Welcome international healthcare professionals

This site is no longer supported and will not be updated with new content. You are welcome to browse and download all content already included in the site. Please note you will have to register your email address to access the site.

You are here

Practical management of adverse events in multiple myeloma: Can therapy be attenuated in older patients?

Blood Reviews, 4, 25, pages 181 - 191

Abstract

The current standard of care for elderly patients with newly diagnosed multiple myeloma is melphalan and prednisone (MP) in combination with either bortezomib (VMP) or thalidomide (MPT), with lenalidomide plus dexamethasone increasingly being employed. The addition of bortezomib or thalidomide to the established MP regimen significantly improves outcomes and prolongs survival in elderly and transplant-ineligible patients. However, these benefits are accompanied by increases in treatment-related adverse events (AEs), which may be particularly pronounced in older individuals. Patients receiving bortezomib as part of a VMP regimen commonly experience transient and cyclical thrombocytopenia and neutropenia, along with gastrointestinal AEs. Fortunately, these AEs can be managed with appropriate supportive care and, when necessary, adjustments in dose. Peripheral neuropathy (PN) is the most important side effect of bortezomib, and although it is reversible in a high proportion of patients, it affects their quality of life. Furthermore, PN can require temporary or permanent withholding of bortezomib, which will reduce treatment efficacy. PN is also a common adverse effect of thalidomide; thromboembolic events are also a key concern, requiring thromboprophylaxis in patients receiving thalidomide in combination. For lenalidomide in combination with dexamethasone, the most clinically important adverse effects are hematologic toxicity (particularly neutropenia) and thromboembolic events. Recent phase III studies in newly diagnosed elderly patients are providing further insight into the most appropriate treatment regimens to maximize outcomes and minimize toxicity in individual patients. Of note, once-weekly bortezomib dosing (in combination with MP ± T) was shown to reduce the incidence of peripheral neuropathy and gastrointestinal events compared with twice-weekly dosing, while maintaining efficacy. Elderly patients may be less able to withstand the AEs associated with newer treatment regimens and combinations of multiple drugs, and may experience greater declines in quality of life and, subsequently, reduced treatment adherence. It is therefore critical that these patients are closely monitored and any emergent AEs promptly and appropriately managed. For very elderly, frail patients, tailored therapy, reduced intensity regimens, and adverse event management are necessary to encourage treatment adherence and reduce discontinuation. This article will provide practical guidance on the management of bortezomib-, thalidomide-, and lenalidomide-associated AEs, to maximize treatment feasibility and active drug delivered, and thus help minimize toxicity and maximize outcomes.

Keywords: Bortezomib, Thalidomide, Lenalidomide, Elderly, Multiple myeloma, Adverse events.

1. Introduction

Multiple myeloma (MM), characterized by the malignant proliferation of clonal plasma cells, is a disease that primarily affects older individuals. The median age at diagnosis is 70 years; 26% of patients are aged between 65 and 74 years, and 37% are older than 75 years. 1 Only 16% of patients are diagnosed while younger than 55 years. In general, patients who are older than 65 years (elderly) are in poor physical condition and/or have comorbidities, and are generally considered ineligible for high-dose chemotherapy and stem cell transplantation, which is the current standard of care for younger patients.2 and 3 Reduced-intensity chemotherapy and transplantation are possible for older patients in good clinical condition; however, for the majority, conventional treatment with cytotoxic drugs is the only option.

Regimens incorporating novel agents, such as the proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide, have shown improved efficacy and outcomes over traditional chemotherapy regimens,4, 5, 6, 7, 8, 9, 10, 11, and 12 and are now incorporated into standard regimens for newly diagnosed and relapsed or refractory MM. 2 The current standard of care for newly diagnosed elderly patients is a three-drug combination of melphalan and prednisone (MP) with either bortezomib (VMP) or thalidomide (MPT). 2 Promising data for the combination of MP plus lenalidomide followed by lenalidomide maintenance (MPR + R) have also been reported recently. 13 When compared with MP in newly diagnosed elderly patients, VMP was associated with significantly higher complete response rates (4% versus 30%; p < 0.001), and significantly prolonged time to progression (16.6 versus 24.0 months; p < 0.001) and overall survival (OS) (3 year OS 54% versus 69%).6 and 14 The addition of bortezomib to the MP regimen did, however, significantly increase the incidence of grade 3 adverse events (AEs) (44% for MP versus 53% for VMP; p = 0.02). 6 Similarly, as an example of one of six phase III studies, when compared with MP in newly diagnosed, elderly patients, significantly more patients receiving MPT achieved complete response (CR), very good partial response (VGPR), or partial response (PR) (66% [MPT] versus 45% [MP]; p < 0.001), yet the rate of grade ≥ 2 AEs was higher in patients receiving MPT (87%) than in those receiving MP alone (60%). 9 Adding thalidomide to a once-weekly VMP regimen (VMPT) further increased response rates, although the increased efficacy was accompanied by an increased incidence of grade 3/4 neutropenia and grade 3/4 cardiac complications in the VMPT group compared with those receiving VMP alone. 10 In patients receiving MPR-R, a recent phase III study showed that this regimen was highly active, but was associated with a higher frequency of hematologic AEs compared with those receiving MP alone. 15

AEs, while unavoidable, are an important consideration when planning treatment for elderly patients, particularly as increasingly effective yet potentially more toxic combination regimens become standard. Appropriate management of treatment-related complications is critical to ensure that patients receive the optimal dose and duration of treatment, to maximize treatment efficacy and improve survival. In addition, effective management and, where possible, relief from treatment-related AEs will improve patients' quality of life and ability to withstand the stresses of cancer treatment. While the elderly generally experience similar AEs to younger patients, their ability to tolerate such toxicities is lower, thus increasing the risk of serious complications and/or treatment discontinuation. In this review, we aim to provide practical guidance for optimizing the management of AEs associated with novel therapies in elderly patients, thus enabling patients to obtain maximum benefit from treatment. Furthermore, based on experience from phase III studies, we consider whether treatment can be attenuated to provide greater activity while actively managing toxicities.

2.1. Hematologic toxicities: thrombocytopenia, neutropenia, and anemia

Hematologic toxicities are common in MM patients, and are the result of both disease- and treatment-related factors. With this in mind, caution is advised in elderly patients with low platelet or complete blood counts prior to starting therapy. During treatment, platelet and complete blood counts should be closely monitored, and any myelosuppression managed with supportive care and dose modifications (Table 1, Table 2, and Table 3). Bortezomib: Bortezomib has been associated with transient and cyclical thrombocytopenia and neutropenia, 16 which affected 35–52% and 19–49% of patients, respectively, receiving single-agent or combination therapy.5, 6, and 17 Furthermore, the fluctuations in platelet counts and absolute neutrophil counts (ANC) in VMP regimens appear to be mainly driven by the melphalan component, which, as a myelosuppressive drug, is known to be associated with substantial hematologic toxicity. 18 Platelet counts should be determined at the beginning of each cycle and then after every other bortezomib dose ( Table 1 ). For those patients receiving bortezomib alone or in combination with non-myelosuppressive treatments, if grade 4 thrombocytopenia is present (platelet count < 25,000/μL) therapy should be paused on the day of discovery, and reinitiated after resolution to at least grade 2 (platelets ≥ 50,000/μL). However, if bortezomib is used in combination with an alkylating agent such as melphalan or cyclophosphamide, these guidelines should be slightly modified — prior to initiating any cycle, platelet count should be ≥ 70,000/μL. If the patient's platelet count is lower than 70,000/μL, treatment should be withheld and platelet counts should be repeated every week until recovery, upon which treatment should be reinitiated at a lower dose (reduced by 1 dose level). On any bortezomib dosing day during the cycle after day 1, if the platelet count is ≤ 30,000/μL, the bortezomib dose should be withheld and be reinitiated, when the platelet level has recovered, at a lower dose (reduced by 1 dose level). If several dose interruptions have been necessary in the previous cycle for hematologic AEs, the dose may be reduced by one level (e.g. from 1.3 mg/m2 to 1.0 mg/m2). Thalidomide: Hematologic toxicities are among the most commonly reported AEs associated with thalidomide; however, these can usually be managed through standard supportive care ( Table 2 ). Furthermore, phase III experience indicates that the combination of thalidomide, bortezomib and MP does not appear to result in excessive hematologic toxicity. 10 Lenalidomide: Neutropenia and thrombocytopenia are major dose-limiting toxicities of lenalidomide therapy; 11, 12, and 19 respective grade 3/4 rates of around 12–20% and 7–8% have been reported in combination with dexamethasone in newly diagnosed patients, 20 although in relapsed/refractory patients, rates of up to 41% and 15% have been observed.11 and 12 Most patients experience their highest grade of neutropenia during early treatment cycles. A complete blood count should be undertaken at baseline, every week for the first 8 weeks of therapy and monthly thereafter ( Table 3 ). If the patient's platelet count is lower than 75,000/μL, treatment should be withheld until recovery to grade 1, at which time treatment should be reinitiated at a lower dose (reduced by 1 dose level). If the platelet count drops below 25,000–50,000/μL, anticoagulation therapy should be withheld and at the next cycle of lenalidomide, therapy should be reinitiated at a lower dose (reduced by 1 dose level). Melphalan: As a myelosuppressive agent that is commonly combined with novel therapies, the melphalan component of treatment regimens can contribute heavily to development of hematologic toxicities. In the pre-transplant setting, low-dose chemotherapy precedes high-dose treatment, which serves to reduce tumor mass and is associated with few adverse effects; a recent phase II study, investigated whether this attenuated approach could be adapted for unfit, elderly MM patients. 13 Low-dose melphalan as part of a lenalidomide and prednisone (RP)-MPR regimen resulted in fewer grade 4 events of neutropenia, thrombocytopenia and anemia, as well as less frequent use of granulocyte colony-stimulating factor (G-CSF) therapy, compared with the standard melphalan dosing in an MPR regimen; furthermore, > 50% of patients receiving the low-dose melphalan regimen achieved PR. 13

