Chapter 4 – Treatment of elderly patients with myeloma

Contributors: Eileen M Boyle, Charline Legrand, Hélène Demarquette, Stéphanie Guidez, Charles Herbaux, Xavier Leleu, and Thierry Facon

7 – Tailoring the treatment to the patient

High-risk cytogenetics

With the exception of the NCRI trials (Myeloma IX and XI) and the registration studies [47,58,69,74], most of the cytogenetic data collected in the past few years have come from younger, transplant-eligible, newly diagnosed patients. The Intergroupe Francophone du Myélome (IFM) group reported on a series of 1890 elderly patients (median age 72 years; 651 patients >75 years of age), including 1095 patients with updated data on treatment modalities and survival [7]. Regardless of treatment, both t(4;14) and del(17p) were associated with a worse clinical outcome. The median PFS in patients with t(4;14) and del(17p) was 14 and 11 months, respectively, compared with 24 months for patients lacking both abnormalities. Similarly, the median OS was 32 and 19 months, respectively, compared with 50 months. Furthermore, some data suggest that MPV may overcome the adverse prognosis associated with certain high-risk cytogenetic abnormalities [45]; similar data are not available for MPT.

Comorbidities to take into consideration

Comorbidities are frequent in elderly patients and several comorbidities may be present in a given patient. As they may be aggravated by treatments for myeloma, some comorbidities should be taken into account before a treatment decision is made. The most common are summarized below.

Thromboembolic events
Age, cancer, and impaired mobility are well known risk factors of deep vein thrombosis [75]. This risk is increased by IMiDs such as thalidomide or lenalidomide, especially when combined with conventional chemotherapy agents (including steroids). Thromboprophylaxis using low-molecular weight heparin is an effective preventive measure [76] but alternative approaches may be preferable in patients who are unable to tolerate these agents or who have a past medical history of thrombosis while on prophylaxis. The risk of thrombosis is nevertheless limited when these drugs are used alone, which is an option worth exploring in selected cases [77].

Renal failure
The use of fast-acting combinations is important to minimize tumor burden and maximize the chance of restoring a near to normal renal function in patients with myeloma-related kidney failure. The dose of lenalidomide must be adjusted to the level of renal function. Thalidomide and bortezomib can be used at full doses in patients with renal dysfunction, including those in patients requiring hemodialysis [78]. Dose adjustments and side effects are also easier to manage with cyclophosphamide than melphalan in cases of renal failure. Compared with thalidomide, bortezomib exerts faster and deeper responses, which could result in a greater chance of reversal of renal failure [78]. Bisphosphonates should be used with caution in patients with renal dysfunction as they may increase tubular necrosis [79]. Of note, in a randomized clinical trial that compared the effects of zoledronic acid with clodronate in patients with newly diagnosed multiple myeloma, the incidence of renal adverse events was low and did not differ between the treatment groups [80]. Finally, as age and renal dysfunction both increase morbidity and mortality of patients undergoing transplantation, ASCT should not be performed in older patients regardless of the etiology of the renal failure [81].

Cardiovascular disease
Steroids are associated with multiple side effects, the most common being cardiovascular diseases such as hypertension and heart failure as well as fluid retention, which make regimens such as Rd with reduced steroid dosing appealing. Clinicians should, nevertheless, be made aware that thalidomide (and to a lesser extent lenalidomide) may cause bradycardia [82]. The concomitant use of these drugs with a beta-blocker may increase that risk [83]. This should be taken into consideration before prescribing the drug and may, in the event of a symptomatic bradycardia, require a change in treatment. Furthermore, plasma levels of digoxin may be increased when co-administered with lenalidomide. Digoxin levels should therefore be monitored closely upon treatment initiation [84]. Finally, maintaining adequate hemoglobin is important in patients with cardiovascular disease to minimize the risk of ischemic episodes and heart failure [85].

Diabetes
Diabetes and diabetes-related end-organ damage are common in elderly patients. Monitoring and adjusting the glycemia control regimen while on steroids is essential. A retrospective review of 1240 patients with myeloma suggested that patients with diabetes, steroid-induced diabetes in particular, had a worse prognosis compared with non-diabetic patients [86]. Furthermore, as diabetic patients are also at risk of peripheral neuropathy, a clear evaluation of baseline diabetes-related complications is required prior to introducing drugs such as thalidomide and bortezomib.

