Quality of life and supportive care in multiple myeloma.

INTRODUCTION

Introduction Multiple myeloma (MM) is the second most common haematological malignancy, comprising an estimated 1% of all cancers with an incidence of about 4.5 cases per 100,000 per year [ 1 ]. Significant progress in the treatment of MM has been achieved in the past 5 years [ 2 , 3 , 4 ]. Novel therapies led to improvement in survival, which resulted in an increasing symptom burden due not only to the disease itself, but also to the cumulative effects of treatments [ 5 ]. The significant challenge of current myeloma management is matching the progress made in improved survival through disease control while optimising quality of life with effective supportive care from initial diagnosis to end-of-life care [ 5 ].

It is difficult to define clearly the meaning of the term “quality of life” and it carries different senses for everyone. It involves broad concepts that affect overall life contentment, including good health, adequate housing, employment, personal and family safety, interrelationships, education, and leisure pursuits. Therefore, the life satisfaction most affected by health or illness is defined by the term “health-related quality of life” (HRQoL) [ 6 , 7 ]. Related to HRQoL, we can define supportive care as the treatment given to prevent, control, or relieve complications and side effects and to improve the patients’ and their families’ comfort and quality of life.

Quality of Life Questionnaires

Karnofsky and Burchenal developed a clinical scale to quantify the functional performance of cancer patients in 1949 [ 8 , 9 ] ( Table 1 ). Systematic assessment of HRQoL in cancer patients has received increasing interest over the past 2 decades. Cella et al. defined several advantages to including comprehensive HRQoL surveys in symptom trials in oncology. The most obvious is to test the hypothesis that HRQoL will be improved in addition to the symptom benefits [ 10 ]. Nevertheless, assessment of HRQoL has become an important focus of benefit for the treatment of patients with neoplastic diseases [ 11 ]. Wisloff reported that measurement of HRQoL before and during treatment contributes important prognostic information [ 12 ]. Therefore, it is very important to choose proper assessments and questionnaires. Effective and reliable questionnaires that include generic health status instruments, generic illness instruments, and disease-specific instruments are available for assessment of HRQoL [ 13 ]. Among the most widely used cancer questionnaires are the Functional Living Index-Cancer (FLIC), the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-30, a specifically designed instrument for use among patients with MM known as the EORTC QLQ-MY20, and the Functional Assessment of Cancer Therapy (FACT) scale. Moreover, a disease-specific form of the FACT scale was developed through a structured iterative process for MM patients, called FACT-MM. This questionnaire incorporates open-ended questions with classic survey methods, detecting both known and new HRQoL issues for MM patients and the health care providers who treat them [ 4 ]. Etto et al. support the use of the EORTC QLQ-C30 as part of routine clinical care in MM patients in developing countries. Their results also suggest that the QLQ-C30 questionnaire for cancer patients seems to be more informative and easier to complete for the patients than the generic questionnaire [5]. The QLQ-C30 incorporates 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health and quality-of-life scale, and some single symptom measures. It is available in 16 languages. The EORTC QLQ-MY20 is meant for use among MM patients varying in disease stage and treatment modality (i.e. surgery, chemotherapy, radiotherapy, and hormonal treatment). It should always be complemented by the QLQ-C30. Therefore, it remains difficult to determine the best questionnaire for measurement purposes and patient groups [ 14 ].

In 2005, the Eastern Cooperative Oncology Group (ECOG) launched a clinical trial (E1A05) to evaluate a new treatment regimen for MM. HRQoL was determined to be a secondary goal for this trial, with the purpose of quantifying treatment-induced reduction of disease-specific symptoms as well as treatment-related symptoms and toxicities. Based on a comprehensive literature search, the authors concluded that no HRQoL instrument existed to adequately capture key MM symptoms and concerns from the patient’s perspective. This led to collaboration among the ECOG Myeloma, Patient Outcomes and Survivorship, and Patient Representative committees to develop a patient-reported outcome (PRO) measure to assess MM symptoms and concerns [4]. The task force identified several types of measures that fall under the PRO umbrella, including HRQoL, functional status, symptom status, overall well-being, satisfaction with care, and treatment adherence.

What Affects the Quality of Life?