Table 1 Summary of recommended strategies to treat or prevent clinically-relevant bortezomib-related adverse events in elderly patients with multiple myeloma.

Adverse event Recommended action
Thrombocytopenia Measure platelet count at the beginning of each cycle and thereafter, after every other bortezomib dose
On Day 1 of each cycle:  
 Platelets < 70,000/μL (when combined with alkylating agents) Withhold until platelet count increases to required level, then reinitiate at a lower dose (see Table 4 for dose reductions)
   
 Platelets < 25,000/μL (other combinations) Withhold until platelet count increases to at least 50,000/μL, then reinitiate at lower dose (see Table 4 for dose reductions)
Platelet transfusion if required
These rules may not apply if cytopenia is due to massive bone marrow infiltration
On bortezomib dosing day (after Day 1):  
 Platelets < 25,000–30,000/μL Withhold until platelet count increases to at least 50,000/μL, then reinitiate at lower dose (see Table 4 for dose reductions)
Platelet transfusion if required
These rules may not apply if cytopenia is due to massive bone marrow infiltration
   
Neutropenia G-CSF as primary or secondary prophylaxis to reduce severity of neutropenia
On Day 1 of each cycle:  
 Neutrophils < 1000/μL (when combined with alkylating agents) Withhold bortezomib until neutrophil count is recovered, then reinitiate at lower dose (see Table 4 for dose reductions)
For patients receiving melphalan, reduce melphalan dose to 0.18 mg/kg (7.5 mg/m2) then 0.13 mg/kg (5 mg/m2)
For patients receiving VMP, first reduce melphalan to 0.18 mg/kg (7.5 mg/m2), then bortezomib to 1.3 mg/m2 weekly, then melphalan to 0.13 mg/kg (5 mg/m2), then bortezomib to 1.0 mg/m2 weekly, etc., in an alternating pattern
These rules may not apply if cytopenia is due to massive bone marrow infiltration
   
 Neutrophils < 500/μL (despite G-CSF) or grade 2–3 with infection (other combinations) Withhold bortezomib until neutrophil count is at least 1000/μL, then reinitiate at lower dose (see Table 4 for dose reductions)
  For patients receiving melphalan, reduce melphalan dose to 0.18 mg/kg (7.5 mg/m2) then 0.13 mg/kg (5 mg/m2)
  For patients receiving VMP, first reduce melphalan to 0.18 mg/kg (7.5 mg/m2), then bortezomib to 1.3 mg/m2 weekly, then melphalan to 0.13 mg/kg (5 mg/m2), then bortezomib to 1.0 mg/m2 weekly, etc., in an alternating pattern
  These rules may not apply if cytopenia is due to massive bone marrow infiltration
On bortezomib dosing day (after Day 1):  
 Neutrophils < 750/μL (when combined with alkylating agents) or < 500/μL(other combinations) Withhold bortezomib until neutrophil count is recovered, then reinitiate at lower dose (see Table 4 for dose reductions)
Anemia  
 Hemoglobin < 10 g/dL ESA treatment; no bortezomib dose modifications required
Thromboembolic events If required due to patient risk factors or concomitant therapies: aspirin or low molecular weight heparin
Peripheral neuropathy Monitor carefully for symptoms before and during treatment
See Table 5 for dose modifications
Gastrointestinal complications High fluid intake
 Diarrhea Anti-diarrhea drugs
 Constipation High-fiber diet, with stool softeners/laxatives as needed
 Vomiting Anti-emetics
 Grade 2 event Reduce bortezomib dose
 Grade 3–4 event Withhold until resolution to grade 2. Reintroduce with dose reduction to once-weekly dosing
Infection Antiviral prophylaxis against herpes zoster
 Grade 3–4 Appropriate anti-infective treatment; reduce bortezomib dose
Hypotension Rehydrate, adjust hypertensive medications, administer mineral corticosteroids and/or sympathomimetics

ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor.

Table 2 Summary of recommended strategies to treat or prevent clinically-relevant thalidomide-related adverse events in elderly patients with multiple myeloma.

Adverse event Recommended action
Thrombocytopenia Monitor platelet counts regularly
Neutropenia G-CSF as primary or secondary prophylaxis to reduce severity of neutropenia
Anemia RBC transfusion
 Hemoglobin < 10 g/dL As ESAs may increase the risk of venous thromboembolism, these agents should be used with caution and discontinued if hemoglobin is ≥ 12 g/dL
Thromboembolic events Concomitant ESA therapy should be used with caution.
Single-agent thalidomide Thromboprophylaxis is not generally required; may be used depending on individual patient risk factors
   
In combination with MP All newly diagnosed patients should receive thromboprophylaxis with either LMWH, aspirin or warfarin, depending on the baseline risk of VTE associated with the given regimen
Peripheral neuropathy Monitor carefully for symptoms before and during treatment.
See Table 5 for dose modifications
Skin reactions In the event of a toxic skin reaction (e.g. Stevens–Johnson Syndrome), thalidomide treatment should be permanently discontinued
Syncope and bradycardia Patients should be monitored for syncope and bradycardia Dose reduction or discontinuation may be required

RBC, red blood cell; VTE, venous thromboembolism; LMWH, low molecular weight heparin.

Table 3 Summary of recommended strategies to treat or prevent clinically-relevant lenalidomide-related adverse events in elderly patients with multiple myeloma.

Adverse event Recommended action
Thrombocytopenia Measure platelet count as part of a complete blood count at baseline, every week for the first 8 weeks of therapy and monthly thereafter
 Platelets < 75,000/μL On Day 1 of a new cycle, withhold until platelet count recovers to grade 1 toxicity, then reinitiate at a lower dose (see Table 4 for dose reductions); do not dose below 5 mg once daily
 Platelets < 25,000–50,000/μL If platelets drop during a cycle, withhold anticoagulation therapy, then reinitiate lenalidomide at the next cycle at a lower dose (see Table 4 for dose reductions); do not dose below 5 mg once daily
Neutropenia Monitor blood count at baseline, and biweekly thereafter if baseline value is normal
G-CSF as primary or secondary prophylaxis to reduce severity of neutropenia
 Neutrophils < 1500/μL On Day 1 of a new cycle, withhold lenalidomide until neutrophil count is recovered to at least grade 1, then reinitiate a lower dose (see Table 4 for dose reductions); do not dose below 5 mg once daily
 Neutrophils < 500/μL If ANC drops below 500/μL during a cycle, start G-CSF therapy until recovery to > 1500/μL, then withhold lenalidomide until neutrophil count is recovered to at least grade 1, then reinitiate at a lower dose (see Table 4 for dose reductions); do not dose below 5 mg once daily
 Febrile neutropenia Antibiotic prophylaxis should be provided after occurrence of febrile neutropenia; patients should receive clear instructions to seek medical advice within 3 h if febrile while neutropenic
Anemia  
 Hemoglobin < 10 g/dL or severely symptomatic As ESAs may increase the risk of venous thromboembolism, these agents should be used with caution and discontinued if hemoglobin is ≥ 12 g/dL
RBC transfusion
Thromboembolic events In symptomatic patients, sonography for diagnosis of VTE is recommended
Concomitant ESA therapy should be used with caution
Single-agent lenalidomide Thromboprophylaxis is not generally required; may be used depending on individual patient risk factors
In combination with low-dose dexamethasone or melphalan Patients with risk factors should receive 4–6 months of prophylaxis with either low-dose aspirin (lower risk patients) or LMWH (higher risk patients). Low-dose warfarin is not recommended as prophylaxis
If a patient experiences a thromboembolic event, lenalidomide treatment can either be continued or discontinued and reinitiated once stabilized and any complications managed, depending on severity of the event
Anticoagulation therapy: for patients previously receiving aspirin, switch to LMWH; patients previously receiving prophylactic LMWH should have the dose increased to therapeutic levels for 6 months, before returning to prophylactic doses
Cardiovascular disorders Patients with known cardiovascular risk factors should be closely monitored
Modifiable cardiovascular risk factors should be minimized
 Smoking: encourage smoking cessation
 Hypertension: antihypertensive medications such as ACE inhibitors, calcium channel blockers, or angiotensin II receptor antagonists
 Hyperlipidemia: dietary modifications; if greater reductions in low-density lipoprotein cholesterol are required, consider statin therapy
Thyroid function Monitoring of thyroid function should be considered
Skin reactions In the event of a severe toxic skin reaction (e.g. Stevens–Johnson Syndrome or toxic epidermal necrolysis), lenalidomide treatment should be permanently discontinued
For other forms of skin reaction, treatment may be withheld or discontinued depending on severity
Patients with a history of severe rash should not receive lenalidomide

ACE, angiotensin-converting enzyme.

