Nuances in the Management of Older People With Multiple Myeloma
Charlotte Pawlyn1,2 & Francesca Gay3,4 & Alessandra Larocca3,4 & Vivek Roy5 & Sikander Ailawadhi5
Abstract Multiple myeloma is a disease of the elderly, with about a third of patients at diagnosis older than 75 years of age. Yet, the population of elderly patients is heterogeneous: older patients are more likely to have comorbidities and
frailties complicating both their initial diagnosis and subsequent management, but these are not consistent across the
group. Furthermore, patients with comorbidities and frailty are generally underrepresented in clinical trials. Despite the survival of myeloma patients increasing following the introduction of novel agents, older patients continue to have worse
outcomes with increased treatment-related toxicity. Treatment tolerability is not defined by age alone, rather a combination of age, physical function, cognitive function, and comorbidities. These factors all influence patients’ tolerability of treatment and therefore treatment efficacy and should also be considered when reviewing the results of clinical trials. It is the
nuances of determining how these factors interact that should influence initial treatment and ongoing management decisions and these will be discussed here.
Keywords Multiple myeloma . Elderly . Treatment Introduction
Myeloma is a malignancy of plasma cells that damages bone integrity and leads to kidney and bone marrow dysfunction. It
predominantly affects patients over 65 years old and as such the incidence is increasing as life expectancy of the population increases. The diagnostic criteria for myeloma have recently been updated [1•] but the disease can still be divided into distinct clinical stages with progression from the premalignant stage monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma to myeloma. MGUS, present in 3 % of the population aged over 50, carries a risk of progression to myeloma of 1 % per year [2]. Smoldering myeloma, characterized by a higher percentage of bone marrow
plasma cells but without end organ damage or newly defined Bbiomarkers of myeloma,^ carries a higher risk of progression, approximately 10 % per year [3].
The highest rates of new myeloma diagnoses are in the 80– 89-year age group [4], yet older patients are underrepresented in clinical trials and are the most challenging to treat. This is due to the fact that older patients are more likely to have
comorbidities and frailties complicating both their initial diagnosis and subsequent management. The introduction of novel
agents in the last decade has improved outcomes for all patient groups, but in the older population, outcomes still lag behind those of younger patients [5, 6].
In younger patients, induction treatment for myeloma generally
comprises a combination of a proteasome inhibitor, immunomodulatory agent, and corticosteroid. Patients’ response
is then consolidated with an autologous stem cell transplant for those who are fit enough to tolerate this high-dose therapy. Strict age criteria are not employed, with suitability for transplant
generally decided on an individual patient basis based on a combination of performance status, comorbidities, clinician judgment, and patient preference. Generally, however, patients over the age of 70 years are less likely to benefit from
high-dose therapy and are treated with combination regimens, either doublets or triplets, frequently followed, where available, by maintenance therapy [7•, 8, 9]. At disease relapse,
there are now numerous treatment options including the recently FDA-approved new agents carfilzomib, pomalidomide,
panobinostat, and daratumumab [10]. The availability of these agents in different healthcare systems and their suitability for older patients, however, varies.
In older patients, therapeutic agents are often given at lower doses than in younger fitter patients. Such modifications are commonly made based primarily on patient age, but treatment tolerability is not defined by age alone, rather a combination of age, physical function, cognitive function, and comorbidities. These factors will influence patients’ tolerability of treatment and therefore their response. It is the nuances of determining how these factors interact that should influence initial
treatment and ongoing management decisions and these are discussed here.
Barriers to Myeloma Diagnosis and Ongoing Healthcare in the Older Patient
Frailty may not only affect the management of patients with myeloma once diagnosed but also the appropriate and timely diagnosis of myeloma initially. Access to healthcare in general is poorer in older adults with financial barriers, including insurance
status (where relevant) and rural living cited among
sources of inequity [11, 12]. Existing comorbidities may also confound myeloma diagnosis in older adults where the presenting features, e.g., anemia, renal impairment, and back
pain, are common manifestations of many diseases affecting the cohort. One study demonstrated that patients with anemia, back pain, and comorbidities were more likely to experience diagnostic delay with an odds ratio of 1.6 (95 % CI 1.3, 2.0) [13]. Physicians need to be aware of these influences to try and minimize then, and ongoing education of primary care physicians along with clear guidelines may assist in timely diagnosis and management.