Previous studies have demonstrated that the most common physical symptoms indicated by MM patients at presentation are especially skeletal pain and fatigue. Despite significant improvements in the treatment of MM, it remains a chronic incurable disease that is associated with reduced HRQoL due to spontaneous fractures, spinal cord compression, osteolytic lesions, recurrent infections, renal failure, anaemia, mood disorders accompanied by reduced physical functioning, and side effects of different types of treatment used to control this disease [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. It is an important point that myeloma patients are typically in their sixth to seventh decade of life and have comorbidities. Although the influence of comorbidities in MM patients is yet unsettled, it has been demonstrated to affect progression-free survival and overall survival [ 22 ]. This can be considered as an important factor affecting the quality of life. Kleber et al. suggested that assessing the comorbidity status in MM, rather than considering specific age cut-offs alone, may allow better definition of patients’ status, more tolerability of treatment, and more knowledge about the best treatment allocations in upcoming patient cohorts [ 22 ]. Concern for the future and loss of labour are other contributing concerns that affect quality of life for younger patients. Blood tests raise anxiety and amplify the emotional effects of the disease. Wagner et al. reported that expert clinicians provided the highest HRQoL relevance ratings for bone pain, bodily pain, difficulty walking, tiring easily, feeling discouraged, interference with activities, and difficulty with self-care as a result of bone pain and fatigue. Quantitative ratings by patients identified sexual function, uncertainty about health, fatigue, weight gain, and emotional concerns, such as worry about new symptoms and difficulty planning for the future, as most relevant to HRQoL [ 4 ]. In a prospective population-based study HRQoL and disease-specific complaints of patients with MM up to 10 years after diagnosis were described [ 23 ]. The findings of this study showed that patients with MM experience a much lower HRQoL compared to the general population, irrespective of the number of years since diagnosis. Patients with MM reported mean decreases between baseline and 1-year follow-up scores for quality of life (74%), fatigue (50%), nausea and vomiting (71%), pain (59%), and dyspnea (66%). The most bothersome symptoms during the past week were tingling hands/feet (32%), back pain (28%), bone aches/pain (26%), pain in arm/shoulder (19%), and feeling drowsy (18%). Additionally, 37% worried about their future health, 34% thought about their disease, and 21% worried about dying [ 23 ].

Treatments and Quality of Life

Some studies have been conducted about the relationship between myeloma treatments and quality of life. Alegre et al. specified that patients with relapsed or refractory MM treated with long-term lenalidomide reported clinically relevant improvements in certain quality-of-life and symptoms scores regardless of treatment response [ 24 ]. Transplant-setting studies have shown that patients’ treatment can have a transient adverse impact on HRQoL [ 25 ], but response and improved long-term outcomes are associated with an overall improvement in HRQoL [ 25 , 26 ]. Etto et al. reported that autologous stem cell transplantation (ASCT) improved the quality of life in Brazilian MM patients [ 5 ]. Khalafallah et al. reported that dose-reduced tandem ASCT is well tolerated with low toxicity, although it has transient reduction in HRQoL during both transplants. Post-transplant follow-up showed significant improvement in overall HRQoL, reflecting positively on the overall disease outcome [ 27 ]. The activity of bortezomib was associated with improved HRQoL in a phase 3 APEX study [ 28 ]. Another phase 3 VISTA study showed that there were clinically expressive and statistically significant temporary reductions in HRQoL from baseline in patients receiving bortezomib-melphalan-prednisone (VMP) treatment and relatively lower HRQoL compared with patients treated with melphalan-prednisone (MP), associated with the toxicities arising from the addition of bortezomib to MP [ 29 ]. However, the results demonstrated that HRQoL is not compromised in the long term with VMP vs. MP. Moreover, analyses of bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. Additionally, Delforge et al. suggested that clinically and statistically significant improvements in several aspects of HRQoL may occur following response onset in patients achieving an overall response to therapy and particularly complete remission (CR), the rate of which was significantly higher with VMP vs. MP [ 29 ]. A recent analysis of the HOVON49 phase 3 trial of MP plus thalidomide (MPT) vs. MP alone in previously untreated elderly MM patients showed that the higher rates of toxicity associated with MPT, despite adversely affecting some HRQoL parameters during treatment, did not negatively affect global health scores vs. MP [ 29 , 30 ]. In a Nordic multicentre trial, 583 previously untreated MM patients were randomised to receive MP or MP + interferon α-2b at a dose of 5 million units subcutaneously, 3 days per week. During the first year of treatment the patients on interferon reported significantly more fever, chills, dry skin, fatigue, pain, nausea/vomiting, and appetite loss than the control patients. There was a moderate reduction of the global quality-of-life score and slight, nonsignificant, reductions of physical, emotional, cognitive, social, and role functioning scores. After the first year there were no statistically significant differences in any toxicity, symptoms, or quality-of-life scores, except for an increased frequency of dizziness in the interferon group [ 31 ].