Across the three novel agents, an age-appropriate dose reduction may be advisable ( Table 4 ). It should be noted that if hematologic deficiencies have occurred as a result of bone marrow infiltration by plasma cells, a reduction in therapeutic dose may not be required if tumor reduction occurs following treatment. However, hematologic toxicities occurring in the context of older age or with a long pre-treatment duration require dose reductions.

Table 4 Age-adjusted dose reduction for treatment with novel agents. 70

Treatment < 65 years 65–75 years > 75 years 65–75 years with comorbidities Further dose reduction
Bortezomib 1.3 mg/m2 twice weekly 1.3 mg/m2 twice weekly 1.3 mg/m2 once weekly 1.0 or 0.7 mg/m2 once weekly
    1.3 mg/m2 once weekly a    
Thalidomide 200 mg daily 200 mg daily 100 mg daily 50 mg daily
Lenalidomide (in combination with MP) 25 mg (days 1–21) 10 mg (days 1–21) 5 mg (days 1–21) 5 mg (every other day)
Lenalidomide (in combination with low-dose dexamethasone) 25 mg (days 1–21) 25 mg (days 1–21) 15 mg (days 1–21) 10 mg

a According to physician choice MP, melphalan and prednisone.

G-CSF is the recommended treatment for neutropenia, and can be given either as primary or secondary prophylaxis, or in response to measurable neutropenia. Where neutropenia is due to tumor infiltration of the bone marrow, no dose reduction or modification is required. Bortezomib: In patients experiencing grade 4 treatment-related neutropenia (neutrophil count < 500/μL) despite G-CSF use, bortezomib should be withheld until resolution to grade 2 (neutrophil count ≥ 1000/μL). When bortezomib is combined with alkylating agents, the following recommendations should be considered: At day 1 of each bortezomib treatment cycle, ≥ 1000/μL granulocytes are required; on other bortezomib dosing days, ≥ 750/μL granulocytes are required. In patients who don't achieve these levels, treatment should be withheld until recovery, and reinitiated at a dose reduced by one level. In patients receiving bortezomib in combination with melphalan who experience prolonged grade 4 neutropenia or thrombocytopenia with bleeding, the dose of melphalan should be reduced from 0.25 mg/kg to 0.18 mg/kg, then to 0.13 mg/kg, or from 9 mg/m2 to 7.5 mg/m2, then to 5 mg/m2. Bortezomib and melphalan dose reductions should be introduced alternately in patients receiving VMP who are experiencing severe hematologic toxicity; first reduce the melphalan dose to 0.18 mg/kg or to 7.5 mg/m2, then switch to once-weekly bortezomib dosing at 1.3 mg/m2, continuing with further, alternating dose reductions as described above. Patients with grade 4 neutropenia in the absence of G-CSF, those who require more than 2 weeks' dose delay due to neutropenia or thrombocytopenia, or those who require withholding of several bortezomib doses in consecutive cycles due to hematological toxicity, can be re-started at a reduced bortezomib dose of 1.3 mg/m2 weekly. If grade 4 neutropenia or thrombocytopenia persists, further dose reductions to 1.0 mg/m2 weekly, then 0.7 mg/m2 weekly, may be implemented. Lenalidomide: In patients experiencing grade 2 treatment-related neutropenia (neutrophil count 1000 to < 1500/μL) on the first day of a new cycle, lenalidomide treatment should be withheld until resolution to grade 1; treatment should then be reinitiated at a lower dose (reduced by 1 dose level). If the patient's neutrophil count drops below < 500/μL during treatment (grade 4), G-CSF therapy should be initiated until recovery to grade 1, with lenalidomide therapy reinitiated at a lower dose level for the next cycle of treatment. 21

Erythropoiesis-stimulating agents (ESAs) can be used to treat anemia when hemoglobin levels do not rise despite a response to treatment.2 and 3 The use of ESAs does not appear to impact on the efficacy of VMP treatment, 22 and despite concerns that ESA use may be associated with reduced OS, 23 recent data indicate that ESA use in patients with newly diagnosed MM who were treated with either VMP or MP was not associated with an adverse impact on long-term outcomes. 22 However, ESAs are also associated with an increased risk of thromboembolic events 23 and as such, should be used with caution in patients receiving either thalidomide or lenalidomide as part of combination regimens. If appropriate based on therapy, ESA treatment is generally recommended when hemoglobin levels fall below 10 g/dL, 2 and the ESA dose should be adjusted to maintain the lowest hemoglobin concentration sufficient to avoid red blood cell transfusion. 23 In elderly patients with heart disease or those having difficulties with everyday activities, ESA treatment could be started earlier, when hemoglobin is between 10 and 11 g/dL. Iron supplementation is recommended to improve ESA effectiveness.24 and 25

2.2. Thromboembolic events

Bortezomib does not appear to increase the risk of thromboembolic events, 6 and may even protect against the increased risk of thrombosis with thalidomide/lenalidomide-based therapies.26, 27, and 28 Thromboprophylaxis, if required due to patient risk factors (e.g. prior thrombosis), 29 or concomitant use with thalidomide/lenalidomide-based chemotherapy regimens, 30 includes aspirin or LMWH. 29

As single agents, thalidomide and lenalidomide do not appear to increase the incidence of venous thromboembolism (VTE);30, 31, and 32 however, as part of MPT or RD regimens, the risk of VTE is substantially increased.9, 20, 30, and 33 The risk of thromboembolic events is increased in patients with previous history of such, and in those receiving concomitant ESA or hormone replacement therapy.19, 33, and 34 Both physicians and patients must therefore be vigilant for signs and symptoms of thromboembolism. Thalidomide: The risk of thromboembolic events is highest during the first 5 months of thalidomide therapy. 34 Antithrombotic prophylaxis is recommended in patients receiving MPT, such as low molecular weight heparin (LMWH) or adjusted-dose warfarin. 29 In the phase III Italian Myeloma Network GIMEMA study, 35 which prospectively assessed the impact of LMWH, aspirin or low-dose warfarin in newly diagnosed patients receiving thalidomide as part of either VMPT, VTD, or TD regimens, the risk of VTE was similar between the thromboprophylactic therapies after 6 months of follow up (5.0%, 6.4%, and 8.2%, respectively), and all were considered likely to be effective. Current guidance recommends LMWH in patients receiving MPT; 33 other thromboprophylactic agents may also be used, although in elderly patients specifically, warfarin showed lower efficacy. 35 Lenalidomide: As for thalidomide, the risk of VTE is highest in newly diagnosed patients receiving lenalidomide in combination. 33 Depending on patient risk factors, prophylaxis with either aspirin or LMWH is recommended ( Table 3 ). Aspirin therapy has been shown to reduce the incidence of VTE to less than 10% in patients receiving lenalidomide in combination with low-dose dexamethasone or melphalan. 33 In addition, the use of low-dose dexamethasone is associated with a lower risk of VTE compared with higher-dose dexamethasone. 33 Of interest, in a recent phase II study in elderly patients with newly diagnosed MM, 13 the rate of DVT stayed constant despite patients progressing through regimens containing different doses of lenalidomide.