Quality of life

The current treatment aims in myeloma are to control the disease, to improve OS and increase QOL. Despite improvements in OS, novel agents are associated with adverse events that may, in conjunction with persistent myeloma-related symptoms, impair QOL [87]. The impairment in QOL may be transient as seen in the VISTA trial where bortezomib was associated with a deterioration of the QOL indices for the first 4 cycles only [47]. The QOL scores improved among responders. Similar results were seen with bortezomib in the APEX and SUMMIT trials [44,88]. In both the MPR setting and the Rd setting, lenalidomide-treated patients had improved QOL [86]. As some treatment options result in prolonged survival in myeloma patients, and owing to the impact of treatment-related toxicity on QOL, these data have become increasingly relevant. In the absence of differences in treatment efficacy, the choice of initial treatment should be based on QOL indicators, among other patient-related factors. Quality-adjusted survival analyses that integrate QOL considerations may be important, particularly in treatments that do not show significant benefits on survival.

Tailoring clinical trials for the elderly

Concerns over toxicity leads frequently to clinical trials that reflect an idealized population rather than the ‘real world’ reality of elderly patients who are often clinically frail and vulnerable. Despite the majority of myeloma diagnoses and myeloma-related deaths occurring in patients over 65 years, elderly and frail patients are not fully characterized and are under-represented in clinical trials especially in those investigating new drugs. Therefore, frail patients often receive regimens only tested in fit patients which may be too toxic for them and thus result in treatment discontinuation, low efficacy and reduced quality of life [89]. There have been a few studies that have been dedicated to patients over the age of 75 years [20,34] however, to date no trial has prospectively investigated a tailored treatment regimen in older patients based on frailty and/or comorbidities [90]. Recruiting these patients into trials is challenging but would help to define safe, tailored regimens for this subset of patients. Ongoing and future clinical trials, specifically designed for frail patients will hopefully better define frailty-directed treatment selection [91].

Treatment decisions

For an elderly patient with a recent diagnosis of symptomatic myeloma, the primary objective is to determine an appropriate treatment approach on the basis of biologic age, performance status, comorbidities, and drug availability (Table 4.2).
MPT and VMP are currently the two standard treatment options in elderly patients with myeloma, and therefore the most widely used regimens. Since 2013, bortezomib has usually been administered subcutaneously, and weekly dosing seems to be preferred over twice-weekly infusions for frail patients. Some experts still recommend twice-weekly dosing for patients with renal impairment or extensive bone disease [92]. In the absence of direct, prospective comparisons, it is not possible to recommend one regimen over another; although several patient- and disease-related characteristics may suggest one approach over the other. There is no risk of thrombosis with MPV, whereas this is a significant risk with MPT. The use of bortezomib and thalidomide is associated with peripheral neuropathy, whereas lower rates of peripheral neuropathy are typically reported in myeloma patients treated with lenalidomide but it is not currently available in the upfront setting. This is of particular relevance in patients with diabetic neuropathy. An all-oral regimen, such as MPT, is more convenient than a bortezomib-containing combination in the elderly. Although the use of MPT and MPV upfront are supported by phase III studies, their choice as first-line therapy in transplant-ineligible patients will certainly be challenged by the encouraging results seen with Rd. Rd has the advantages of oral administration and a favorable safety profile, especially in terms of neuropathy, cytopenia, and thrombosis, including in patients with mild renal failure, and may eventually be the treatment of choice in elderly patients although it is not approved currently in this setting in Europe.
Selected patients benefit from single-agent bortezomib or lenalidomide, agents normally used with corticosteroids. The key aspect of therapy is to use all available drugs and combinations appropriately. Rechallenge with any of the drugs is reasonable, provided it was effective when used previously.

Table 4.2 Randomized clinical trials for the elderly in myeloma using a novel agent upfront.

CPR, cyclophosphamide, lenalidomide, prednisone; CTDA, cyclophosphamide, thalidomide, and dexamethasone; DVT, deep vein thrombosis; EFS, event-free survival; exp, experimental; Mel100, melphalan 100 mg/m2; mths, months; MP, melphalan-prednisone; MPR, melphalan-prednisone-lenalidomide; MPT, melphalan- prednisone-thalidomide; N, number; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide-dexamethasone; Rd18, lenalidomide-dexamethasone to a fixed duration of 18 cycles; std, standard; TD, thalidomide-dexamethasone; Vd, bortezomib-dexamethasone; VMP, bortezomib-melphalan-prednisone; VTP, bortezomib-thalidomide-prednisone; yrs, years.