Once diagnosed, physical limitations, more common in older patients, may influence attendance to hospital perhaps influencing patients’ ability to access specialist treatment centers and influencing the choice of regimen, with some not
possible to be delivered in the community. In addition, older patients have previously been less likely to be included in clinical trials [14–16], either due to stipulated age limitations or more subtly due to co-existent comorbidities often excluded, sometimes without good evidence, or due to practical barriers [17]. To try and counter this effect, guidance for medical research for and with older people has been published by several bodies including the European Forum of Good Clinical Practice [18] and the PREDICT consortium [19, 20]. Heterogeneity of Older Patients and the Use of Frailty Assessment Tools for Making Management Decisions Older myeloma patients comprise a highly heterogeneous
population that is not determined by age alone [21]. Patients of equivalent age can have entirely different physical and cognitive functions, and these need to be evaluated carefully prior
to making treatment decisions both in the induction and relapse treatment setting. Normal aging processes and health
problems combine to impact the functional status of older people. Tools for assessing these factors have been described with a recent publication from the International Myeloma Working Group suggesting the combination of three tools assessing different modalities [22••]. The Katz Activity of Daily Living [23] and Lawton Instrumental Activity of Daily Living [24] scores assess self-care and independence including household tasks. The Charlson comorbidity index [25] considers the number and severity of comorbidities. These indices were combined with age in the study into a
global frailty score defined by the best regression model predictive of overall survival (Table 1). In this retrospective analysis,
the frailty score was shown to be predictive of both
survival and toxicity. An increase in frailty score was associated with an increased risk of death, progression, nonhematologic adverse events (AEs), and treatment discontinuation
that was independent of classical definitions of risk including ISS stage and cytogenetic risk and also independent of treatment regimen [22••]. As such, it was suggested to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but this remains to be validated either in an independent retrospective data set or
Treatment Options
Historically, various treatment guidelines for MM have divided patients rather rigidly into Btransplant eligible^ or
Btransplant ineligible,^ and in some cases, used these terms synonymously for young and old patients, respectively. The major focus of this dichotomous approach has been avoiding melphalan-based regimens for induction and/or salvage therapy in younger, transplant-eligible patients and reserving them only for the elderly population, at least before the stem cells have been collected [26]. Over time, the need for separate treatment approaches for young and older patients has become
less defined. The combination therapeutic regimens of immunomodulatory drugs (IMiDs) and proteasome inhibitors being
used widely, e.g., cyclophosphamide, bortezomib, and dexamethasone (CyBorD), lenalidomide, bortezomib, and dexamethasone
(RVd), carfilzomib, lenalidomide, and dexamethasone (CaRD), are fairly well tolerated even in elderly patients, with appropriate dose reduction, and have made the routine use of melphalan-based regimens less frequent, at least in the USA [27, 28]. Also, several studies have shown the feasibility and efficacy of autologous stem cell transplantation (ASCT) in older patients [29, 30]. Still, the majority of reported and ongoing clinical trials focusing on transplant ineligible, and hence, elderly patients, in the newly diagnosed, previously untreated setting (Table 2), have so far utilized melphalanbased regimens, though this practice may be changing, particularly in the USA [31].
Myeloma—Frontline
Several trials have reported the comparison between the traditional regimen of melphalan with prednisone (MP) for elderly,
transplant ineligible patients and those containing novel agents, both IMiDs and proteasome inhibitors in the frontline setting (Table 2). Many of these large trials, especially those conducted in Europe, used melphalan-prednisone
thalidomide (MPT) as the comparator arm, making it the recommended regimen for elderly patients with newly diagnosed
MM (NDMM) [32, 33]. The primary endpoint of all these trials was an improvement in progression-free survival (PFS) [32–35], but some did show a benefit with MPT in median overall survival (OS) as well [33, 34, 36]. A meta-analysis comparing various frontline thalidomide-containing regimens, spanning six large randomized clinical trials
(n =1685), was also able to establish the benefit of MPT compared with MP, with a high overall response rate (ORR) of
59 %, a median PFS of 20.3 months, and a median OS of
39.3 months [37]. Among other thalidomide-containing frontline regimens, CTD, a combination of cyclophosphamide with
thalidomide and dexamethasone, has shown significantly improved response rates over MP, although only a small benefit
in PFS [38]. Another IMiD partner for melphalan and prednisone has been lenalidomide (Revlimid®) with a large randomized trial reporting the benefit of MPR followed by maintenance using lenalidomide as compared to MP (MM-015) [39].