Supportive

Care The role of the physician in combining life quality and supportive care in MM patients is important because effective supportive treatment results in improved quality of life. Although much of the supportive care can be provided by haematologists, in some patients symptomatic management is achieved through the collaboration of colleagues in the fields of palliative medicine, pain management, clinical oncology, and orthopaedics [ 6 ]. A study by Wagner et al. revealed that patients may not discuss more personal aspects of their illness experience (e.g., anxiety, uncertainty, and sexual function) with their physicians. Physicians should educate patients about cognitive dysfunction associated with treatment and should assess them for cognitive decline [ 4 ].

In addition to chemotherapy, prophylaxis and supportive treatment of bone destruction, pain, anaemia, renal failure, fatigue, infections, hypercalcaemia, and emotional distress are essential parts of the therapeutic management of myeloma patients. The concerted action of supportive therapies can significantly help to maximise the benefits of treatment and to improve the wellbeing of myeloma patients in phases of disease progression as well as during phases of remission. Management of symptoms in patients with myeloma at all stages should follow the principles of evidence-based palliative medicine [ 6 ]. Thus, some guidelines were constituted. The aim of these guidelines is to summarise a national consensus of the haematological community and colleagues involved in the supportive care of patients with myeloma [ 6 ]. The supportive care definition is sufficiently broad to cover not only symptomatic treatment and palliative care but also the wide range of management options considered to be ‘haematological supportive care’, including anti-infectives, transfusion therapy, anticoagulation, and growth factors [ 6 ].

Supportive Care for Bone Disease

Bone pain, particularly in the spine and chest, is the major symptom in MM, which presents at diagnosis in more than two-thirds of patients. Osteolytic lesions, fractures of long bones, vertebral collapse, and plasmacytomas, which directly affect neural tissues, are the most common causes of bone pain. Later in the course of the disease, pain often arises as a side effect of therapies, e.g., thalidomide or bortezomib neuropathy [ 32 ]. Long bone fractures usually require stabilisation by surgical fixation. Radiotherapy may be used as the sole treatment in selected cases, but it should be applied to all lesions prone to fracture. A single 8-10-Gy fraction is recommended [ 32 ]. Vertebroplasty by percutaneous injection of low-viscosity liquid bone cement into the vertebral body has been used for pain relief in patients with spine involvement [ 33 ]. Kyphoplasty involves the creation of a cavity in the vertebral body and filling it with highly viscous cement, which will result in complete or partial restoration of the collapsed vertebral body. Analgesics, bed rest, and bracing are the other interventions, whose benefits are limited. Some patients may present with or develop instability of their spine or root compression because of primary disease or complications of vertebroplasty, requiring orthopaedic or neurosurgical interventions. Bisphosphonates inhibit bone destruction by blocking the osteoclasts’ recruitment from progenitor cells, suppressing migration, proliferation, and differentiation of osteoclasts and inducing apoptosis of osteoclasts and myeloma cells. Bisphosphonates also inhibit the production of matrix metalloproteinase I and IL-6, which is the most important growth hormone for myeloma cells [ 33 , 34 , 35 , 36 , 37 ]. The efficacy of clodronate, pamidronate, and zoledronate in preventing bone lesions has been investigated in several randomised trials, while for ibandronate limited data from randomised trials are available [ 32 ]. Additionally, a network meta-analysis showed superior overall survival with zoledronate compared with etidronate and a placebo. However, there was no difference between zoledronate and other bisphosphonates [ 38 ]. Recommended regimens of bisphosphonates are shown in Table 2 . Pain improved and quality-of-life and performance statuses were better in patients who received bisphosphonates [33]. Bisphosponate-induced jaw osteonecrosis is an increasingly recognised complication of bisphosphonate therapy that was first described in 2003. Current evidence suggests that the risk is greater for jaw osteonecrosis with zoledronate than with other bisphosphonates. Cumulative dose and duration of treatment are important factors that play a role in this complication [ 39 ]. The risk increases in patients who have been taking bisphosphonates for more than 3 years [33]. Thus, bisphosphonates should be discontinued after 2 years of therapy in patients who have achieved CR and/or a plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be tapered to 1 dose every 3 months [ 32 ].

