the past 6 months 3 Requires assistance with taking medications 1 Limited to walking one block 2 Decreased social activity due to health 1 Reprinted with permission. (2011) American Society of Clinical Oncology. All rights reserved. 33 Figure 1. Risk of grade 3-5 chemotherapy toxicity in older adults by CARG risk score Reprinted with permission. (2011) American Society of Clinical Oncology. All rights reserved. 33 included diastolic blood pressure >72 mm Hg, dependence in IADLs, lactate dehydrogenase level >0.74, which is the upper limit of normal, and greater chemotox, a measure of the frequency of toxicity for a particular chemotherapy regimen as previously published in the literature. 35 Grade 3-4 nonhematological toxicity was predicted by ECOG performance status, cognition as measured by the Mini- Mental Status Exam, nutritional risk as measured by the Mini Nutritional Assessment, 36 and chemotox. Geriatric assessment is also predictive of older adults who will suffer early death (i.e., within 6 months of their initial chemotherapy). 37 In this study, 364 patients over age 70 who were scheduled to begin their first course of chemotherapy for solid tumors or non-hodgkin lymphoma underwent an abbreviated geriatric assessment. Early deaths occurred in 56 patients, with 73% attributable to cancer, 14% treatment-

6 related, and 12% other intercurrent illnesses/issues. Factors associated with early death included male gender, advanced tumor stage, patients at nutritional risk using the Mini- Nutritional Assessment, and a slow time on the Timed Up and Go test. 26 Several studies have also demonstrated the prognostic utility of geriatric assessment in hematological malignancies. In older adults with acute myelogenous leukemia (AML), in addition to expected disease-focused factors like cytogenetics and secondary AML, comorbidities, impaired cognition and poorer physical performance were associated with poorer survival. 38 Among older adults with diffuse large B-cell lymphoma, categorization of frailty based on dependence in Activities of Daily Living (ADLs) or IADLs, comorbidities, and age >80 years better predicted OS than whether the patient received curative versus palliative intent chemotherapy. 39,40 As in the general geriatric population, the real utility of CGA in older adults with cancer will likely lie beyond its predictive and prognostic ability, but is guiding interventions to help older patients maintain their independence and to prevent future decline. Mohile and colleagues recently published a Delphi Consensus of 30 experts in geriatric oncology wherein recommendations for geriatric assessmentguided care processes were made. Figure 2 presents an algorithm for suggested care processes for older adults with cancer, which is directed by vulnerabilities detected by the CGA. Geriatric assessment in multiple myeloma Accumulating evidence supports a role for geriatric assessment to aid in decision-making for older adults with MM. Several studies have examined the impact of comorbidities on survival in older patients with myeloma. A German group developed a comorbidity index named the Freiburg Comorbidity Index (FCI), which incorporates risk factors that include Karnofsky Performance Status 70%, moderate or severe lung disease, or creatinine clearance <30 ml/min. 41 They found this index to be prognostic, independent of the International Staging System (ISS); controlling for ISS stage, treatment, and age, those with a greater number of risk factors in the FCI had poorer survival [HR 2.3 (95% CIs ) for one risk factor and 2.9 ( ) for two to three risk factors]. 42 Another group found that the FCI was a better predictor of overall survival than the more complex and more widely used Charlson Comorbidity Index. 43 Other studies have examined the predictive and prognostic significance of specific comorbidities, namely diabetes. While some have found no independent prognostic significance of diabetes 41, others have found that the disease is associated with a lower complete response rate and that corticosteroidinduced diabetes is a particularly poor prognostic finding [HR 1.6 (95% CIs )]. 44 Numerous studies have demonstrated that in older adults with cancer, functional status and comorbidities are independent of one another; 45,46 indeed, the same holds true in MM where comorbidities and functional limitations in IADLs are independently associated with poorer survival. 47 Thus, clinicians and researchers alike must examine both Figure 2. Care for older adults with cancer Impairment Domain Functional Status Cognition Social Support Objective Physical Performance Psychological Status: Anxiety/ Depression Nutrition Process options Physical therapy Occupational therapy Home safety evaluation Refer to social work Evaluate fall risk Exercise Involve caregiver Assess/minimize medications Delirium prevention Refer to social work Assess capacity and ability to consent to treatment Identify health care proxy Cognitive testing/neuropsychology referral Refer to social work Transportation assistance Nursing/home health Caregiver management Home safety evaluation Support groups Refer to psychiatry/psychology Spiritual care Physical therapy Exercise Occupational therapy Home safety evaluation Rehabilitation Nursing/home health Refer to social work Counseling Refer to psychiatry/psychology Start medications Support programs Spiritual care Nutrition consult Make specific dietary recommendations Oral care Supplements Refer to social work Physical/occupational therapy Mohile SG, Velarde C, Hurria A, et al. Geriatric assessment-guided care processes for older adults: a Delphi consensus of geriatric oncology experts. J Natl Compr Canc Netw 2015;13(9): Figure 2. Reprinted with permission from JNCCN-Journal of the National Comprehensive Cancer Network.

