How I treat fragile myeloma patients

Multiple myeloma (MM) is largely a disease of older adults, with a median age at diagnosis of 70 years. A consistent and continuous increase in life expectancy is recorded worldwide and the global population is rapidly aging. Consequently, the number of patients with MM is expected to considerably increase by nearly 80% each year in the next 2 decades.^1-3 

Although effective novel agents and supportive care have substantially improved outcome, patients ≥75 years have a shorter survival.^4-6  Thus, a deeper knowledge of the factors causing such poor outcomes is needed.

Aging is a complex process characterized by a gradual, progressive decrease in physiological reserve, with changes in body composition and clinically significant reductions in renal, gastric, hepatic, and cardiovascular functions.^7,8  It is commonly associated with the concomitant occurrence of multiple diseases (comorbidity),⁹  and an increased risk of developing physical and cognitive decline (disability).^10,11 

In addition, older people are at high risk of developing cancer and frailty. Frailty is a state of increased vulnerability, with cumulative deficits in several physiological systems, which results in diminished resistance to stressors such as MM and its treatment. This state has a negative effect on patients’ quality of life (QoL) and on treatment efficacy and tolerability, with a consequent increase in health care costs.

Approximately one-third of MM patients at diagnosis are frail.^1,12  Yet, these patients are poorly characterized, underrepresented, or even excluded from clinical trials due to stringent eligibility criteria or the presence of comorbidities, abnormal laboratory test results, and physical disability.¹³  Thus, frail patients usually receive regimens tested in fit patients, which may be too toxic for them and lead to early treatment discontinuation, low efficacy, and poor QoL. On the contrary, fit elderly patients may receive reduced-dose treatments based solely on their age. An appropriate definition of frailty is fundamental to better assess patients and provide them with effective, tailored treatments.

An 82-year-old woman presenting with anemia (hemoglobin [Hb], 9.8 g/dL) and high immunoglobulin G level (4630 mg/dL) was diagnosed with immunoglobulin Gk MM in December 2005. Her medical history was significant for hypertension and colic diverticula; her Eastern Cooperative Oncology Group (ECOG) performance status was 1. Treatment at diagnosis consisted of 6 cycles of reduced-dose melphalan-prednisone-thalidomide (MPT; melphalan, 4 mg/m² on days 1-4; prednisone, 40 mg/m² on days 1-4; thalidomide, 50 mg/d), followed by thalidomide maintenance, resulting in a partial response. The first relapse occurred in January 2009 when the patient was 86 years old. The disease was symptomatic for anemia (Hb, 8.3 g/dL) and pathological fractures of tibia and fibula requiring surgical stabilization. Her ECOG performance status was 3. The patient received 9 cycles of reduced-dose bortezomib-melphalan-prednisone, with intravenous weekly bortezomib (1.3 mg/m²), melphalan (2 mg), and prednisone (25 mg) every other day. The patient achieved a complete response and experienced a significant improvement in her QoL and performance status (ECOG 1), without any serious adverse event (AE), except for grade 3 diarrhea and hyperglycemia. In March 2011, the patient was 88 years old and experienced a second relapse. She had anemia (Hb, 8.8 g/dL) and a mild renal impairment (creatinine, 1.6 mg/dL). Her ECOG performance status was 2. The patient was treated with reduced-dose lenalidomide (15 mg every other day according to renal function) and prednisone (25 mg every other day). Treatment was well tolerated: no significant toxicities occurred, except for grade 3 hyperglycemia, grade 1 thrombocytopenia, and grade 1 cramps, and no lenalidomide dose reduction was required. The patient achieved a partial response, anemia resolved (Hb, 11.6 g/dL), and renal function improved (creatinine, 1.2 mg/dL). In February 2012, the patient was 89 years old and experienced a third relapse. Due to her rapidly worsening clinical conditions, she received palliative care and she died in April 2012.

This case shows that when frail patients are recognized and treatment is appropriately tailored, a long-term control of the disease and of the related symptoms may be obtained.

Elderly MM patients are highly heterogeneous; chronological age, performance status, or clinician judgment is not sufficient to properly differentiate them. In MM, the term “frail” often refers to a person >75 years old, which sometimes leads to improper undertreatment when the treatment is based only on age.