Supportive Care for Anaemia

Anaemia affects more than two-thirds of MM patients [ 33 ]. Anaemia is promoted by erythropoietin deficiency, shortened existence of red blood cells, death of immature erythroblasts due to the Fas ligand and TRAIL, decreased responsiveness of the erythron to proliferative signals of erythropoietin, and the myelosuppressive effect of the chemotherapy [ 32 , 33 ]. Anaemia may be managed by red blood cell transfusions in the short-term in a symptomatic patient or by treatment with erythropoiesis-stimulating agents (ESAs) [ 6 ]. The improvement with transfusion is transient, and repeated transfusions will be required at intervals of 2-3 weeks. Transfusions have some risks, such as immunological reactions, infections, volume and iron overload, and, in rare cases, even induction of graft-versus-host disease [ 40 ]. The high efficacy of erythropoietin in myeloma was documented as early as 1990 in a study on a small number of patients [ 41 ]. This pilot study’s findings have been confirmed by several phase 2 and 3 studies. ESAs are the preferred option as they decrease the frequency of transfusions, increase the mean haemoglobin levels, and improve quality of life and performance status [ 42 , 43 ]. It is recommended to start ESAs in patients with haemoglobin levels below 10 g/dL or with haemoglobin levels below 12 g/dL if symptoms due to anaemia are already present [ 44 ]. Patients with mild anaemia (Hb 12 g/dL) should be treated because a higher improvement in quality of life occurs when the haemoglobin level increases from 12 to 13 g/dL [ 33 ]. However, British guidelines suggest that the haemoglobin concentration should not rise above 120 g/L [ 45 ]. Treatment should be initiated with erythropoietin α or β at a dose of 10,000 U 3 times a week or at 30,000 U or 40,000 U once weekly, or with darbepoetin at 150 mg weekly or 500 mg every 3 weeks. The dose can be doubled after 4 weeks in patients with haemoglobin increases of <10 g/dL. ESA treatment should be stopped after 6-8 weeks if there has been no haemoglobin response. ESA doses of <20,000 U/week may be adequate in patients where renal disease is the main cause of the anaemia [ 6 ]. American Society of Hematology and American Society of Clinical Oncology guidelines recommend ESAs to be administered at the lowest dose possible and the haemoglobin to be increased to the lowest concentration possible to avoid transfusions [46]. There is an increased risk of thrombotic events and hypertension in patients with cancer who are treated with ESAs [ 32 ]. There is a significant improvement in quality of life with a better sense of wellbeing, better exercise capacity, less fatigue, and abrogation of transfusion needs in patients responding to ESAs [ 47 , 48 , 49 ].

Supportive Care for Infections

Infections, especially bacterial infections, are frequent complications of MM. Augustson et al. reported that up to 10% of myeloma patients die within 60 days after the diagnosis because of infective causes [ 50 ]. Increased predisposition to infections in myeloma is caused by deficits in humoral and cellular immunity, suppression of production of polyclonal immunoglobulins, and use of high-dose steroids in elderly patients or those with poor performance. Active disease is a risk factor for infections. Administration of trimethoprim/sulfamethoxazole at 160 mg/800 mg, twice daily orally during the first 2 months of conventional induction chemotherapy, resulted in significantly decreased frequencies and severities of bacterial infections [ 51 ], but routine usage is not recommended because of antibiotic resistance and increased Clostridium difficile infection [ 6 ]. Although scientific data on antibiotic prophylaxis are insufficient, several studies suggested that prophylactic antimicrobial therapy should be based on the patient’s risk factors, such as previous history of infections and the type and dose of myeloma therapy [ 32 ]. Chapel et al. reported that replacement of intravenous immunoglobulin (IVIG) monthly for 1 year reduced the frequency and severity of infections in plateau-phase patients [ 52 ]. A dose of IVIG of 500 mg/kg administered every month for up to 6 months is recommended by guidelines for patients who suffer from recurrent infections and hypogammaglobulinaemia [ 6 , 32 ]. Patients treated with vincristine-adriamycin-dexamethasone (VAD), high-dose dexamethasone, or a bortezomib-based regimens who are at high risk of reactivation or new acquisition of herpetic infections should receive antiviral prophylaxis with oral acyclovir, at 800 mg 4 times daily, or one of the newer antiviral drugs such as famciclovir or valacyclovir [ 32 ]. There are also current studies comparing antiviral prophylaxis with acyclovir at 400 mg orally, 3 times daily, and acyclovir at 400 mg once daily in patients treated with bortezomib. There was no statistically significant difference between the 2 groups in terms of herpetic infections [ 53 ]. Acyclovir should be given prior to starting to bortezomib treatment and discontinued 4 weeks after the last dose of treatment. Risk factors for infections and the recommended form and dose of prophylaxis are shown in Table 3 . Granulocyte colony stimulating factor (G-CSF) may have a role in reducing treatment-associated neutropenia. It is routinely used after autologous and allogeneic transplantations. Addition of G-CSF (5 µg/kg/day) to broad-spectrum antibiotics after high-dose chemotherapy decreases the mortality and morbidity rates, curbs superinfections, and prevents fungal infections [ 54 ], but there are also studies that do not support these data. Vaccination against influenza, Streptococcus pneumonia, and Haemophilus influenzae is recommended by guidelines, but the efficacy is not guaranteed [ 6 ].