2.3. Peripheral neuropathy (PN)

PN, including neuropathic pain, is a recognized toxicity of both bortezomib and thalidomide treatment, with the incidence of PN of any grade in large clinical studies ranging from 31% to 47% for bortezomib4, 5, 6, and 36 and 6% to 54% for thalidomide.7, 8, 9, 37, 38, and 39 By contrast, PN is not considered a particular concern in patients receiving lenalidomide therapy, 21 with grade > 3 rates of around 2% reported for lenalidomide plus dexamethasone. 20 Treatment-induced neuropathy is primarily sensory; symptoms of neuropathy usually occur first in the toe, foot, and distal leg, followed by the fingers and hands. 40 Neuropathic pain, located primarily in the fingertips and toes, is a cardinal symptom of bortezomib-induced PN, and may range from very mild to very severe. 41 Patients may report sensations that are burning, tingling, sharp stabbing, shock-like or hot and cold. 40 Other patients report numbness, which can indicate sensory loss, weakness or even ataxia. 40 Motor neuropathies are less common, 42 but can present as distal weakness in the feet (foot drop) or hands (difficulty opening jars, turning keys or buttoning clothes).40 and 41 In some patients, symptoms of PN may persist for many months, which can impact on their quality of life. 43 Bortezomib: Most cases of bortezomib-induced PN are mild or moderate; approximately 13% of patients report grade 3 PN, and less than 1% experience grade 4.4, 5, 6, and 36 In addition to the signs and symptoms described above, autonomic neuropathy should be suspected if urinary retention or constipation with paralytic ileus is observed. 44 With appropriate management, bortezomib-induced PN is reversible in a substantial proportion of patients;6, 36, 42, and 45 for example, in the VISTA trial, 79% of PN events had improved by at least one toxicity grade within a median of 1.9 months, and 60% of events had resolved completely in a median of 5.7 months. 36 Thalidomide: PN has long been associated with thalidomide and is considered the most clinically relevant side effect of chronic thalidomide. 46 Indeed, a recent meta-analysis of elderly and/or transplant-ineligible patients highlighted the increased risk of PN in patients receiving MPT versus those receiving MP alone. 47

Prior treatment with neurotoxic regimens or baseline diabetes do not appear to increase the risk of PN,36, 42, and 45 although recent data suggest an interaction between myeloma-related factors and patients' genetic background in the development of treatment-emergent PN.48 and 49 At present however, presence of existing PN is the only factor known to increase the risk of treatment-emergent PN. 36 As such, patients with pre-existing severe neuropathy should only receive bortezomib or thalidomide after a careful risk/benefit assessment,34 and 50 and should potentially be started at a lower dose of therapy (e.g. bortezomib 1.0 mg/m2 weekly). Patients should be provided with information and advice at the start of treatment to ensure that they can rapidly identify, and notify their physician of, new or worsening symptoms. The use of bortezomib and thalidomide in combination may require particular attention. 34 However, in two phase III studies where bortezomib and thalidomide have been combined (either as VMPT or VTP), the rate of PN was not significantly increased compared with VMP.10 and 51

Continual monitoring during treatment is critical; patients and physicians need to be continually alert for the signs of PN and/or emerging neuropathic pain, which typically occur during the first 2–4 months of bortezomib treatment,36 and 42 and within around 10 months of thalidomide treatment, 34 although longer duration of thalidomide therapy increases the risk of PN. 46 A neurotoxicity assessment tool such as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-Ntx] questionnaire is suitable for ongoing assessments. All symptoms of PN, including paresthesia, require immediate action, and monitoring for signs and symptoms of PN in patients receiving thalidomide is particularly important to prevent long-term and potentially irreversible damage. As there is currently no effective treatment for PN, dose modification is the most appropriate approach to PN management. Bortezomib: Dose-modification guidelines for bortezomib (as included in current FDA- and EMA-approved prescribing information) developed based on experience in SUMMIT and CREST phase II trials 52 and applied during the phase III APEX and VISTA trials, may be utilized; patients managed using these guidelines had a higher rate of resolution of PN than those who did not undergo dose modification, with no apparent adverse effects on response rate or survival. 42 Although in the initial recommendations, dose reduction was not suggested until grade 1 (with pain) or grade 2 PN emerged, in our practices, we reduce the dose as soon as there are consistent grade 1 symptoms, with the possibility of re-escalating if the symptoms don't worsen ( Table 5 ). 46 Thalidomide: Dose modification guidelines (as included in current FDA- and EMA-approved prescribing information) are well established. 34 In our practices, thalidomide-associated PN is managed in the same way as bortezomib-associated PN (described above).

Table 5 Recommended actions for bortezomib- or thalidomide-related neuropathic pain and/peripheral sensory or motor neuropathy. source: Adapted from Delforge M, et al. Lancet Oncol. 2010;11(11):1086–1095. 46

Peripheral neuropathy severity Potential action based on recent phase III studies
Bortezomib Thalidomide
Grade 1 (paresthesia, weakness and/or loss of reflexes) without pain or loss of function If the patient is on a biweekly schedule a : reduce current bortezomib dose by one level or prolong dosing interval to once weekly Continue to monitor patient with clinical examination. Consider reducing dose if symptoms worsen. However, dose reduction is not necessarily followed by improvement of symptoms
If the patient is already on a weekly schedule: reduce current bortezomib dose by one level
     
Grade 2 (interfering with function but not with activities of daily living) If the patient is on a biweekly schedule: reduce current bortezomib dose by one level or prolong dosing interval to once weekly Reduce dose or interrupt treatment and continue to monitor the patient with clinical and neurological examination. If no improvement or continued worsening of the neuropathy, discontinue treatment. If the neuropathy resolves to grade 1 or better, the treatment may be restarted, if the benefit/risk is favorable
If the patient is already on a weekly schedule: reduce current bortezomib dose by one level or consider temporary discontinuation of bortezomib. If the neuropathy resolves to grade 1 or better, once-weekly treatment with reduced bortezomib dose may be restarted if the benefit-to-risk ratio is favorable
     
Grade 3 (interfering with activities of daily living) Discontinue bortezomib b Discontinue thalidomide
     
Grade 4 (sensory neuropathy that is disabling or motor neuropathy that is life-threatening or that leads to paralysis) Discontinue bortezomib b Discontinue thalidomide

a Patients ≥ 75 years may initiate bortezomib on a once-weekly regimen.

b If the neuropathy resolves to grade 1 or better, once-weekly treatment with reduced bortezomib dose may be restarted if the benefit-to-risk ratio is favorable.

Building on existing dose-modification guidelines, recent phase III experience suggests that lower dose intensity of bortezomib achieved through once-weekly dosing in combination regimens may lower the risk of PN without impacting efficacy.10, 45, and 51 Suggested dosing modifications based on the results of these studies are shown in Table 5 and Table 6. In an Italian study involving 511 elderly, newly diagnosed MM patients treated with VMP or VMPT followed by VT maintenance, 10 the first 139 patients received twice-weekly bortezomib infusions and the last 372 patients were treated with once-weekly bortezomib. The incidence of all-grade sensory PN was significantly lower in patients who received once-weekly versus twice-weekly bortezomib (27% versus 46%, respectively; p < 0.001); rates of grade 3 or higher sensory PN were also lower with once-weekly dosing (3% versus 16%, respectively; p < 0.001). 10 Complete response rate was similar (30% versus 35% for once-weekly versus twice-weekly dosing; p = 0.27), and neither 3-year progression-free survival (PFS) nor OS was significantly lower in patients dosed once weekly compared with those dosed twice weekly (3-year PFS: 50% versus 47%, p = 1.00; 3-year OS: 88% versus 89%, p = 0.54). 45 In their recent phase III study comparing VMP and VTP induction in newly-diagnosed patients aged older than 65 years, 51 Mateos et al. administered bortezomib twice weekly for one 6-week cycle before switching to once-weekly bortezomib for the remaining five 5-week cycles. In this study, bortezomib plus melphalan/prednisone was associated with a 7% incidence of grade ≥ 3 PN; in comparison, twice-weekly dosing with bortezomib plus melphalan/prednisone in the VISTA trial was associated with a 13% incidence of grade ≥ 3 PN. 36 Bortezomib (plus thalidomide) may also be used within less intensive maintenance regimens without substantially increasing the risk of PN.10 and 51

Table 6 Dose modifications.

Dose reduction level Bortezomib a Thalidomide Lenalidomide
Full dose Twice-weekly infusion of 1.3 mg/m2 200 mg orally once daily 25 mg orally once daily for 21 days, every 28 days
Days 1, 4, 8, and 11 every 21 days
First dose reduction Once-weekly infusion of 1.3 mg/m2 100 mg orally once daily 15 mg orally once daily for 21 days, every 28 days
Days 1, 8, 15, and 22 every 35 days
Second dose reduction 1.0 mg/m2 once-weekly 50 mg orally once daily 10 mg orally once daily for 21 days, every 28 days
Days 1, 8, 15, and 22 every 35 days
Third dose reduction 0.7 mg/m2 once-weekly 5 mg orally once daily for 21 days, every 28 days
Days 1, 8, 15, and 22 every 35 days

a In the current summary of product characteristics for bortezomib, 50 dose reductions are recommended as 1.0 mg/m2 twice weekly (from 1.3 mg/m2) or 0.7 mg/m2 twice weekly (from 1.0 mg/m2).