This combination of MPR was not very well tolerated in patients >75 years of age, but overall, the adverse event profile
did not raise any significant concerns for the population treated with this regimen. While there has been some concern
about the second primary malignancies (SPMs) with lenalidomide treatment, especially in regimens involving
maintenance therapy, the MM-015 showed only a small increase in SPMs with the lenalidomide-containing regimens as
compared to MP [39].
Non-IMiD regimens building upon MP have also been
studied including the most prominently VMP, which in a randomized setting was the first trial to show an improvement in
median OS for transplant ineligible patients [8]. Even with long follow-up (median 60.1 months), VMP continues to show benefit over MP with respect to ORR, OS, PFS, and time to next treatment (TTNT), without any emerging safety concerns for SPMs. [40] Since the initial reports of
bortezomib-based regimens, which utilized intravenous and twice weekly dosing, its use has evolved into weekly and subcutaneous administration due to maintained efficacy and significantly decreased adverse events based on several reported clinical trials in various settings [41–43].
These three-drug regimens, building upon the historic MP
combination, were an improvement whether the novel therapeutic agent used was an IMiD or proteasome inhibitor.
However, in an effort to simplify the management of elderly patients withMM, alkylator-free regimens have been explored over the past few years. The first of these reported was thalidomide with dexamethasone (TD) but was only able to improve
a benefit in PFS or OS [37]. On the other hand, several large trials utilizing lenalidomide have reported its improved efficacy and safety profile when combined with low-dose (40 mg weekly) dexamethasone (Rd) in elderly patients [9, 44]. Of these, a large cooperative group clinical trial conducted in the USA (E4A03) compared lenalidomide with high-dose dexamethasone (RD) (the standard dosing for dexamethasone at
that time) to lenaldiomide with a lower dose of dexamethasone (Rd) for newly diagnosed MM patients [44]. Although
this trial was not restricted to elderly patients, more than 50 % of the 445 patients enrolled in both arms were ≥65 years of age, with Rd showing a 75 % 3-year median OS in this population. This led to the widespread utilization of this alkylatorfree
regimen in newly diagnosed elderly patients, especially in the USA. These results have been confirmed in a recent European phase 3 trial (FIRST, MM-020/IFM 07–01) of 1623 transplant-ineligible patient frontline treatment with continuous Rd until disease progression or intolerance was compared with fixed-duration Rd (72 weeks; Rd18) or MPT for 12 cycles (72 weeks). Continuous Rd significantly improved PFS as well as OS as compared with
MPT. At a median follow-up of 37 months, the median PFS with continuous Rd (25.5 months) was superior to Rd18 (20.7 months) or MPT (21.1 months). Furthermore, Rd was superior to MPT for ORR, time to progression (TTP), TTNT, and duration of response as well as being better tolerated [9]. With an aggregate of this data, and following the recent licensing of lenalidomide by the
EMA, the choice of regimens for frontline treatment of elderly patients with MM most commonly tends to be MPT or VMP, with the increasing use of Rd in Europe and Rd in the USA.
Several studies have recently explored the optimal duration of therapy in elderly patients, evaluating the choice as well as the length of maintenance treatment strategies. These include VMPT followed by VT maintenance [41, 43], MPR-R [39], VMP or VTP followed by VT or VP maintenance [42], and
continuous Rd [9]. While they have all utilized different treatment regimens, all of them have reported an improvement in
PFS as well as time to second-line anti-myeloma therapy with continuous treatment strategies. This is an influencing general prescribing practice in healthcare systems where maintenance therapies are funded.
Ongoing clinical trials (GIMEMA) are also reporting that Rd and Vd may have similar efficacy and better tolerability as compared to alkylator-based three-drug regimens as frontline treatment for elderly patients with MM [45, 46]. Recently reported data from a large intergroup clinical trial (S0777; n =525) is challenging this paradigm though by demonstrating a non-alkylator-based triplet, and bortezomib with Rd
(VRd) can improve outcomes as compared with Rd for both PFS (43 vs. 31 months) and OS (not reached vs. 63months) in newly diagnosedMMpatientswithout an intent for immediate ASCT [47]. This study was not necessarily designed for elderly patients but clearly shows that in the non-transplant setting, the non-alkylator-based three-drug regimen was superior
to a two-drug regimen. Furthermore, VRd had an acceptable safety and tolerability profile despite some increased
neurotoxicity.