Supportive Care for Peripheral Neuropathy

Many patients with myeloma have subclinical or even clinical peripheral neuropathy at diagnosis, often due to comorbidities like diabetes mellitus, vitamin B12 deficiency, or carpal tunnel syndrome [ 6 ]. This will pose a risk for drug-induced neuropathy with bortezomib and thalidomide. The cause of the neuropathy in many cases of myeloma is not clear, but neurotoxic drugs, amyloidosis, and spinal cord or nerve root compression by plasmacytoma or lytic or extramedullary bone disease are the most common causes [ 6 ]. Bortezomib-induced neuropathy (BiPN) is characterised by pain and distal sensory neuropathy with suppression of reflexes, resulting in distal weakness in the lower limbs [ 55 ]. Grade 2 neuropathy requires 50% dose reduction of bortezomib and grades 3 and 4 neuropathies require drug discontinuation. Neuropathy grading is shown in Table 4 .

The symptoms of BiPN improve or completely resolve in the majority of patients after a median of 3 months following discontinuation of the drug, while in some patients maximum improvement may take 2 years [ 56 ]. Treatment for BiPN is symptomatic relief. Prophylactic treatment is not effective. Thalidomide-induced neuropathy occurs in up to 75% of patients. Daily drug dose, dose intensity, cumulative dose of ≥400 mg, and duration of therapy have been implicated in the pathogenesis. Symptomatic treatment for thalidomide- and bortezomib-induced neuropathy usually comprises gabapentin, pregabalin, or tricyclic antidepressants [ 57 ]. Correction of vitamin B12 deficiency and treatment of comorbidities that cause neuropathy are important points for the management of neuropathy. Neuropathic pain scales can be used to define the degree of pain. Guidelines recommend that superficial neuropathic pain should be treated with topical 5% lidocaine plaster and patients with chronic peripheral neuropathic pain should be considered for multimodal analgesic treatment, including an opioid, ion channel blocker, and serotonin-norepinephrine reuptake inhibitors (SNRIs) [ 6 ].

Supportive Care for Renal Failure

Roughly 15%-25% of myeloma patients have a creatinine value of >2 mg/dL at diagnosis. Patients with reversed renal failure have better overall survival than those without improvement [ 58 ]. Dehydration, infections, analgesics, hypercalcaemia, and hyperuricaemia increase tubular cast formation. Fluid intake of at least 3 L per day, limitation of analgesic usage, prevention of infections, and oral or intravenous bicarbonate replacement can improve renal functions. The most frequent metabolic complication of MM is hypercalcaemia, predominantly caused by tumour-induced bone resorption by osteoclast-activating factors such as various cytokines and prostaglandins [ 32 ]. Symptomatic hypercalcaemia (nausea, vomiting, anorexia, constipation, polydipsia, polyuria, fatigue, confusion, impairment of cognitive functions, coma) requires immediate supportive therapy with 3-6 L/day intravenous saline and high doses of loop diuretics (80-100 mg/day) with frequent evaluations of serum electrolytes [ 32 ]. Bisphosphonates can be used for the treatment of hypercalcaemia.

Supportive Care for Pain

Pain is frequently the predominant symptom of myeloma at diagnosis. It is also a common indicator of relapse or progressive disease. Many myeloma patients suffer from pain, particularly in the skeleton [ 32 ]. Fractures, osteolytic bone lesions, spinal cord compression, and neuropathy are the most common causes of the pain in myeloma patients. Pain is a subjective experience, and for sufficient treatment, some pain scales must be used ( Figure 1 ).

Effective analgesia can be achieved by regular administration of oral medication in myeloma patients. The WHO Pain Treatment Ladder (shown in Table 5 ) has been widely accepted for the treatment of tumour-related pain.