The geriatric assessment (GA) is a more sensitive predictor of frailty. A comprehensive GA is a systematic procedure to objectively appraise the health status of older people, focusing on somatic, functional, and psychosocial domains.¹⁴  Because a full comprehensive GA is a time-consuming procedure that is difficult to use in everyday clinical practice, a simplified GA that includes Katz and Akpom’s basic activities of daily living (ADL) scale,¹⁵  Lawton and Brody’s instrumental ADL (IADL) scale,¹⁶  and the Charlson Comorbidity Index (CCI),¹⁷  should be adopted for elderly patients. The ADL and IADL scores are used to assess self-care activities, tasks of household management, and independence status; the CCI is used to estimate the number and severity of comorbidities (Tables 1-3).^15-18 

Frail patients are at high risk of nonhematologic AEs and treatment discontinuation, regardless of other prognostic factors, and should be appropriately evaluated to determine their ability to tolerate treatment.

Age and GA are the fundamental determinants of our approach. The cutoff age that we consider to define frail patients is 80 years.¹⁹  However, irrespective of age, the presence of either a functional decline on ADL and IADL, or the presence of comorbidities, may identify frail patients. The Web site http://www.myelomafrailtyscorecalculator.net/ offers a quick and easy way to calculate the frailty score (Table 4).¹⁹ 

In frail patients, treatment should be delayed in cases of nonspecific symptoms, and it should be started based on the presence of confirmed CRAB (hypercalcemia, renal failure, anemia, bone lesions) criteria.^20-22 

Particular attention is needed with comorbid conditions. Frail patients may present with CRAB-like symptoms that do not lead to actual organ dysfunction and require no immediate antimyeloma treatment but only close monitoring.²³  For instance, patients may have age-related osteopenia, mild renal impairment due to hypertension or diabetes, or mild anemia secondary to iron or vitamin deficiency, renal failure, chronic inflammatory diseases, or concomitant dyserythropoietic/myelodysplastic syndrome.

Clear clinical manifestations of serious end-organ damage that can be attributed to myeloma should be considered CRAB, such as a progressive worsening of serum creatinine caused by light-chain cast nephropathy or a decrease in Hb levels from baseline. Creatinine clearance should be considered with caution. Many of the methods used to estimate glomerular filtration rate have not been well validated at the extremes of age. For example, using the Cockcroft-Gault method, a serum creatinine level of 1.5 mg/dL in a patient weighing 70 kg corresponds to an estimated glomerular filtration rate of 38 and 33 mL/min in an 80-year-old man and woman, respectively. In this case, progressive renal impairment rather than a fixed concentration cutoff should be considered to confirm MM diagnosis.

Recently, the International Myeloma Working Group provided updated criteria for MM diagnosis.²⁴  The changes are based on the identification of biomarkers associated with near inevitable development of CRAB features. They include clonal bone marrow plasma cell percentage ≥60%, involved/uninvolved serum free light-chain ratio ≥100, and >1 focal lesion on magnetic resonance imaging studies. Even if no data are present for this special patient population, the assessment of these parameters may avoid organ damage that could inevitably worsen patients’ condition. We use a skeletal survey and a low-dose computed tomography scan as routine investigations to assess bone disease. More complex investigations such as magnetic resonance imaging or positron emission tomography can be unnecessary on a routine basis in frail patients but should be considered in selected cases.

Although the achievement of a complete response is highly important and has become an attainable aim also in the elderly, toxicity may cancel the benefits derived from such a response.²⁵ 

In frail patients facing a serious disease such as MM, the choice of therapy should focus not on the quality of response but rather on controlling symptoms, maintaining an independence status, and preserving cognitive function and QoL.

The achievement of stable disease without symptoms related to myeloma is an acceptable goal, and therapy should not be changed.

Treatment should not cause excessive toxicities, which may lead to treatment interruption and reduced efficacy. If toxicities occur, it is likely that inappropriate drug doses are being used and dose reductions are needed. Therefore, keeping the balance between disease control and toxicity is fundamental.

The treatment of elderly MM patients has evolved substantially over the last decade.¹²  New effective treatments including thalidomide, bortezomib, and lenalidomide have replaced the former standard melphalan-prednisone (MP). MPT and melphalan-prednisone-bortezomib are the reference treatments for elderly patients ineligible for high-dose therapy.^26-33  Recently, continuous lenalidomide-dexamethasone (Rd) was shown to be more effective than MPT at diagnosis.³⁴  Of note, currently approved combinations were validated in studies that included highly selected elderly patients, and a geriatric evaluation was not performed.

The major advances obtained with new drugs were limited in older patients, primarily due to an increased treatment-related toxicity. Advanced age (≥75 years); the occurrence of severe cardiac, gastrointestinal, and infective AEs; and drug discontinuation predicted shorter survival in newly diagnosed MM patients treated with MP, either alone or in combination with thalidomide and/or bortezomib. The negative effect of such factors was particularly evident with the use of more complex combinations including both bortezomib and thalidomide.^35,36  Moreover, drug discontinuation due to AEs was correlated with an increased risk of death within the first 6 months of treatment.