In selected patients, those with a good physiological reserve and performance status, even above the age of 65 years, ASCT may be an option to consider. The tools to assess this are the same as mentioned for newly diagnosed patients while selecting an induction regimen [22••, 48]. Reduced intensity ASCT (rASCT) using melphalan 100 mg/m2 (MEL100) has been compared with MP alone for patients of varying ages, who were not considered fit for standard ASCT. This study showed that at a median follow-up of 3 years, MEL100 was superior to standard therapy with an improvement in eventfree survival (EFS) from 16 to 37 % and OS from 62 to 77 %
(p <0.001). The highest improvement in median OS was seen in the 65–70-year age group (37.2 months with MP vs. 58 months with MEL100). A subsequent trial evaluating a sequential approach with bortezomib-based induction,
MEL100-ASCT, and subsequent consolidation and maintenance with lenalidomide in patients between 65–75 years of
age showed a higher rate of toxic deaths in the 70–75-year age group and a better feasibility of treatment in the 65–70-year group [49]. These data highlight the importance of ASCTas a therapeutic tool in selected elderly patient subgroups. In addition to the frequently studied and reported agents melphalan, bortezomib, and IMiDs, alternatives including bendamustine are being studied in two- or three-drug regimens for the initial treatment of transplant-ineligible patients
[50, 51]. Another emerging agent reported recently for the treatment of newly diagnosedMMpatients who are transplant ineligible is ixazomib, an oral proteasome inhibitor. In a recent randomized phase 2 trial exploring different doses of
ixazomib with cyclophosphamide and dexamethasone, ORR of 80 % (CR 10 %) was reported at a 7-month follow-up [52]. Similarly, monoclonal antibodies, which are a promising new class of anti-myeloma agents, have just begun their foray into ongoing clinical trials exploring alternative short- and longterm
treatment strategies with these agents for transplantineligibleMMpatients and results will be available in the near
future [53].
Treatment of Older Patients with Multiple Myeloma—Previously Treated
The distinctions between treatment choices for elderly and young patients with relapsed and/or refractory MM (RRMM) are less well defined as compared to those for NDMM patients. Factors that are frequently considered for patients with RRMM to decide the timing and choice of treatment include the nature of relapse (symptomatic vs. biochemical), duration of response to initial therapy (<6 vs. >6months),
and previous therapeutic agents used and the nature of response to them (relapsed or refractory). There are other factors
that are significant for all patients but may be more pertinent to the elderly such as comorbidities and functional status, mode
of administration of the agent (oral vs. intravenous vs. subcutaneous), or toxicities from the regimen including any residual
(single vs. combination). As discussed above, various tools are available to assess the patient’s performance status and match that with the anticipated toxicities from the treatment regimens in order to maximize treatment tolerability and, hence, potential efficacy [22••, 48].
The US National Comprehensive Cancer Network
(NCCN) treatment guidelines for patients with RRMM suggest utilizing proteasome inhibitors (bortezomib, carfilzomib), IMiDs (thalidomide, lenalidomide, pomalidomide), steroids (prednisone, dexamethasone), conventional cytotoxic agents (cyclophosphamide, bendamustine, etoposide, cisplatin, doxorubicin), or histone deacytylase (HDAC) inhibitors
(panobinostat, vorinostat) in various combinations as options, although no distinction is made for specific choices for elderly patients [54]. In other healthcare systems, despite evidence of efficacy, limitations on prescribing may affect choice but, in general, it is important to individualize treatment in this setting, realizing that the same agents/regimens may be less tolerated in elderly patients with a relatively smaller physiological reserve and presence of more comorbidities as well as residual adverse events from prior regimens. Recent clinical trials are helping shape these decisions by providing increasing comparative data even among the novel therapeutic agents such as trials showing improved efficacy of carfilzomib as compared with bortezomib with an acceptable safety profile, although more mature data and studies focusing on elderly patients will help make the results of these trials more applicable in this population [28, 55]. Other novel agents include
orally available proteasome inhibitors (ixazomib, oprozomib), which will make it easier to provide patients with an oral regimen, even in triplet drug combinations. Clinical trials with ixazomib in elderly patients have recently been reported at least in the newly diagnosed patient setting [52]. An emerging class of agents that is expected to benefit all patients but may be especially attractive for elderly patients due to a favorable adverse event profile are the monoclonal antibodies (MoAbs). The first of these agents, a CD38 MoAb, daratumumab, has been recently FDA approved in the USA for treatment of patients with RRMM who have at least received three prior lines of treatment and have utilized a proteasome inhibitor as well as an IMiD [56].
