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

6 – Disease-specific treatment options

Steroids

Steroids such as prednisone and dexamethasone remain very active agents in myeloma. Despite obvious advantages such as their lack of myelotoxicity and their oral administration, these drugs have many adverse effects including hypertension, hyperglycemia, gastritis, weight gain, fluid retention, mood swings, acute confusion, insomnia, infection, cataract development, and osteopenia, all of which may be particularly challenging in the elderly [28].

Stringent monitoring, supportive therapy and dose modification are often required in the elderly population in order to deliver treatment in a safe fashion. Dose modification entails a reduction of dexamethasone to 10 or 20 mg from the initiation of therapy. Weekly schedules are a common alternative despite there being no formal supportive evidence. Single-agent dexamethasone should be avoided in the elderly, as there are currently other agents that are better tolerated such as prednisone. This can be used intermittently (2 mg/kg daily for 4 days every 4 weeks), or continuously (20–60 mg three times a week). Low doses of steroids may be considered as the sole option at any stage of therapy in elderly frail patients but should otherwise be discouraged unless there are no other available treatment options.

Melphalan-based therapy

Melphalan-prednisone (MP) remained the gold standard for many years since its first description by Alexanian et al in 1968 [29] despite the low response rates and poor OS yielded by this regimen. Combining MP with other conventional agents such as anthracyclines and vincristine did not improve outcome [30]. Nevertheless, when used as a backbone therapy with novel agents such as thalidomide and bortezomib, MP demonstrated an improvement in OS (discussed in more detail below).

Thalidomide-based therapy

With the availability of other immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which are both more potent agents, thalidomide is often overlooked. A key characteristic thalidomide shares with steroids is the lack of myelosuppression and the absence of renal adjustment, which makes it particularly appealing in the elderly.

Single-agent thalidomide
Single-agent thalidomide is a reasonable option in patients with relatively low-grade disease, especially if marrow function is compromised. Responses are nevertheless improved by combining thalidomide and steroids given their synergistic properties [31].

Thalidomide-dexamethasone
Thalidomide was first combined with dexamethasone by Ludwig et al. Despite showing higher response rates than MP, thalidomide-dexamethasone (TD) had a shorter OS, a less favorable toxicity profile, and increased early mortality. This was particularly obvious in the subgroup of patients aged 75 and over [32].

Melphalan-prednisone-thalidomide
The combination of MP with thalidomide (MPT) is currently one of the standard options for newly diagnosed patients who are not eligible for autologous stem cell transplantation (ASCT) [33–35]. MPT was shown to delay disease progression in several randomized trials [33,36–41] and to improve OS in some of the trials [33,36,37]. The longer the treatment was continued, the better the outcome was in every trial. A meta-analysis of published data from six randomized trials confirmed an improvement in progression-free survival (PFS) and OS with MPT compared with MP [34]. The reported median PFS and OS with MPT were 20.3 and 39.3 months, respectively. However, the adverse event profile observed in the MPT arms was less favorable compared with MP [33,37,39].

Cyclophosphamide, thalidomide, and dexamethasone
The combination of cyclophosphamide, thalidomide, and dexamethasone (CTDa) improved response rates compared with MP [42,43]. Evidence from the Myeloma IX trial suggested, there was a survival benefit in CTDa- treated patients with favorable cytogenetics, although early deaths from infections related to high-dose dexamethasone were significant [42,43].

Bortezomib based-regimens

Single-agent bortezomib has excellent activity in myeloma and is an appropriate therapy at any stage of the disease. Single-agent bortezomib is superior to dexamethasone for relapsed disease in terms of response rates, PFS and OS [41] including in elderly patients [44,45] and those with renal impairment [45]. Combination strategies have been developed based on the synergistic activity between bortezomib and other agents [46].