These data underline the importance of avoiding treatment interruption and reducing the risk of side effects during the initial phase of therapy; thus, low dose–intensity treatments should be preferred for frail patients.

After the diagnosis of symptomatic MM, an appropriate treatment should be determined on the basis of several factors, particularly patient age and GA (Table 5). Based on the results of the GA, it is possible to stratify patients into fit patients suitable for full-dose therapy with 3-drug combinations, and frail patients requiring dose-adjusted therapies. Treatment strategies for frail patients should have minimal cumulative toxicity, which will not exacerbate any preexisting comorbid conditions. In particular, in this setting, 2-drug regimens showed similar efficacy and lower toxicity compared with multidrug combinations.³⁷ 

A recent phase 3 trial compared Rd, melphalan-prednisone-lenalidomide (MPR), and cyclophosphamide-prednisone-lenalidomide in newly diagnosed elderly MM patients.³⁸  The addition of an alkylating agent to the lenalidomide-steroid combination did not show any significant advantage in patients >75 years. In another trial, the doublet bortezomib-dexamethasone proved to be less toxic and equally effective in comparison with the triplets bortezomib-melphalan-prednisone and bortezomib-thalidomide-dexamethasone in an elderly and frail population.³⁷ 

Dosing, schedule, and route of administration can make a substantial difference in the safety profile of therapy. Different trials showed that once-weekly bortezomib significantly reduced the incidence of grade 3-4 AEs (35% vs 51%) and the rate of discontinuation due to toxicity (17% vs 23%) compared to the twice-weekly schedule. In addition, bortezomib administered subcutaneously showed to be as effective as the IV administration³⁹ ; this, combined with an improved safety profile, had a very positive effect on the QoL. Similarly, lenalidomide plus low-dose dexamethasone was better tolerated than lenalidomide plus high-dose dexamethasone and proved to be even more effective.⁴⁰ 

In frail patients, we prefer the oral regimen Rd in cases of nonaggressive disease. Bortezomib has the inconveniences of hospitalization and subcutaneous injection (Table 6). Lenalidomide has the advantage of oral administration, and patients do not need to attend frequent hospital visits. In addition, Rd may be the treatment of choice in patients with preexisting neuropathy.^34,40  We use bortezomib-dexamethasone in cases of aggressive disease, which needs a rapid cytoreduction and symptom control.^37,41  Similarly, with acute renal dysfunction, bortezomib exerts a faster and more potent action and has a greater chance to reverse renal failure.

In frail patients, we also administer modified drug doses to minimize toxicity. The initial dose of lenalidomide should not exceed 10 to 15 mg/d, and the dose can be adjusted on the basis of renal function and blood counts to avoid profound and prolonged myelosuppression. In this setting, it is reasonable to use prophylactic growth factors and an antimicrobial (at a fixed dose and timing) to avoid myelosuppression and infections, and to permit the patient to stay longer on treatment. A previous history of cardiovascular disease or thromboembolism does not preclude the use of lenalidomide when an adequate thromboprophylaxis is associated.

Corticosteroids may cause elevation of blood pressure and fluid retention, and should therefore be reduced, particularly in cardiac patients. Other adverse effects include hyperglycemia, gastritis, mood swings, insomnia, and increased risk of opportunistic infections. The dose of dexamethasone should be reduced to as little as 10 mg once a week. Alternatively, prednisone, 25 mg every other day, is a valid option.

Subcutaneous weekly bortezomib can be used without dose reductions, although thrombocytopenia could be a concern.^42,43  This regimen is especially relevant in frail patients, in whom the better tolerability may allow them to continue treatment, with a higher chance of disease control.

Bortezomib can cause peripheral neuropathy differently from novel proteasome inhibitors.^44,45  In frail patients, the use of weekly carfilzomib and oral ixazomib and oprozomib may be implemented in the future.

A conservative approach should be suggested in frail patients: an initial, gentler therapy may be used, and dose escalation may be considered in subsequent cycles if the treatment is optimally tolerated, in the absence of significant toxicities, or in the case of inadequate response.

Finally, in patients with severe impairment of cognitive function or social dependency, palliation is suggested. In these cases, we treat patients with reduced-dose corticosteroids, MP, or cyclophosphamide-prednisone to induce only a relief of disease symptoms.