The response rates from current therapeutic regimens for MM have been steadily improving, and achieving an objective response to induction treatment in almost all newly diagnosed patients and in a significant proportion of patients with relapsed disease has become the norm. Thus, the bar for future clinical trials has been set quite high. The comparator arm can no longer be single-agent steroids or a combination of steroids with conventional cytotoxic agents. Newer combination regimens have to show further improvement over the benefit from IMiD and proteasome inhibitor containing doublets at the least. This holds true for trials focusing on elderly patients as well. The goals of treatment and therapeutic
decision-making have in turn been broadened to address several previously overlooked questions, e.g., the use of
frailty-adjusted dosing, quality of life (QoL), survivorship, improving depth of response, minimizing longterm complications, refining the duration of treatment, and even demonstrating an improvement in OS [57–59]. Management of Side Effects
As mentioned previously, comorbidities and frailty often negatively impact on the ability of patients to tolerate therapy [60] and, ultimately, on treatment efficacy.
General strategies in the management of myeloma patients are of particular importance in the older patient
including the maintenance of a good fluid intake to protect renal function and the use of bone protective agents, such as the bisphosphonate zoledronic acid, to reduce skeletal-related events. The effective management of adverse events (AEs) is also extremely important in this population of patients. A prompt dose reduction at the occurrence of toxicity, or even upfront, can be a
good strategy to reduce the rate of treatment discontinuation and optimize treatment efficacy.
Hematologic Adverse Events
Myelosuppression is a common finding in MM patients, both at diagnosis and during treatment; it may be related to different
factors such as extensive bone marrow infiltration and/or chemotherapeutic toxicity. Anemia is frequently seen in NDMM
patients, whereas thrombocytopenia tends to occur in later stages of the disease. Neutropenia is a common side effect of both conventional chemotherapeutics and novel agents, such as IMiDs, as well as thrombocytopenia, which is also fairly
common in patients treated with proteasome inhibitors. Supportive care and dose modifications are needed to manage myelosuppression.
Anemia
Anemia occurs in approximately 73 % [61] of myeloma patients at diagnosis, two thirds of whom are over 65 years of
age [62]. Anemia is usually multifactorial. It may be related to bone marrow invasion by monoclonal plasma cells and therefore usually improves when the disease is under control. Other causes include myelotoxicity of chemotherapy, iron and vitamin deficiency (folic acid and vitamin B12), and concomitant
myelodysplasia (particularly in elderly patients). Additionally, it is important to exclude other causes of anemia than myeloma. Erythropoiesis-stimulating agents (ESAs) have demonstrated to reduce the frequency of transfusions but have also been related to a higher rate of thromboembolic events [63,
64]. ESA treatment is generally recommended when the hemoglobin concentration is less than 10 g/dL, or higher (<11 g/
dL) for patients with heart disease or those who have difficulties undertaking daily activities [65]. This is particularly important among elderly patients in whom cardiovascular comorbidities are more frequent. ESAs can be administered to
patients undergoing chemotherapy, and iron supplements can improve the effectiveness of treatment. Treatment goal is the achievement of a hemoglobin concentration of 11 to 12 g/day. For patients at high risk for thrombosis, the risks and benefits of these drugs must be carefully weighed.
Neutropenia can be related to alkylating agents, IMiDs, and PIs. The longer and the deeper the neutropenia, the higher is the risk of infections. Older patients are at greater risk of infections than younger patients because of a higher incidence of comorbidities, such as chronic obstructive pulmonary diseases, renal failure, and diabetes. Hence, myelotoxic regimens
and prolonged treatment with corticosteroids need to be administered with cautions in this particular population.