Supportive care and symptomatic treatment may be considered; however, despite some evidence of beneficial effects,42 and 46 there is currently little evidence to support symptomatic treatment approaches. Early intervention with appropriate dose modification is, at present, the most appropriate way to manage PN. Nevertheless, physical exercise and physiotherapy can help to preserve muscle strength and improve coordination. Adequate fiber and fluid intake, stool softeners, and laxatives are recommended to prevent constipation, and adjustment of antihypertensives to prevent/manage orthostatic hypotension.

2.4. Gastrointestinal complications

The gastrointestinal complications of bortezomib treatment, which are generally mild, include nausea, diarrhea, vomiting, and constipation. Such AEs are common, with diarrhea, constipation, and vomiting occurring in 46%, 37%, and 33% of elderly patients receiving VMP, respectively. 6 Severe constipation with ileus may be related to bortezomib-induced autonomic neuropathy; however, information relating to this link is limited. 50 Diarrhea can be managed with a high fluid intake and anti-diarrhea drugs, if required, while anti-emetics can be prescribed for vomiting ( Table 1 ). Patients suffering constipation should be advised to maintain a high fluid intake and a high-fiber diet; stool softeners or osmotic laxatives may also be appropriate in more severe cases. In addition, recent research suggests that changing the bortezomib dosing schedule to once-weekly dosing may help reduce the incidence of gastrointestinal AEs. 51 If grade 3 or 4 gastrointestinal events occur, bortezomib should be withheld until symptoms have resolved to grade 1 or baseline; bortezomib may then be reinitiated at a lower dose (reduced by 1 dose level).

Gastrointestinal complications such as constipation and diarrhea are also common in patients receiving thalidomide- or lenalidomide-based therapy.19 and 34 For example, in elderly patients with MM, MPT was associated with a greater frequency of grade 1/2 constipation compared with MP (37% versus 13%, respectively). 39 Thalidomide and lenalidomide-associated gastrointestinal complications can generally be managed symptomatically, with dose reductions or interruptions required only rarely. 21

2.5. Infections

Infections such as pneumonia are a particular concern in elderly patients, with grade ≥ 3 events affecting around 9%, 5% and 7% of patients receiving Rd, MPT, or VMP, respectively.6, 8, and 20

Reactivation of latent varicella zoster virus (VZV) leading to herpes zoster has been linked to bortezomib therapy.6 and 53 Prophylaxis with antivirals can be used to greatly reduce the risk of VZV reactivation, 6 and is recommended for all patients receiving bortezomib. A number of different regimens might be employed: Acyclovir 400 mg orally twice or 3-times daily, valacyclovir 500 mg orally 3-times daily or famciclovir 500 mg orally 3-times daily. 54 In the VISTA trial, 13% and 4% of patients receiving VMP and MP, respectively, developed herpes zoster; this dropped to 3% in the VMP group after acyclovir prophylaxis was introduced. 6 Infections in general should receive appropriate treatment, and grade 3–4 infections require dose modifications ( Table 1 ). As for all combination therapies, patients are at greatest risk of infection during the first 3 months of bortezomib treatment; prophylaxis with cotrimoxazole is advised during this time to reduce the infection risk. When bortezomib is given in combination with MP, incidence of grade 3 or higher infection is around 7%, 6 likely resulting from immunosuppressive effects of the combination agents, as regimens such as once-weekly VTP show rates of less than 1%. 51

2.6. Cardiovascular disorders

Myocardial infarction has been reported in patients receiving lenalidomide, particularly those with predisposing cardiovascular risk factors. 19 Patients should be closely monitored and every effort should be made to minimize all modifiable risk factors such as smoking status, hypertension and hyperlipidemia.

Orthostatic/postural hypotension, although reported in around 13% of patients receiving bortezomib, is typically mild to moderate.50 and 55 In patients with a history of syncope, caution is advised when treating with bortezomib. Orthostatic or postural hypotension can be managed by adjusting antihypertensive medications, diuretics, rehydration, or administering mineral corticosteroids and/or sympathomimetics. Although no clear link between bortezomib and cardiac complications has been established, in patients receiving VTP, grade 3 or higher cardiac events were reported in 8.5% of patients compared with none in the VMP arm, and were the most frequent cause of death during induction. 51 As such, an accurate and upfront cardiac screening may be necessary in elderly patients and standard therapies should be used as appropriate for individual cardiac events; for example, beta blockers, ACE inhibitors, or diuretics.

2.7. Skin reactions

Up to one-fifth of patients receiving bortezomib may experience a rash 4, 5, and 6; this can be treated with diphenhydramine or hydrocortisone creams, though some patients may ultimately require low-dose oral prednisone. Skin reactions have been reported in around 3% of patients receiving thalidomide,8 and 37 and have also been observed in patients receiving lenalidomide. 19 In the case of a skin severe reaction (e.g. Stevens–Johnson Syndrome), treatment with either lenalidomide or thalidomide should be permanently discontinued. In patients receiving lenalidomide, it may be appropriate to merely interrupt treatment for other forms of skin reaction depending on severity, although discontinuation may be required.

2.8. Other frequent toxicities

Bortezomib: Fatigue is common among patients receiving bortezomib, affecting 29–42% of patients,4, 5, and 6 although most cases are mild to moderate. Once other causes of fatigue have been excluded (such as infection, depression, hypothyroidism, etc.), patients should be encouraged to increase their fluid intake and improve their nutritional intake. Thalidomide: Syncope and bradycardia have been associated with thalidomide; 34 patients should be monitored closely and dose reduction or discontinuation may be required. Somnolence is often observed in patients receiving thalidomide, affecting 6–8% patients;7 and 38 supportive care, as outlined above for bortezomib, may be of benefit, although some patients may discontinue therapy. 39 Lenalidomide: Fatigue is also observed in patients receiving lenalidomide and should be managed as outlined above for bortezomib. Some cases of hypothyroidism have been reported during lenalidomide therapy, thus thyroid function monitoring may be advisable.

3. Novel agents in specific patient populations

As a general guide, elderly patients with significant co-morbidities such as diabetes or cardiopulmonary disease should also undergo evaluation by the appropriate specialist before starting treatment with novel agents. This should be followed by another examination after treatment has commenced to monitor any impact on comorbid conditions.

3.1. Patients with renal impairment

Renal impairment is a frequent complication in MM and recent guidelines recommend rapid intervention to reverse renal dysfunction. 56

As the pharmacokinetics of bortezomib and thalidomide are not affected by the degree of renal impairment,57, 58, and 59 these agents can be used without dose reductions in patients with renal impairment.34 and 50Bortezomib: Bortezomib was highly active and well tolerated in MM patients with moderate renal impairment, 60 or advanced renal failure, 61 and has been shown to improve renal function.60 and 62 In combination with MP, bortezomib appears to reverse renal impairment at a more rapid rate than MP alone, in a greater proportion of patients. 60 A phase I study also indicated that bortezomib was well tolerated in patients with mild-to-severe renal impairment, including a small number of dialysis-dependent patients. 57 In dialysis-dependent patients, we suggest that bortezomib can be employed but should be administered 2–3 h after a dialysis procedure. As bortezomib can quickly achieve disease reduction, as evidenced by the short median time to response (1–2 months) reported in clinical studies,4 and 5 it is a particularly valuable treatment for patients with myeloma cast nephropathy, who benefit from rapid removal of deposited light chains. Thalidomide: Although there are limited data regarding the use of thalidomide in patients with renal impairment, a number of small-scale studies have shown that thalidomide is effective and well tolerated in these patients, including those undergoing dialysis.63, 64, and 65 Further, recovery of a normal renal function has also been reported following thalidomide therapy. 63 However, hyperkalemia has also been reported to occur, usually within the first few weeks of treatment.65 and 66 As such, recent guidance indicates that thalidomide should only be used in patients with renal impairment in the context of clinical trials. 56

Lenalidomide is substantially excreted by the kidneys. 67 Regular monitoring is advised in patients with renal impairment, 19 and, based on pharmacokinetic studies, recent guidelines recommend the following dose adjustments: 56 in patients with creatinine clearance (CrCl) of 30–50 mL/min, doses should be reduced to 10 mg/day; in patients with CrCl < 30 mL/min and who are not on dialysis, the dose should be reduced to 15 mg every other day; in dialysis patients, 5 mg once daily is recommended, with dosing post-dialysis.