NSAIDs must be given carefully because of renal toxicity and gastrointestinal effects. COX-2 inhibitors have less gastrointestinal and renal toxicity. Opioids’ long-term effect and tolerance are better, but they are more expensive. The adverse effects of opioids are dryness of mouth, nausea, and emesis. The combination of opioids and NSAIDs is more effective, but also more toxic. Adjuvant medications such as corticosteroids, anti-emetics, neuroleptics, antidepressants, and benzodiazepines should be given as required [ 32 ].

Supportive Care for Thromboembolism

Myeloma and other plasma cell disorders have an association with venous thromboembolism (VTE) [ 59 ]. The incidence of VTE is highest during the first 3 to 4 months following the diagnosis [ 57 ]. Active disease, infections, previous VTE, and immobilisation are all known risk factors for VTE in myeloma patients. Thalidomide and lenalidomide have been demonstrated to further increase this risk, particularly when combined with steroids or cytotoxic agents [ 6 ]. All myeloma patients starting thalidomide or lenalidomide should undergo a risk assessment for VTE. However, the optimal prophylaxis remains controversial. If the patient does not have a risk factor or has only one risk factor (risk factors are shown in Table 6 ), a standard dose of 325 mg/day or a low dose of 75-80 mg/day of aspirin is recommended, but in the case of 2 or more risk factors, low-molecular-weight heparin (LMWH) at a high-risk prophylactic dose, i.e. enoxaparin at 40 mg, or warfarin (target international normalised ratio [INR]: 2.5) is recommended, unless contraindicated [ 6 ]. Aspirin and warfarin showed similar efficacy in reducing thromboembolic events in patients with myeloma treated with thalidomide-based regimens compared with LMWH, but in elderly patients warfarin showed less efficacy than LMWH [ 60 ]. The duration of thromboprophylaxis remains unclear, but it is guided by risk factors such as active disease (e.g., for the first 4-6 months of treatment until disease control is achieved) and deescalated or discontinued unless there are ongoing significant risk factors [ 6 ].

CONCLUSION

Supportive treatment is an essential part of the therapeutic management of myeloma patients because while directed towards improving the patient’s quality of life, they also have significant effects against the disease and can improve survival [ 62 ]. Careful consideration of patients’ and caregivers’ reported symptoms and effective supportive care will result in improved quality of life and improved survival. Some recommendations are given below as clues for supportive treatment from the guidelines.

Recommendations [ 45 ]

• A therapeutic trial of ESA should be considered in a patient with persistent symptomatic anaemia (typically haemoglobin concentration of <100 g/L) in whom haematinic deficiency has been excluded.

• One of darbepoetin, epoetin alfa, or epoetin beta can be chosen. Dose-doubling after 4 weeks in patients with a haemoglobin increase of <10 g/dL can be considered. ESA treatment should be stopped after 6-8 weeks if there has been no haemoglobin response. The haemoglobin concentration should not rise above 12 g/dL.

• All patients who are due to start thalidomide- or lenalidomide-containing therapy should undergo a risk assessment for VTE.

• In patients receiving thalidomide or lenalidomide, aspirin (75-325 mg) may be considered as VTE prophylaxis in low-risk patients, but in the case of ≥2 risk factors, LMWH or warfarin (target INR: 2.5) is recommended, unless contraindicated.

• The duration of thromboprophylaxis remains unclear but is guided by risk factors such as active disease and is deescalated or discontinued unless there are ongoing significant risk factors.

• Prophylactic immunoglobulin is not routinely recommended but may be useful in patients with severe, recurrent bacterial infections and hypogammaglobulinaemia.

• Prophylactic acyclovir is recommended for patients receiving VAD, high-dose dexamethasone, or a bortezomib-based regimen who are at high risk of reactivation or new acquisition of herpetic infections and following autologous stem cell transplantation.

• Pain should be assessed regularly in myeloma patients at all stages of the disease and measured using a 0-10 or a verbal none-mild-moderate-severe scale.

• Patients who repeatedly score pain as ≥5/10 should be referred to a palliative care or pain team.

• Effective analgesia can be achieved by regular administration of oral medication. The WHO Pain Treatment Ladder ( Table 5 ) has been widely accepted for the treatment of tumour-related pain.

• Local radiotherapy is helpful for pain control; a single-fraction dose of 8 Gy is recommended. The use of vertebroplasty or kyphoplasty may be considered in patients with persistent pain.

• Clinical evidence of a significant (e.g., above NCI grade 2) or progressive peripheral neuropathy at diagnosis should be appropriately investigated to identify treatable causes, and referral to a neurologist should be made so that appropriate neurological investigations can be performed.

• Patients who develop a significant (e.g., above NCI grade 2) or progressive chemotherapy-induced peripheral neuropathy should be managed with graded dose reduction or drug withdrawal.