Granulocyte colony-stimulating factor (G-CSF) is a safe and effective strategy for primary and secondary prophylaxis to reduce the depth and duration of neutropenia and,
consequently, the risk of infections. In patients receiving regimens associated with a high risk of myelosuppresion or in
those having already experienced treatment-related grades 3– 4 neutropenia, G-CSF should be considered. Anti-myeloma treatment is normally withheld in case of treatment induced grade 4 neutropenia (neutrophil count <500/mm3); when the AE resolves to at least grade 2 (neutrophil count ≥1000/mm3),
treatment can be reintroduced at the same dose with the prophylactic use of G-CSF. In the presence of recurrent neutropenia
or other cytopenias, dose modifications are required.
Prophylaxis with G-CSF is also recommended for the prevention of febrile neutropenia in patients at high risk. The current evidence for the use of antibiotic prophylaxis in myeloma outpatients is contradictory but randomized trials are ongoing [66, 67].
Thrombocytopenia
(more commonly in the late stages of the disease) or
anti-myeloma therapy with a higher incidence for those patients taking proteasome inhibitors than immunomodulatory
drugs. Treatment interruption is indicated in case of grade 4 thrombocytopenia (platelet count <25,000/mm3). When the AE resolves to at least grade 2 (platelet count ≥50,000/ mm3), treatment can be restarted with appropriate dose reductions.
Non-Hematologic Toxicity Renal Failure
Renal impairment is a common finding among elderly patients, due the presence of underlying diseases such as hypertension and diabetes. Nonetheless, renal insufficiency is a typical feature in at diagnosis, as it has been reported in 20–40 %
of cases [68, 69]. Several factors may be implied in the development of renal failure: deposition of the light-chain component
of the immunoglobulin that causes proximal tubular damage, hyperviscosity, dehydration, hypercalcemia, hyperuricemia, infections, and use of nephrotoxic drugs. Particularly in elderly patients, even in the presence of normal values of
serum creatinine, a creatinine clearance (CrCl) must be estimated, in order to correctly define the appropriate dose of
drugs. Renal failure related to MM urges an immediate treatment, including supportive therapy (hydration, steroids) and
anti-myeloma therapy. Many of the currently available novel agents have proven to be safe and effective in patients with renal impairment, with bortezomib being the most active [70, 71]. Both thalidomide and bortezomib need no dose adjustment
according to renal function, as their pharmacokinetics is
not affected by renal impairment. Lenalidomide can be administered in the presence of altered renal function but according
to a dose reduction schedule: CrCr 30–60 mL/min, 10 mg per day; CrCl <30 mL/min but the patient does not require dialysis, 15 mg every other day; and CrCl <30 mL/min and the
patient requires dialysis, 5 mg per day administered after dialysis on dialysis days. Pomalidomide is extensively metabolized before excretion and only 2 % of the compound is excreted unchanged by the kidneys. In light of these, according to available data, pomalidomide can be given, without dose modifications, to patients with a CrCl ≥ 45 mL/min. Ongoing trials will elucidate the safety profile of pomalidomide in patients with moderate to severe renal failure [72].
Peripheral Neuropathy
Peripheral neuropathy (PN) is frequently reported; it can be related to the disease itself or be induced by antimyeloma treatment. In addition, non-myeloma-related
causes of PN must be investigated among elderly patients, such as diabetes mellitus and vitamin deficiencies.
Thalidomide and bortezomib are the two novel
agents more frequently associated with the development of PN. Bortezomib-related PN is generally distal and sensory and depends on the dose, schedule, and way of administration of bortezomib. Grades 1–2 and grades 3–4 bortezomib-related peripheral neuropathy occur in 31 and 13 % of NDMM patients, respectively, with
treatment-naïve patients (39 vs. 19 %) [73]. Autonomic dysfunction may also occur, manifesting as constipation,
diarrhea, and orthostatic hypotension [74], which might have a particular impact on the elderly/frail patient. Resolution or improvement of PN is commonly reported 2 to 4 months after the last administration of
bortezomib, though in some cases recovery may take longer. Alternative route of administration, subcutaneously, or schedule, once weekly instead of standard
twice weekly, demonstrated to reduce the rate of PN without impairing the efficacy of bortezomib. [43, 75]. A prompt recognition, followed by dose reductions or modifications of the dose and schedule, is the most important measure to treat treatment-related PN. As far as bortezomib is concerned, in the presence of grade 1 with pain or grade 2 PN, a change in the schedule from twice weekly to once weekly or a reduction of the dose, from 1.3 to 1.0 mg/m2 , is recommended. Dose interruption until PN resolves with restart at 0.7 mg/m2 is recommended for grade 2 with pain or grade 3 peripheral
neuropathy. Treatment discontinuation is recommended for grade 4 peripheral neuropathy. For thalidomide, in the presence of sensory PN complicated by pain, motor deficiency, or interfering with daily function, a dose
reduction is mandatory. Generally, the dose of thalidomide may be maintained if neuropathy is grade 1,
decreased by 50 % if neuropathy is grade 2, and
is suggested if PN resolves to at least grade 1 PN. In order to try and minimize the onset of this toxicity in the elderly, thalidomide is generally be started at a lower dose (50–100 mg daily) and increased (to max.