3.2. Patients with hepatic impairment

As the exposure of bortezomib is increased in patients with moderate and severe hepatic impairment, 55 patients with impaired liver function should be treated with caution and a reduced bortezomib dose should be considered. Patients with mild hepatic impairment may not require any adjustment in starting doses; those with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2 during the first cycle, with a subsequent dose escalation to 1.0 mg/m2, or a dose reduction to 0.5 mg/m2, on the basis of patient tolerance. 55

Neither lenalidomide nor thalidomide have formally been studied in patients with hepatic impairment, thus there are no specific dose recommendations.19 and 34

3.3. Patients with bone disease

Patients with lytic bone disease should be managed with bisphosphonates according to standard guidelines; 68 no precautions or treatment modifications are required. In elderly patients, data suggest that bortezomib in combination with MP is associated with fewer skeletal AEs, lower use of bisphosphonates, and greater osteoblastic activation than MP alone. 69

3.4. Frail patients aged over 75 years

Like younger patients, individuals aged 75 years or over can still derive significant benefit from the addition of novel agents, although additional dose modifications ( Table 4 ) may be implemented for frail elderly patients. 70 Bortezomib: The addition of bortezomib to the MP regimen in this patient population, was associated with higher CR (26% versus 3%; p < 0.0001) and overall response rates (ORRs) (60% versus 40%; p = 0.005) versus MP, as well as longer time to progression and OS compared with MP alone. 71 Adverse event rates in older patients have generally been similar to the rates observed in patients aged less than 75 years, although the rate of serious AEs was higher in older patients. 71 Patients aged 65–75 years with impaired heart, lung, liver or renal function that is unrelated to MM, and all patients aged over 75 years, should receive once-weekly bortezomib at 1.3 mg/m2. Further dose reductions, to 1.0 mg/m2 then 0.7 mg/m2 once-weekly, may be considered. Appropriate dose reductions (starting dose/further reduction) for co-administered drugs are as follows: melphalan: 0.18/0.13 mg/kg days 1–4, or 7.5/5 mg/m2; dexamethasone: 20/10 mg/week, or substitute prednisone for improved tolerability; thalidomide: 100/50 mg/day. Thalidomide: In a study of thalidomide (100 mg/day, with reduction to 50 mg/day permitted as required) plus melphalan (0.2 mg/kg days 1–4 of a 6-week cycle) and prednisone (2 mg/kg days 1–4 of a 6-week cycle) in patients aged 75 years or over, the novel agent combination was superior to MP alone in terms of overall (44 versus 29 months; p = 0.028) and PFS (24 versus 18.5 months; p = 0.001). Toxicity was acceptable despite the greater frequency of PN and grade 3/4 neutropenia in the thalidomide arm. 38 This is comparable with results of a similar study in patients aged 65–75 years, where MPT (melphalan 0.25 mg/kg and prednisone 2 mg/kg for 4 days per 6-week cycle; thalidomide not exceeding 400 mg/daily) was superior to MP in terms of overall and PFS. 7 Lenalidomide: In a phase III study of lenalidomide plus MP, the efficacy of MPR and MP in patients aged > 75 years was similar between treatments, whereas in patients aged 65–75, MPR was associated with significantly longer PFS compared with MP (HR 0.675; p = 0.030). 15 This may have been related to a higher discontinuation rate due to AEs in patients aged > 75 years receiving MPR (19%) versus MP (8%). However, addition of lenalidomide maintenance therapy in patients aged > 75 years resulted in a 61% reduction in the risk of disease progression.

A tailored approach to treatment is particularly important for these older individuals. Careful attention should be paid to emerging AEs, and treatment modified accordingly. In these more fragile patients, the occurrence of a grade 4 hematologic or grade 3 non-hematologic adverse event should prompt immediate treatment cessation until the adverse event resolves to grade 1; treatment may then be re-started at a reduced dose, as described above. In addition to dose modifications, consideration should also be given to additional supportive care and attention from oncology nurses for these patients at highest risk of serious AEs.

4. Optimal use of bortezomib: experience from phase III studies

Clinical studies have clearly established an important ongoing role for bortezomib in the management of MM, and research into alternative regimens incorporating bortezomib that may further improve outcomes while minimizing toxicity in older patients is continuing. A recent report from a large phase III Italian study involving patients aged 65 years or older indicates that VMPT followed by VT maintenance produces a significantly higher response rate post-induction (CR: 38% versus 24%, p < 0.001; ≥ PR 89% versus 81%, p = 0.01) and 3-year PFS (56% versus 41%; p = 0.008) compared with VMP alone. 10 At 3 years, the proportion of patients who did not proceed to next therapy was also significantly greater in the VMPT-VT arm compared with VMP (72% versus 60%; p = 0.007). 10 Thus, the addition of thalidomide to the standard VMP regimen increases response rates, while maintenance therapy prolongs remission. The PFS and time to next therapy rates in this study are notable as such outcomes are unprecedented in elderly patients. In a sub-analysis of patients aged 75 years or older, there was, however, no significant difference between the two treatment arms. 72 In the entire patient population, the incidence of grade 3/4 PN was not significantly increased by the addition of thalidomide (8% for VMPT-VT versus 5% for VMP; p = 0.19); however, significantly more patients experienced grade 3/4 neutropenia (38% versus 28%; p = 0.02) and cardiac complications (10% versus 5%; p = 0.04) in the VMPT-VT group than the VMP group. 10 In patients aged 75 years or older, the incidence of non-hematologic events, cardiac events and treatment discontinuation due to AEs was higher in patients receiving VMPT-VT compared with VMP. 72 On the basis of these results, VMPT-VT is a more appropriate choice than VMP for patients aged 65–75 years; however, VMP remains the best option for patients aged over 75 years or with comorbidities, due to its more favorable toxicity profile.

Another large, phase III, Spanish study has investigated whether melphalan or thalidomide is a better partner for bortezomib in elderly patients, and whether reduced intensity induction can minimize toxicity while maintaining efficacy. 51 Patients were randomized to receive either VMP or VTP induction; following induction patients were randomized to maintenance with either VT or VP. In both arms, induction consisted of one 6-week cycle of twice-weekly bortezomib and five 5-week cycles of once-weekly bortezomib. Results indicated that the modified induction schedules produced similar CR rates, at 20% and 28% for VMP and VTP, respectively; ORR (≥ PR) was 80% and 81%, respectively. Similarly, there were no significant differences in PFS and 3-year OS between the two arms. Maintenance therapy increased the CR rate to 44% and 39% in the VTP and VMP arms, respectively. The two regimens did, however, produce different AE profiles; during induction there was a higher incidence of grade 3 or higher neutropenia in the VMP arm (39% versus 22%) and a higher rate of grade 3 or greater infections (7% versus 1%). In contrast, the incidence of grade 3 or higher PN was lower in the VMP arm than the VTP arm (7% versus 9%; p = not significant), as was the incidence of cardiac events (0% versus 8%; p = 0.001).

In this Spanish study, 51 the median PFS for all patients was 31 months and the median TTP was 35 months. Similarly, in the Italian study, 10 median PFS for patients receiving weekly bortezomib in a VMP combination was 27.3 months. These data compare favorably with the median time to progression of 24 months reported in the VISTA study, 6 and with data reported for MPT schemas, which show median PFS of 13–27.5 months.7, 9, and 39 The experiences of the Spanish and Italian phase III trials evaluating once-weekly administration of bortezomib,10 and 51 demonstrate that the therapeutic approach of reduced-intensity induction followed by maintenance with a bortezomib-based therapy, resulted in high efficacy with a favorable tolerability profile. This improved tolerability yet similar efficacy was likely related with the similar total delivered doses of bortezomib in the once- versus twice-weekly regimens. This was evaluated further in the Italian trial, 10 which reported that patients in the twice-weekly and once-weekly groups received median cumulative doses of 40.1 mg/m2 and 39.4 mg/m2, respectively. This corresponded to a dose intensity of 59% for twice-weekly and 84% for once-weekly regimens, supporting the hypothesis that a once-weekly schedule of bortezomib can reduce the rate of discontinuation and prolong time on therapy, with positive effects on the length of remission.

Finally, interim results from a prospective, community-based phase IIIb study in elderly newly diagnosed patients indicated that response rates and outcomes were similar when standard-dose bortezomib was given in combination with either dexamethasone (VD), thalidomide and dexamethasone (VTD), or melphalan and prednisone (VMP); 73 ORR was 69%, 79%, and 72% in the VD, VTD, and VMP arms, respectively, including 36%, 44%, and 39% VGPR or better. grade 3 or higher AEs were experienced by 69%, 82%, and 79% of patients in the VD, VTD, and VMP arms, respectively. PN occurred most frequently in the VTD arm, at 59%, compared with 41% for VD and 43% for VMP; similar trends were seen for grade 3 or higher PN (25% versus 14% and 19%, respectively). Rates of DVT were 7%, 4%, and 2% with VD, VTD, and VMP, respectively.