7 Table 3. Regimens received by older adults with myeloma in clinical trials in which the Palumbo Frailty Index was developed Study Regimen Novel agent dosing Alkylator dosing Corticosteroid dosing Duration Bringhen and colleagues 57 CCD Carfilzomib Cycle 1: 20 mg/m 2 IV Days 1 & 2; 36 mg/m 2 Days 8, 9, 15, 16 q Cycles 2-9: 36 mg/m 2 Days 1, 2, 8, 9, 15, 16 q Maintenance 36 mg/m 2 Days 1, 2, 15, 16 q 28 days Gay and Rd Lenalidomide 25 mg Days colleagues q MPR CPR Lenalidomide 10 mg/day Days 1-21 q Lenalidomide 25 mg Days 1-21 q Larocca and VP Bortezomib 1.3 mg/m 2 colleagues 59 SC Days 1, 8, 15, 22 q 28 days VCP Bortezomib 1.3 mg/m 2 SC Days 1, 8, 15, 22 q 28 days VMP Bortezomib 1.3 mg/m 2 SC Days 1, 8, 15, 22 q 28 days Cyclophosphamide 300 mg/m 2 po Days 1, 8, 15 q Dexamethasone 40 mg po Days 1, 8, 15, 22 q None Aged 65-75: dexamethasone 40 mg Days 1, 8, 15, 22 q Aged 65-75: melphalan 0.18 mg/kg Days 1-4 q Age>75: melphalan 0.13 mg/kg Days 1-4 q Aged 65-75: Cyclophosphamide 50 mg po daily Days 1-21 q Aged >75: Cyclophosphamide 50 mg po Days 1-21 q Cyclophosphamide po 50 mg Melphalan 2 mg po Aged >75: dexamethasone 20 mg Days 1, 8, 15, 22 q Prednisone 1.5 mg/kg Days 1-4 q Prednisone 25 mg Prednisone 50 mg Prednisone 50 mg Prednisone 50 mg Until progression or intolerance 9 cycles, then randomized to maintenance lenalidomide 10 mg Days 1-21 q 28 with or without prednisone 25 mg every other day 9 cycles, then every other week bortezomib maintenance until progression

8 comorbidities and functional status separately and not consider one a surrogate for the other. Palumbo and colleagues sought to combine comorbidities, age, and functional status into a frailty model predictive of toxicity of therapy and prognostic of survival. 48 The investigators conducted a pooled analysis of 869 older clinical trial participants with newly diagnosed MM from three trials. Participants completed a brief geriatric assessment of functional status and comorbidities at diagnosis. Details of the therapeutic regimens are detailed in Table 3. Even among this highly selected group of older adults eligible for clinical trials, limitations in daily function and comorbidities were frequent, with 14% of people dependent in two or more ADLs, 18% dependent in three or more IADLs, and 17% with comorbidities. On multivariate survival analyses, individuals over 80 years of age, those with limitations in two or more ADLs (ADLs </=4) or three or more IADLs (IADL </=5), or those with two or more comorbidities were at greater risk of death. The investigators transformed the hazard ratios into a point system to derive a Frailty Score. See Table 4 for development of the Frailty Score. OS differed among the frailty categories, with a 3-year overall survival of 84% in the fit category, 76% in the intermediate-fit, and 57% among the frail. Even with regimens modified for older adults and dose modifications by age group as detailed in Table 3, frail patients had a higher risk of nonhematological toxicity, treatment discontinuation and death due to disease progression. The rates of grade 3-4 nonhematological toxicity were 22% among patients in the fit category, 26% among the intermediate-fit group, and 34% among those in the frail category. Similarly treatment discontinuation increased from 16% in the fit group to 21% in the intermediate-fit category, with 31% in the frail group. Grade 3-4 hematological toxicity did not differ across the frailty categories (38% in the fit group, 35% in the intermediate-fit, and 30% among the frail), presumably related to the empiric dose reductions. These data support the utility of geriatric assessment in predicting toxicity and survival in older adults with MM, but have some limitations. The predictive model will require external validation and confirmation of its applicability in routine practice beyond the clinical trial population in which it was developed. Compared with the paucity of clinical trials enrolling older adults with other malignancies, clinicians treating MM have the benefit of a large body of clinical trials focused on transplant-ineligible patients. Even with that knowledge base, clinicians still recognize the risk for toxicity in their more vulnerable older patients, who may not have been eligible for clinical trials due to comorbidities or poor functional status. The European Myeloma Network has proposed a framework to guide clinicians in tailoring initial therapy for older MM patients. 49 Table 5 details an adaptation of their proposed dose modifications. 49,50 While this framework has not been prospectively validated, its principles have been incorporated into clinical trials with encouraging preliminary results. 51,52 Anticipatory supportive care and prophylaxis may help prevent or mitigate potential toxicity. Varicella zoster prophylaxis reduces the risk of reactivation. Prophylaxis for venous thromboembolic events (VTEs) is effective, and a randomized trial of patients receiving thalidomide demonstrate similar rates of VTE with aspirin, warfarin, or low-molecular-weight heparin, though a subgroup analysis of older patients receiving the combination of bortezomib, melphalan, prednisone, and thalidomide showed warfarin to be inferior to low-molecular-weight heparin. 53 Bisphosphonates are effective for prevention of skeletal-related events, and zoledronic acid, in particular, is associated with improved overall survival. 54 While the original clinical trials examined bisphosphonate use over a finite time period (generally 2 years), experts suggest treatment with bisphosphonates beyond 2 years in those with active disease. 55,56 Conclusion MM is a disease of aging and will increase in prevalence as the population ages. Though the novel agents have significantly improved survival, further refinements are needed to personalize therapy and optimize outcomes for older adults with MM. Weaving the principles of geriatrics into the care of older individuals with MM may aid in therapeutic decision-making, minimizing toxicity, maximizing response, and comprehensively addressing the needs of our most vulnerable patients. Table 4. Frailty score for older adults with MM Points Age 75 years years Charlson Comorbidity Index Score 0-1 >/=2 ADL score >4 </=4 IADL score >5 </=5 Sum points from each category: Total score 0 = Fit; 1 = Intermediate fitness ; >/=2 = Frail >80 years