• All patients with chronic peripheral neuropathic pain should be considered for multimodal analgesic treatment including an opioid, ion channel blocker, and SNRI.

• Dehydration, infections, analgesics, hypercalcaemia, and hyperuricaemia increase tubular cast formation. Fluid intake of at least 3 L per day, limitation of analgesic usage, prevention of infections, and oral or intravenous bicarbonate replacement can improve renal functions.

CONFLICT OF INTEREST STATEMENT

The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.

References

1 Smith A Howell D Patmore R Jack A Roman E Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network Br J Cancer 2011 105 1684 1692 22045184 10.1038/bjc.2011.450 PMC3242607

2 Brenner H Gondos A Pulte D Recent major improvement in long-term survival of younger patients with multiple myeloma Blood 2008 111 2521 2526 17901246 10.1182/blood-2007-08-104984

3 Brenner H Gondos A Pulte D Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010 Haematologica 2009 94 270 275 19144659 10.3324/haematol.13782 PMC2635407

4 Wagner LI Robinson D Jr Weiss M Katz M Greipp P Fonseca R Cella D Content development for the Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM): use of qualitative and quantitative methods for scale construction J Pain Symptom Manage 2012 43 1094 1103 22575718 10.1016/j.jpainsymman.2011.06.019 PMC3419469

5 Etto LY Morelli VM Silva VC Hungria VT Ciconelli RM Almeida MS Oliveira JS Barros JC Durie BG Colleoni GW Autologous stem cell transplantation improves quality of life in economically challenged, Brazilian multiple myeloma patients Clinics 2011 66 1855 1859 22086513 10.1590/S1807-59322011001100002 PMC3203955

6 Snowden JA Ahmedzai SH Ashcroft J D’Sa S Littlewood T Low E Lucraft H Maclean R Feyler S Pratt G Guidelines for supportive care in multiple myeloma 2011 Br J Haematol 2011 154 76 103 21517805 10.1111/j.1365-2141.2011.08574.x

7 Bergner M Quality of life, health status, and clinical research Med Care 1989 27 148 156 10.1097/00005650-198903001-00012 2646487

8 Karnofsky DA Burchenal JH Macleod CM The clinical evaluation of chemotherapeutic agents in cancer Evaluation of Chemotherapeutic Agents New York Columbia University Press 1949

9 Schag CC Heinrich RL Ganz PA Karnofsky performance status revisited: reliability, validity, and guidelines J Clin Oncol 1984 2 187 193 6699671 10.1200/JCO.1984.2.3.187

10 Cella D Wagner L Cashy J Hensing TA Yount S Should health-related quality of life be measured in cancer symptom management clinical trials? Lessons learned using the functional assessment of cancer therapy J Natl Cancer Inst Monogr 2007 53 60 17951232 10.1093/jncimonographs/lgm009

11 Wisløff F Hjorth M Health-related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma Nordic Myeloma Study Group. Br J Haematol 1997 97 29 37 10.1046/j.1365-2141.1997.222667.x 9136939

12 Sloan JA Cella D Frost M Guyatt GH Sprangers M Assessing clinical significance in measuring oncology patient quality of life: introduction to the symposium, content overview, and definition of terms Mayo Clin Proc 2002 77 367 370 11936934 10.4065/77.4.367

13 Kirkova J Davis MP Walsh D Tiernan E O’Leary N LeGrand SB Lagman RL Russell KM Cancer symptom assessment instruments: a systematic review J Clin Oncol 2006 24 1459 1473 16549841 10.1200/JCO.2005.02.8332

14 Albers G Echteld MA Vet HC de Onwuteaka-Philipsen BD Deliens L Evaluation of quality-of-life measures for use in palliative care: a systematic review Palliat Med 2009 24 17 37 19843620 10.1177/0269216309346593

15 Dvorak C Common complaints, difficult diagnosis: multiple myeloma J Am Acad Nurse Pract 2006 18 190 194 16681705 10.1111/j.1745-7599.2006.00122.x

16 Kyle RA Gertz MA Witzig TE Lust JA Lacy MQ Dispenzieri A Fonseca R Rajkumar SV Offord JR Larson DR Plevak ME Therneau TM Greipp PR Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin Proc 2003 78 21 33 12528874 10.4065/78.1.21

17 Gulbrandsen N Hjermstad MJ Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences Eur J Haematol 2004 72 172 180 14962235 10.1046/j.0902-4441.2003.00195.x