Melphalan-prednisone-bortezomib
The addition of twice weekly bortezomib to MP is now a well-established regimen. When first developed in the VISTA trial [47,48], it involved twice weekly intravenous (IV) bortezomib. When first published by San Miguel et al, melphalan-prednisone-bortezomib (MPV) was superior to MP across all efficacy endpoints, including response rate, CR rate, median time to progression (TTP) (24 months versus 16.6 months using a stringent definition of disease progression [change from immunofixation negativity to positivity]), and OS. The CR rates were approximately 30% versus 5% in the MP arm. MPV yielded better results over all cytogenetic and renal failure subgroups [47–49]. Neuropathy was the major side effect of this regimen. In the final analysis of the VISTA trial after a median follow-up of 60 months, the superiority of MPV over MP in terms of median time to second-line anti-myeloma therapy (31 months versus 20.5 months) and median OS (56 months versus 43 months) were sustained. Nevertheless, there were some disparities in salvage regimens that may account for part of the OS differences. Indeed only 13% of patients who received MP received lenalidomide compared with 32% in the MPV arm (p=0.001), and only 50% of patients in the MP arm received bortezomib at relapse [48].

Bortezomib-thalidomide-prednisone
Bortezomib-thalidomide-prednisone (VTP) induction followed by bortezomib-thalidomide (VT) or bortezomib-prednisone (VP) maintenance has also been investigated by Mateos et al [50]. Treatment discontinuation resulting from adverse events was more probable with VTP compared with VMP. The overall CR rates after induction therapy were similar with bortezomib-melphalan-prednisone (VMP) and VTP. Subgroup analysis, hampered by a small sample size, suggested that VMP followed by VT resulted in superior PFS. Palumbo et al compared VMP induction without maintenance with VMP plus thalidomide (VMPT) followed by VT maintenance. VMPT-VT improved response rates and PFS compared with VMPT [51].

Bortezomib-cyclophosphamide-dexamethasone
Bortezomib-cyclophosphamide and dexamethasone (VCD) is not yet approved due to a lack of controlled data. However, this regimen is widely used and has demonstrated high response rates and prolonged PFS [52].

Scheduling and dosing changes with bortezomib
Clinical practice regarding bortezomib evolved from a twice-weekly to a weekly schedule in 2010 based on new clinical evidence [50,51,53,54] and from IV to subcutaneous (SC) administration in 2012 [48,55]. The SC administration of bortezomib was associated with a reduced toxicity and similar activity compared with IV administration. Once-weekly regimens are often used to reduce toxicities such as neuropathy, diarrhea, constipation, and thrombocytopenia and are better tolerated, especially in the elderly [44,56].

Lenalidomide combinations

Lenalidomide is a second generation IMiD with superior efficacy compared with thalidomide in patients with myeloma.

Lenalidomide and dexamethasone
The US Food and Drug Administration (FDA) expanded approval of lenalidomide, in combination with dexamethasone, to include patients newly diagnosed with multiple myeloma [57]. Expanded approval was based on a Phase III trial, the FIRST study (IFM 2007-02/ MM-020), involving 1623 newly diagnosed transplant-ineligible patients, a continuous lenalidomide plus dexamethasone (Rd) regimen administered until disease progression or intolerance, or for a fixed duration of 18 cycles (72 weeks; Rd18), was compared with MPT administered for 12 cycles (72 weeks) [58]. Continuous Rd significantly improved PFS and showed an OS benefit compared with MPT. With a median follow-up of 37 months, the median PFS was 25.5 months for Rd, compared with 20.7 months for Rd18 and 21.2 months for MPT. Median OS was 58.9 months for Rd compared with 48.5 months for patients who received the triple regimen. The 4-year estimated OS was 59% for Rd, 56% for Rd18, and 51% for MPT. In addition, Rd was superior to MPT across all other efficacy end- points, including response rate TTP, time to treatment failure, time to second-line anti-myeloma therapy, and duration of response. Of note, Rd was also generally better tolerated than MPT [58]. Lenalidomide plus low-dose dexamethasone is therefore becoming a new standard of care first-line for patients with MM who are ineligible for ASCT.

Melphalan-prednisone-lenalidomide
The combination of MP and lenalidomide (MPR) is effective in myeloma [59]. However, as lenalidomide and MP are both myelosuppressive regimens, this combination is associated with a significant hematological toxicity that may be challenging especially in elderly patients. The preliminary results of a study comparing MP and MPR induction with or without lenalidomide maintenance (MM-015, MPR-R or MPR) showed that MPR, at the induction level, was significantly superior to MP in terms of response rates and PFS, although it was also associated with significantly higher risk of toxicity [59]. Furthermore, in the E1A06 trial that compared melphalan, prednisone, and thalidomide (MPT-T) with melphalan, prednisone, and lenalidomide (MPR-R) in patients with newly diagnosed myeloma, there was no significant difference in terms of response and outcome between the two arms, suggesting that the potential benefit that may be acquired from lenalidomide is eclipsed by the toxicity profile [60].