9 Table 5. Suggested dose modifications* and considerations in treatment selection for older adults with MM Agent Bortezomib Lenalidomide (in Rd regimen) Dosing adjustments Standard dose Reduced dose Further reduction 1.3 mg/m 2 twice weekly: Days 1, 4, 8, 15 q 4 weeks 25 mg/day Days 1-21 q 1.3 mg/m 2 once weekly: Days 1, 8, 15, 22 q 4 weeks 15 mg/day Days 1-21 q 1.0 mg/m 2 once weekly 10 mg/day D1-21 q Thalidomide 100 mg/day 50 mg/day 50 mg every other day Melphalan 0.25 mg/kg or 9 mg/m 2 Days 1-4, q 4-6 weeks Cyclophosphamide Dexamethasone Prednisone 100 mg/day Days 1-21 q or 300 mg/m 2 Days 1, 8, 15 q 40 mg/day Day 1 weekly or consider 20 mg/ day Day 1/Day 2 each week 60 mg/m 2 Days 1-4 or 50 mg 0.18 mg/kg or 7.5 mg/m 2 Days 1-4, q 4-6 weeks 50 mg/day Days 1-21 q or 150 mg/m 2 Days 1, 8, 15 q 20 mg/d Day 1 weekly 30 mg/m 2 Days 1-4 or 25 mg 0.13 mg/kg or 5 mg/m2 Days 1-4, q 4-6 weeks 50 mg every other day Days 1-21 q 28 days or 75 mg/m 2 Days 1, 8, 15 q 28 days 10 mg/day Day 1 weekly 15 mg/m 2 Days 1-4 or 12.5 mg every other day Other considerations to minimize toxicity Strongly consider SC administration Administer Varicella zoster virus prophylaxis Calculate creatinine clearance to ensure appropriate adjustment for renal function Administer venous thromboembolism prophylaxis Administer venous thromboembolism prophylaxis Avoid as initial therapy in older adults who are eligible for ASCT May be given IV if oral administration is not tolerated or adherence to oral medications is problematic Monitor hyperglycemia in patients with diabetes Monitor hyperglycemia in patients with diabetes Adapted from Palumbo et al 49 and Wildes et al 50 Rd, lenalidomide and low-dose dexamethasone. *Doses listed reflect suggested dose modifications for agents in corticosteroid-incorporating doublets. Starting doses in combination regimens may vary. References 01. SEER Stat Fact Sheets: Myeloma. statfacts/html/mulmy.html. Accessed October 30, Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27(17): Rosenberg PS, Barker KA, Anderson WF. Future distribution of multiple myeloma in the United States by sex, age, and race/ ethnicity. Blood 2015;125(2): Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014;28(5): Pozzi S, Marcheselli L, Bari A, et al. Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis. Br J Haematol 2013;163(1): Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008;112(8): Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reducedintensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99 06): a randomised trial. Lancet 2007;370(9594): Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27(22): Wijermans P, Schaafsma M, Termorshuizen F, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: The HOVON 49 Study. J Clin Oncol 2010;28(19): Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010;116(9): Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 2011;86(1):16-22.

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