5. Optimal use of thalidomide: experience from phase III studies

A number of different doses and schedules of thalidomide have been evaluated in phase III studies of older patients with MM,7, 8, 9, 37, 38, 39, 51, and 74 providing scope for tailoring treatment in this population to the individual patient.

In a study by Waage et al. 39 patients not eligible for transplant received thalidomide (200 mg daily [week 1], 400 mg daily thereafter) in combination with melphalan (0.25 mg/kg on days 1–7) and prednisone (100 mg daily for 4 days every 6 weeks). This combination, in a population with a median age of 75 years, resulted in a median survival of 29 months and a median PFS of 15 months. In an Italian study, 8 a lower dose of thalidomide (100 mg daily) was used in combination with melphalan (4 mg/m2 on days 1–7) and prednisone (40 mg/m2 on days 1–7). As comparable response rates to Waage et al. were observed in terms of CR (15.5% versus 13%, respectively), the potential for fewer AEs and discontinuations while maintaining a respectable CR rate, makes lower dose thalidomide an attractive option for elderly patients. The dose of melphalan as part of an MPT regimen in elderly patients can also be optimized according to individual patient factors. Favorable results have been reported for melphalan at both higher (0.25 mg/kg) 39 and lower (4 mg/m2) 8 doses; thus the dose of melphalan can be reduced according to age and comorbidities from 0.25 to 0.18 to 0.13 mg/kg as appropriate. The importance of tailoring doses according to patient age and comorbidities is evident across the phase III clinical studies of patients with newly diagnosed MM.7, 8, 9, 37, 38, and 39 In those studies where the age of the patient population was less stringently defined (e.g. Waage et al. 39 ), no significant differences in survival outcomes were reported between those patients receiving MPT and those receiving MP alone. This was most likely due to the high proportion of elderly/very elderly patients who were less able to tolerate treatment, and who, as a consequence, were more likely to discontinue, thus receiving a lower cumulative dose of therapy than planned. As these patients who discontinue therapy early will derive less benefit from treatment, to gain maximum benefit, doses should be optimized to a tolerable level that enables patients to remain on therapy for longer.

6. Optimal use of lenalidomide: experience from phase II/III studies

Lenalidomide plus dexamethasone is a highly active regimen in the treatment of MM, with low-dose dexamethasone offering a better safety profile. 20 A recent study by Rajkumar et al., 20 aimed to determine the impact of high- or low-dose dexamethasone in combination with lenalidomide. Treatment-naïve patients with myeloma (n = 445) were randomized to receive lenalidomide 25 mg daily with either low-dose (40 mg on days 1, 8, 15, and 22 of a 21-day cycle) or high-dose (40 mg on days 1–4, 9–12, and 17–20 of a 21-day cycle) dexamethasone. Although the ORR in patients receiving the high-dose dexamethasone regimen was superior to the low-dose regimen (81% versus 70%; p = 0.009), one-year overall survival was significantly shorter in patients receiving the high-dose regimen (87% versus 96%, respectively; p = 0.0002). Furthermore, a greater proportion of patients in the high-dose group reported grade ≥ 3 AEs in the first 4 months (52%) compared with 35% of patients receiving low-dose dexamethasone. Thus the lower-dose of dexamethasone is now preferred in patients receiving lenalidomide, leading to improved outcomes and a more favorable toxicity profile.

The addition of lenalidomide maintenance therapy after lenalidomide plus MP treatment also represents an attractive option in newly diagnosed elderly patients. Recently presented data from a phase III study indicated that, in patients with myeloma aged ≥ 65 years, addition of lenalidomide (25 mg/day) ± dexamethasone resulted in a substantial median PFS of 31 months. 15

Studies such as these, investigating different combinations, intensities and schedules, will not only build upon the knowledge gained during phase II and III studies, but should allow physicians to individualize treatment to minimize toxicity and maximize outcomes. For example, the most appropriate regimen for patients with a history of cardiac or thromboembolic events may be VMP rather than VTP; similarly, VMP may be a better choice if minimizing the risk of PN is a goal. In contrast, VTP may be more appropriate for patients with low neutrophil counts. Such knowledge will be of particular benefit for elderly patients and those who are at highest risk of AEs.

7. Conclusion

The novel agents bortezomib, thalidomide and lenalidomide are highly active in MM. Associated AEs require appropriate management to ensure that optimal dosing is maintained to maximize benefit while minimizing the risks of therapy. The key AEs associated with these novel agents can be substantially managed either through the use of prophylaxis and supportive care, or by careful monitoring and dose reduction/alternative dosing strategies; for example, once-weekly dosing schedules of bortezomib have shown promise as an additional strategy to reduce PN while maintaining efficacy. The experience from the phase III studies of novel agents in elderly patients has provided many valuable indications for optimizing therapy in this population, through attenuation of therapy, or other supportive strategies, to enable physicians to improve treatment for these patient populations. For elderly patients and those without the option of stem cell transplantation, a good outcome from front-line therapy is critical. To achieve this, patients need to receive the best possible therapy for as long as is feasible, a goal that is most likely to be achieved through careful attention to, and management of, treatment-related AEs.

Conflict of interest statement

AP has served on advisory committee for Celgene and Janssen-Cilag and received honoraria from Celgene, Janssen-Cilag, Merck, Amgen.

MVM and JSM have received honoraria from Celgene and Janssen-Cilag.

SB has received honoraria from Celgene, Janssen-Cilag, and Novartis, and has served on the advisory committee for Merck Sharp & Dohme.

Acknowledgments

The authors would like to acknowledge the medical writing assistance of Catherine Crookes of FireKite in the development of this article, which was funded by Millennium Pharmaceuticals Inc.