Evidence of clear benefit of maintenance therapy has only recently emerged in elderly MM patients.^12,46  Continuous Rd improved progression-free survival (PFS) compared to fixed-duration Rd for 18 cycles (Rd18) and significantly prolonged PFS and overall survival compared to MPT.³⁴  The superiority of continuous Rd over Rd18 was achieved at the expense of a modest increase in toxicity, and most toxicities occurred within the first 18 months and decreased over time. In this study, 35% of patients were >75 years old, and 9% had severe renal impairment. The superiority of continuous Rd over MPT for both PFS and overall survival was noted even in patients >75 years. Although toxicities were more common in patients >75 years than in younger patients, there was no marked difference in AE rates with continuous Rd and Rd18 within this age subgroup.

In contrast, the more complex combination of MPR followed by lenalidomide maintenance compared to MPR or MP followed by placebo was associated with a reduced rate of progression in patients 65 to 75 years old but not in patients >75 years old.⁴⁷  This observation can be explained by the increased rate of AEs associated with MPR and the need for more frequent dose modifications in patients >75 years old. In that study, the major benefit to PFS was achieved with lenalidomide maintenance therapy. A landmark analysis showed that lenalidomide maintenance reduced the rate of progression by 66% compared to placebo, regardless of age.

Maintaining an asymptomatic disease status is particularly relevant for frail patients, because advanced age and coexisting morbidities may compromise subsequent salvage therapies at disease relapse. Nevertheless, the benefits associated with continuous therapy should be balanced against the toxicity due to prolonged drug exposure, particularly in frail patients, who are more susceptible to treatment-related toxicities. We use continuous therapy, provided that it does not cause toxicity or worsening of a patient’s condition. Frail patients whose disease is responding slowly and who tolerate therapy well may benefit from maintenance therapy. However, in the case of significant adverse effects, dose reductions or treatment interruption should be considered (Table 6).

In patients with asymptomatic serological relapse, treatment should be delayed. It can be started when clinical relapse, defined by CRAB criteria, occurs. A significant paraprotein relapse with doubling M-component within 2 months is an indirect indicator of increasing disease.⁴⁸  Close monitoring of paraprotein levels is required, and treatment should be started at the first sign of clinical disease progression.

Similarly to diagnosis, rather than achieving a deep response, the aim of therapy at relapse for frail patients is to maintain the disease asymptomatic and preserve the independency of patients, without excessive toxicity.

Novel agents are the mainstay of treatment at relapse. Lenalidomide has proved to be an effective option, and the addition of steroids even at low doses had a synergistic activity.^49-51  Bortezomib combined with steroids is effective and well tolerated,^52,53  particularly when the subcutaneous weekly administration is adopted.^43,54 

The patient’s overall condition and previous toxicities should be considered to determine the patient’s ability to tolerate treatment and, consequently, to choose the appropriate treatment. Time of relapse and type of previous therapy are also fundamental aspects to take into account.

Bortezomib and lenalidomide re-treatment can be a valuable option, with no cumulative toxicity.⁴⁸  Rechallenge with a previously used agent may be considered if the treatment produced a substantial benefit and had an acceptable toxicity. In newly diagnosed patients, we consider re-treatment with the previous agents when a response lasted at least 12 months. In frail relapsed patients, we rechallenge with previous drugs when a benefit lasted at least 6 months.

For short-term response duration (<6-12 months, based on the number of previous lines of therapy) or progression while on therapy, we propose an alternative regimen.⁴⁸  Sequencing of drugs is preferable: if lenalidomide is used as frontline treatment, a drug-class switch is necessary and bortezomib may be used. In frail patients, continuous therapy until progression could be recommended if therapy has an acceptable long-term safety profile. Alkylator-based regimens such as low-dose cyclophosphamide-prednisone, MP, or thalidomide may still play a role in frail patients relapsing after lenalidomide and bortezomib. Cyclophosphamide (50 mg every other day), melphalan (2 mg every other day), or thalidomide (50 mg every other day) may be used.

In the case of aggressive relapse or a short treatment-free interval, a more palliative approach is needed in frail patients with poor condition. In such instances, palliative care aims to optimize the comfort, function, and social support of patients and their families. To relieve the disabling myeloma-related symptoms, low doses of cyclophosphamide, melphalan, corticosteroids, or thalidomide may be used. Treatment of pain should be always introduced.

Frail patients are more susceptible to AEs and treatment interruption. Therefore, appropriate supportive care and early identification of toxicities are needed.

Proteasome inhibitors necessitate antiviral prophylaxis for herpes zoster reactivation; immunomodulatory agents require an appropriate risk-based thromboprophylaxis. Corticosteroids may need gastrointestinal prophylaxis, and a more accurate glycemic control in diabetic patients should be recommended. Antibacterial prophylaxis may be warranted in cases of severe myelosuppression. Neutropenia and anemia may necessitate growth factors.