200 mg daily) only as tolerated. Venous Thromboembolism
Newly diagnosed and relapsed/refractory patients are at increased risk of deep vein thrombosis (DVT) and pulmonary
embolism (VTE). The risk is increased in the presence of risk factors related to the patient (age, obesity, history of VTE, central venous catheter, and comorbidities such as cardiac
disease, chronic renal disease, diabetes, infections, immobilization, surgical procedures, and inherited thrombophilia), to
the disease itself (diagnosis and hyperviscosity), and to the treatment. Patients receiving doxorubicin or IMiDs combined with high-dose dexamethasone are at greater risk of thrombosis. The choice of thromboprophylaxis is therefore based on
patient, disease, and treatment-related risk factors. In elderly patients, the choice of giving anticoagulation must be carefully balanced with the risk of bleeding. In patients receiving IMiDS, a thromboprophylaxis is mandatory, unless strictly contraindicated. Aspirin should be given to patients with no more than one risk factor. Low-molecular weight heparin or full-dose warfarin is recommended for patients with at least two risk factors [76, 77].
Rash
Skin rash is a common adverse event with IMiDs. In phase III trials, all grade rash has been observed in up to a third of
patient receiving lenalidomide, although severe rash was infrequent (<5 %). The onset of cutaneous reaction rises commonly
during the first month of treatment and has been described as morbilliform, urticarial, or dermatitis. Grades 1 and
2 may be treated with topical corticosteroids and oral antihistamines, with lenalidomide interruption if clinically needed.
Grade 3 rash requires oral corticosteroids and antihistamines and lenalidomide prompt interruption and even discontinuation, which is otherwise mandatory in the presence of grade 4
rash [78]. Diarrhea
Diarrhea in myeloma patients may be the manifestation of autonomic dysfunction, as seen with bortezomib, or may be
related to bile acid malabsorption, as it has recently been described with the administration of lenalidomide.
Lenalidomide-induced severe diarrhea is uncommon but has a high impact on patient quality of life and, when other
common causes of diarrhea have been excluded, such as gastrointestinal infections, dietary indiscretion, celiac disease,
and inflammatory bowel disease, may be treated by reducing the dietary fat intake and eventually with a bile acid
sequestrant such as colesevelam [79]. Conclusions
Older myeloma patients comprise a highly heterogeneous population that is not determined by age alone. Age, physical function, cognitive function, and comorbidities influence patients’ tolerability to treatment and consequently
of patients with myeloma but also the appropriate
and timely diagnosis of myeloma. Physicians should consider the influences of age, comorbidities and frailty in the
treatment choice, dosing, and side effect management with patients. The use of standardized frailty assessments needs to be validated in a community-based and prospective setting. Several combinations of novel agents (thalidomide,
lenalidomide, bortezomib, and recently, the second generation of IMIDs and PIs) plus chemotherapy or steroids
have proved to be efficacious in clinical trials. Given the better tolerability of doublets comprising a novel agent plus steroids, they are often preferred over triplets.
However, selected fit patients may benefit from more aggressive therapy, and the use of triplets may increase with
the development of new agents with fewer side effects. In the context of the multiple available options, the challenge of myeloma treatment is to correctly identify the appropriate therapy, with the most favorable safety/efficacy profile that can be tolerated to maximize patient benefit. Interventions that should be investigated to improve the management of older patients with myeloma include increasing the ability to deliver treatment in the community,
the use of prospective dose adjustments according to frailty index, and the side effect profile of new agents. These have the potential to further improve older patients’ length and quality of life.
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