References

  • [1] S. Altekruse, C. Kosary, M. Krapcho, et al. SEER Cancer Statistics Review 1975–2007. based on November 2009 SEER data submission, posted to the SEER website (, 2011) http://seer.cancer.gov/csr/1975_2007/ Accessed 12 January 2011
  • [2] M. Engelhardt, M. Kleber, J. Udi, et al. Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches. Leuk Lymphoma. 2010;51(8):1424-1443
  • [3] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™ multiple myeloma (version 1.2011). http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf Accessed 28 January 2011
  • [4] P.G. Richardson, B. Barlogie, J. Berenson, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609-2617
  • [5] P.G. Richardson, P. Sonneveld, M.W. Schuster, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498
  • [6] J.F. San Miguel, R. Schlag, N.K. Khuageva, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917
  • [7] T. Facon, J.Y. Mary, C. Hulin, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial. Lancet. 2007;370(9594):1209-1218
  • [8] A. Palumbo, S. Bringhen, T. Caravita, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367(9513):825-831
  • [9] P. Wijermans, M. Schaafsma, F. Termorshuizen, 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):3160-3166
  • [10] A. Palumbo, S. Bringhen, D. Rossi, et al. Bortezomib–melphalan–prednisone–thalidomide followed by maintenance with bortezomib–thalidomide compared with bortezomib–melphalan–prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28(34):5101-5109
  • [11] M. Dimopoulos, A. Spencer, M. Attal, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-2132
  • [12] D.M. Weber, C. Chen, R. Niesvizky, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-2142
  • [13] A. Palumbo, P. Falco, G. Benevolo, et al. A multicenter, open label study of oral lenalidomide and prednisone (RP) followed by oral lenalidomide melphalan and prednisone (MPR) and oral lenalidomide maintenance in newly diagnosed elderly multiple myeloma patients. Blood. 2010;116(21):1940
  • [14] M.V. Mateos, P.G. Richardson, R. Schlag, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266
  • [15] A. Palumbo, M. Delforge, J. Catalano, et al. A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients > = 65 years with newly diagnosed multiple myeloma (NDMM): continuous use of lenalidomide vs fixed-duration regimens. Blood. 2010;116(21):622
  • [16] S. Lonial, P.G. Richardson, M.J. San, et al. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol. 2008;143(2):222-229
  • [17] P. Richardson, R. Schlag, N. Khuageva, et al. Bortezomib and melphalan as part of VMP are associated with similar hematologic toxicity to MP alone [abstract]. Clin Lymphoma Myeloma. 2009;9(Suppl 1) Abstract 220
  • [18] GlaxoSmithKline. Alkeran prescribing information. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=35194#nlm34084-4 . Accessed 17 August 2010.
  • [19] Celgene. Lenalidomide summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000717/WC500056018.pdf . Accessed 28 January 2011.
  • [20] S.V. Rajkumar, S. Jacobus, N.S. Callander, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11(1):29-37
  • [21] A. Palumbo, M. Dimopoulos, M.J. San, et al. Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Blood Rev. 2009;23(2):87-93
  • [22] P. Richardson, K. Liu, W. Deraedt, et al. Erythropoiesis-stimulating agents: no impact on long-term outcome in MM patients in the VISTA trial [abstract]. Clin Lymphoma Myeloma. 2009;9(Suppl 1) Abstract 217
  • [23] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™ cancer- and chemotherapy-induced anemia (version 2.2011). http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf (2011) Accessed 28 January 2011
  • [24] Medice Arzneimittel Pütter GmbH & Co.KG. Abseamed summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000727/WC500020661.pdf (2011) Accessed 12 January 2011
  • [25] B.V. Amgen Europe. Aranesp summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000332/WC500026149.pdf (2011) Accessed 12 January 2011
  • [26] M. Zangari, B. Barlogie, C.K. Lee, et al. Protective effect of VELCADE(R) on thalidomide associated deep vein thrombosis (DVT). Blood. 2004;104(11):4914
  • [27] L. Rosiñol, M.T. Cibeira, M.V. Mateos, et al. A phase III PETHEMA/GEM study of induction therapy prior autologous stem cell transplantation (ASCT) in multiple myeloma: superiority of VTD (bortezomib/thalidomide/dexamethasone) over TD and VBMCP/VBAD plus bortezomib. Blood. 2010;116(21):307
  • [28] M. Zangari, L.M. Fink, F. Zhan, G.J. Tricot. Bortezomib does not increase thromboembolic risk in multiple myeloma and may offer a protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Blood. 2009;114(22):1873
  • [29] G.H. Lyman, A.A. Khorana, A. Falanga, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505
  • [30] S. Iyengar, E. Jacob, R. Ayto, et al. Improving clinical outcomes of venous thromboprophylaxis in multiple myeloma. Online J Clin Audits. 2010;2(3):20-29
  • [31] B. Barlogie, R. Desikan, P. Eddlemon, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001;98(2):492-494
  • [32] P.G. Richardson, R.L. Schlossman, E. Weller, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002;100(9):3063-3067
  • [33] A. Palumbo, S.V. Rajkumar, M.A. Dimopoulos, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-423
  • [34] Celgene. Thalidomide summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000823/WC500037050.pdf . Accessed 17 August 2010.
  • [35] A. Palumbo, M. Cavo, S. Bringhen, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29(8):986-993
  • [36] M.A. Dimopoulos, M. Mateos, P.G. Richardson, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol. 2011;86(1):23-31
  • [37] M. Beksac, R. Haznedar, T. Firatli-Tuglular, 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
  • [38] C. Hulin, T. Facon, P. Rodon, 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):3664-3670
  • [39] A. Waage, P. Gimsing, P. Fayers, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116(9):1405-1412
  • [40] J.J. Kelly. The evaluation of peripheral neuropathy. Part I: clinical and laboratory evidence. Rev Neurol Dis. 2004;1(3):133-140
  • [41] A.A. Argyriou, G. Iconomou, H.P. Kalofonos. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112(5):1593-1599
  • [42] P.G. Richardson, P. Sonneveld, M.W. Schuster, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009;144(6):895-903
  • [43] C. Tofthagen. Patient perceptions associated with chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2010;14(3):E22-E28
  • [44] J. San Miguel, J. Blade, M. Boccadoro, et al. A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist. 2006;11(1):51-61
  • [45] S. Bringhen, A. Larocca, D. Rossi, et al. Efficacy and safety of once weekly bortezomib in multiple myeloma patients. Blood. 2010;116(23):4745-4753
  • [46] M. Delforge, J. Blade, M.A. Dimopoulos, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11(11):1086-1095
  • [47] P. Kapoor, S.V. Rajkumar, A. Dispenzieri, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011; Prepublished on 14 January 2011 as doi:10.1038/leu.2010.313
  • [48] A. Broyl, S.L. Corthals, J.L. Jongen, et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010;11(11):1057-1065
  • [49] R. Favis, Y. Sun, H. van de Velde, et al. Genetic variation associated with bortezomib-induced peripheral neuropathy. Pharmacogenet Genomics. 2011;21(3):121-129
  • [50] Millennium Pharmaceuticals Inc. Velcade summary of product characteristics. Accessed 17 August 2010.
  • [51] M.V. Mateos, A. Oriol, J. Martinez-Lopez, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11(10):934-941
  • [52] P.G. Richardson, H. Briemberg, S. Jagannath, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24(19):3113-3120
  • [53] A. Chanan-Khan, P. Sonneveld, M.W. Schuster, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26(29):4784-4790
  • [54] M. Nucci, E. Anaissie. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49(8):1211-1225
  • [55] Millennium Pharmaceuticals Inc. VELCADE® (bortezomib) for injection. Prescribing information. Cambridge, MA, USA (, 2009) Rev 10: Issued December 2009
  • [56] M.A. Dimopoulos, E. Terpos, A. Chanan-Khan, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28(33):4976-4984
  • [57] D. Mulkerin, S. Remick, C. Takimoto, et al. Safety, tolerability, and pharmacology of bortezomib in cancer patients with renal failure requiring dialysis: results from a prospective phase 1 study [abstract]. Blood. 2007;110:1018a-1019a
  • [58] A. Arai, A. Hirota, T. Fukuda, et al. Analysis of plasma concentration of thalidomide in Japanese patients of multiple myeloma with renal dysfunction [in Japanese]. Rinsho Ketsueki. 2009;50(4):295-299
  • [59] T. Eriksson, P. Hoglund, I. Turesson, et al. Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis. J Pharm Pharmacol. 2003;55(12):1701-1706
  • [60] M.A. Dimopoulos, P.G. Richardson, R. Schlag, et al. VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 2009;27(36):6086-6093
  • [61] A.A. Chanan-Khan, J.L. Kaufman, J. Mehta, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. 2007;109(6):2604-2606
  • [62] M.A. Dimopoulos, H. Roddie, M. Beksac, et al. Randomized phase 2 trial of bortezomib–dexamethasone (VD) versus VD plus cyclophosphamide or lenalidomide in myeloma patients achieving stable disease after 4 cycles of VD as second-line treatment [abstract]. Haematologica. 2010;95(Suppl 2):144 Abstract 0366
  • [63] P. Tosi, E. Zamagni, C. Cellini, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol. 2004;73(2):98-103
  • [64] P. Tosi, E. Zamagni, P. Tacchetti, et al. Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency. Biol Blood Marrow Transplant. 2010;16(8):1115-1121
  • [65] F. Fakhouri, H. Guerraoui, C. Presne, et al. Thalidomide in patients with multiple myeloma and renal failure. Br J Haematol. 2004;125(1):96-97
  • [66] E. Harris, J. Behrens, D. Samson, et al. Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia. Br J Haematol. 2003;122(1):160-161
  • [67] N. Chen, H. Lau, L. Kong, et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol. 2007;47(12):1466-1475
  • [68] E. Terpos, O. Sezer, P.I. Croucher, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20(8):1303-1317
  • [69] M. Delforge, M. Kropff, I. Spicka, et al. VMP results in fewer bone events and greater ALP increases versus MP in the VISTA study in front-line MM [abstract]. Clin Lymphoma Myeloma. 2009;9(Suppl 1) Abstract 246
  • [70] A. Palumbo, F. Gay. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology. 2009;:566-577
  • [71] M. Kropff, P. Richardson, R. Schlag, et al. Similar benefit in patients aged ≥ 75 years versus < 75 years with VMP in first-line MM and bortezomib in relapsed MM [abstract]. Clin Lymphoma Myeloma. 2009;9(Suppl 1) Abstract 084
  • [72] A. Palumbo, S. Bringhen, D. Rossi, et al. A prospective randomized trial of bortezomib-melphalan-prednisone-thalidomide followed by continuous bortezomib-thalidomide for initial therapy of multiple myeloma: effect of age and co-morbidities [abstract]. Haematologica. 2010;95(Suppl 2) Abstract 0568
  • [73] R. Niesvizky, J. Reeves, I.W. Flinn, et al. Phase 3b UPFRONT study: interim results from a community-based prospective randomized trial evaluating three bortezomib-based regimens in elderly, newly diagnosed multiple myeloma patients [abstract]. Haematologica. 2010;95(Suppl 2):144 Abstract 0358
  • [74] A. Palumbo, S. Bringhen, A.M. Liberati, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112(8):3107-3114

Footnotes

a Myeloma Unit, University of Torino, Azienda Ospedaliero-Universitaria (A.O.U.) S. Giovanni Battista, Torino, Italy

b Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Salamanca, Spain

lowast Corresponding author at: Myeloma Unit, University of Torino, Azienda Ospedaliero-Universitaria (A.O.U.) S. Giovanni Battista, via Genova 3, 10126 Torino, Italy. Tel.: + 39 0116 334260; fax: + 39 0116 963737.