A careful review of the patient’s previous medications and attention to potential drug interactions are essential in frail patients.

Prompt action, particularly in frail patients, is needed when AEs occur. When a grade 3-4 toxicity occurs while on treatment, therapy should be stopped. It can be restarted when toxicity decreases to at least grade 1, and appropriate dose reductions should be applied.¹²  Lenalidomide dose may be decreased from 15 to 10 mg/d, from 10 to 5 mg/d, or, if required, to 5 mg every other day on days 1 to 21 every 4 weeks. Bortezomib may be reduced from 1.3 mg/m² weekly to 1.0 mg/m² once weekly or even to 0.7 mg/m² once weekly.

New targeted agents have improved the treatment options for MM. Carfilzomib is a novel ketoepoxide tetrapeptide proteasome inhibitor recently approved by the US Food and Drug Administration for the treatment of relapsed/refractory MM in patients previously treated with bortezomib and lenalidomide. The most common grade 3-4 AEs reported with this agent were fatigue, anemia, nausea, and thrombocytopenia; peripheral neuropathy was mainly limited to grade 1-2. In a recent phase 3 study, carfilzomib plus Rd was more effective than Rd.⁵⁵  Carfilzomib was also effective in newly diagnosed patients.^56,57 

Ixazomib (MLN9708) is another novel proteasome inhibitor that showed promising results in both relapsed and newly diagnosed settings. Two phase 2 studies are evaluating oral ixazomib as monotherapy in relapsed/refractory patients previously exposed to proteasome inhibitors, and one trial has adopted a weekly administration of the drug.⁵⁸  The most frequent AEs included thrombocytopenia, fatigue, nausea, and diarrhea.⁵⁹  Positive results were also reported in a phase 1/2 study evaluating weekly ixazomib in combination with Rd in newly diagnosed myeloma patients, followed by maintenance with ixazomib alone.⁶⁰ 

Oprozomib, an orally available carfilzomib structural analog, has been tested in a phase 1b/2 trial including patients with relapsed MM. The most common grade 3-4 toxicities included diarrhea, nausea, neutropenia, hypophosphatemia, thrombocytopenia, vomiting, and fatigue.⁶¹ 

The monoclonal antibodies elotuzumab and daratumumab are other promising agents. Daratumumab is an anti-CD38 monoclonal antibody. Infusion reactions were the most common toxicity.^62-64  Elotuzumab is an anti-CS1 fully humanized monoclonal antibody. Elotuzumab was not so effective as monotherapy, and treatment-related toxicities were largely limited to grade 1-2 infusion reactions.⁶⁵  In two phase 1 studies, elotuzumab plus bortezomib⁶⁶  or elotuzumab plus lenalidomide and low-dose dexamethasone proved effective. Two phase 3 trials are comparing elotuzumab plus Rd vs Rd in relapsed and newly diagnosed patients.

Based on the available results, in frail patients, weekly carfilzomib can be a valuable option due to its reduced toxicity. Ixazomib can be an option because of its low toxicity and has the advantage of oral administration. Elotuzumab and daratumumab are effective options and have a very good tolerability.

The growing number of older adults with myeloma is increasing the need for practical strategies to recognize and appropriately manage frail patients, and to avoid the undertreatment of fit patients and the overtreatment of frail patients. The GA is a sensitive assessment tool and should be introduced in everyday clinical practice.

Frail patients need effective tailored treatments to better control the disease while minimizing the risk of toxicity and treatment discontinuation. Improving survival may not be the primary goal of therapy in frail patients. The real aim in this setting should be to keep patients asymptomatic as long as possible, preserve their functional status and independence, and improve their QoL.

The selection of therapy should be based on the risk of toxicity and the capacity of patients to tolerate treatment. Lenalidomide and bortezomib have an essential role in the treatment of frail patients. Two-drug regimens including low-dose steroid in combination with lenalidomide or bortezomib are indicated. Second-generation proteasome inhibitors or immunomodulatory drugs or even monoclonal antibodies are potential candidates to improve the care of frail patients with MM in the future.

The authors thank their assistant, Giorgio Schirripa.

Contribution: A.P. and A.L. collected the data and wrote the manuscript.

Conflict-of-interest disclosure: A.P. has received consultancy fees from Bristol-Myers Squibb, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc, and Onyx Pharmaceuticals; and honoraria from Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Millennium Pharmaceuticals Inc, and Onyx Pharmaceuticals. A.L. has received honoraria from Celgene and Janssen-Cilag.

Correspondence: Antonio Palumbo, Myeloma Unit, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Via Genova 3 Torino, 10126 Italy; e-mail: appalumbo@yahoo.com.