Cyclophosphamide-lenalidomide-dexamethasone
Dose adjusted cyclophosphamide-lenalidomide-dexamethasone (CRDa) is also under investigation in the NCRI-Myeloma XI trial. The early response and toxicity data presented at the American Society of Hematology (ASH) annual meeting in 2013 were encouraging [61].

Other drugs

Bendamustine has also been studied in combination with prednisone [58] or bortezomib and prednisone [59]. Bendamustine is currently approved in Europe for the treatment of newly diagnosed elderly patients that are not eligible for MPT or MPV.
Recently the phase III CLARION trial, which evaluated an investigational regimen of carfilzomib, melphalan and prednisone (KMP) versus bortezomib, melphalan and prednisone (VMP) for 54 weeks in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem-cell transplant. The trial did not meet the primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP, hazard ratio=0.91, 95 percent CI, 0.75–1.10) [64].
Other proteasome inhibitors (such as ixazomib), IMiDs (pomalidomide), and novel families of drugs (histone deacetylase [HDAC] inhibitors such as panobinostat and vorinostat; monoclonal antibodies such as the anti-CD38 antibody daratumumab and the anti-CS1/SLAMF7 antibody elotuzumab) are currently under investigation in either the upfront or relapsed setting.

Autologous Stem Cell Transplantation (ASCT)

Although age does not affect the outcome of ASCT [65], biological features are powerful determinants of prognosis. A cut off of 65 years of age was commonly used to determine ASCT eligibility in MM patients however, the feasibility and efficacy of it as a first-line approach is now well established in fit patients up to the age of 70. Nonetheless, the decision should still be made on a case-by-case basis [66–68]. Evidence from the IFM 99-06 trial, did not suggest any benefit from reduced-intensity ASCT using melphalan 100 mg/m2 in elderly patients with myeloma [69]. However, retrospective data suggest that intermediate-dose melphalan (140 mg/m2) is safe in this population and is equally efficacious as the higher dose of 200 mg/m2 [70]. Lower doses (100–140 mg/m2) are also used for older patients, with Palumbo and colleagues showing that tandem melphalan 100 mg/m2 ASCT was superior to conventional MP therapy, particularly in patients aged 65–70 [71]. ASCT in elderly patients with significantly compromised renal function should however be avoided. Over the age of 70 (generally up to the range of 75–77 years), in the subgroup of patients considered potentially suitable for high-dose chemotherapy, some centers still perform ASCT from second-line onwards; however, this is not common clinical practice in Europe [72].

The role of maintenance

Several studies have evaluated the role of maintenance or ongoing therapy. These approaches include VMPT followed by VT maintenance [53,54], VMP or VTP followed by VT or VP maintenance [50], lenalidomide maintenance after MPR [59], or continuous Rd [58]. Taken together, these studies support the role of continuous therapy, at least in terms of PFS and time to second-line anti-myeloma therapy. Only lenalidomide has a satisfactory long-term safety profile. The role of maintenance therapy, what type (monotherapy or combination), and for how long remains an important question to be answered. It should be noted that recent ESMO guidelines do not recommend the use of systematic maintenance therapy in the elderly due to a lack of OS benefit [52].

Sequential versus alternating therapy
As VMP and Rd are now considered the two most effective first-line treatments for elderly MM patients, there have been studies to investigate if and how these drugs might be used in combination with a view to improve outcomes. The results of the GEM2010MAS65 trial, comparing a sequential arm of VMP for 9 cycles followed by Rd for 9 cycles to an alternating arm consisting of one cycle of VMP alternating with one Rd, demonstrated no difference between the two arms with both approaches shown to be very effective in patients aged 65–75 years. The 3-year overall survival rates were 72 and 74% with complete response rates of 42 and 40%, respectively [73]. These results provide a strong basis for the introduction of continuous treatment upfront in elderly MM patients.