18 Sherman AC Simonton S Latif U Spohn R Tricot G Psychosocial adjustment and quality of life among multiple myeloma patients undergoing evaluation for autologous stem cell transplantation Bone Marrow Transplant 2004 33 955 962 15034542 10.1038/sj.bmt.1704465

19 Wisløff F Eika S Hippe E Hjorth M Holmberg E Kaasa S Palva I Westin J Measurement of health-related quality of life in multiple myeloma Nordic Myeloma Study Group. Br J Haematol 1996 92 604 613 10.1046/j.1365-2141.1996.352889.x 8616024

20 Alexander DD Mink PJ Adami HO Cole P Mandel JS Oken MM Trichopoulos D Multiple myeloma: a review of the epidemiologic literature Int J Cancer 2007 120 40 61 17405120 10.1002/ijc.22718

21 Kyle RA Rajkumar SV Multiple myeloma Blood 2008 111 2962 2972 18332230 10.1182/blood-2007-10-078022 PMC2265446

22 Kleber M Ihorst G Terhorst M Koch B Deschler B Wäsch R Engelhardt M Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score Blood Cancer J 2011 1 35 35 10.1038/bcj.2011.34 PMC3255252 22829196

23 Mols F Oerlemans S Vos AH Koster A Verelst S Sonneveld P Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: results from a population-based study using the PROFILES registry Eur J Haematol 2012 89 311 319 22762785 10.1111/j.1600-0609.2012.01831.x

24 Alegre A Oriol-Rocafiguera A Garcia-Larana J Mateos MV Sureda A Martinez-Chamorro C Cibeira MT Aguado B Knight R Rosettani B Efficacy, safety and quality-of-life associated with lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: the Spanish experience Leuk Lymphoma 2012 53 1714 1721 22292853 10.3109/10428194.2012.662643

25 Gulbrandsen N Wisløff F Brinch L Carlson K Dahl IM Gimsing P Hippe E Hjorth M Knudsen LM Lamvik J Lenhoff S Løfvenberg E Nesthus I Nielsen JL Turesson I Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support Med Oncol 2001 18 65 77 11778972 10.1385/MO:18:1:65

26 Uyl-de Groot CA Buijt I Gloudemans IJ Ossenkoppele GJ Berg HP Huijgens PC Health related quality of life in patients with multiple myeloma undergoing a double transplantation Eur J Haematol 2005 74 136 143 15654905 10.1111/j.1600-0609.2004.00346.x

27 Khalafallah A McDonnell K Dawar HU Robertson I Mediterr J Hematol Infect Dis 2011;3:2011057 2011;3:2011057. 2011 3 2011057 2011057 22220254 10.4084/MJHID.2011.057 PMC3248334

28 Lee SJ Richardson PG Sonneveld P Schuster MW Irwin D San Miguel JF Crawford B Massaro J Dhawan R Gupta S Anderson KC Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX study Br J Haematol 2008 143 511 519 18986387 10.1111/j.1365-2141.2008.07378.x

29 Delforge M Dhawan R Robinson D Jr Meunier J Regnault A Esseltine DL Cakana A Richardson PG San Miguel JF Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs MP: results from the VISTA trial. Eur J Haematol 2012 89 16 27 10.1111/j.1600-0609.2012.01788.x 22469559

30 Verelst SG Termorshuizen F Uyl-de Groot CA Schaafsma MR Ammerlaan AH Wittebol S Sinnige HA Zweegman S Lokhorst HM Sonneveld P Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial Ann Hematol 2011 90 1427 1439 21472373 10.1007/s00277-011-1224-1

31 Wisløff F Hjorth M Kaasa S Westin J Effect of interferon on the health-related quality of life of multiple myeloma patients: results of a Nordic randomized trial comparing melphalan-prednisone to melphalan-prednisone + alpha-interferon The Nordic Myeloma Study Group. Br J Haematol 1996 94 324 332 10.1046/j.1365-2141.1996.d01-1802.x 8759893

32 Ludwig H Zojer N Supportive care in multiple myeloma Best Pract Res Clin Haematol 2007 20 817 835 18070721 10.1016/j.beha.2007.10.001

33 Tricot G Hoffman R Benz EJ Shattil SJ Furie B Silberstein LE McGlave P Heslop H Multiple myeloma Hematology: Basic Principles and Practice Philadelphia Churchill Livingstone Elsevier 2009

34 Abildgaard N Rungby J Glerup H Brixen K Kassem M Brincker H Heickendorff L Eriksen EF Nielsen JL Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma Eur J Haematol 1998 61 128 134 9714526 10.1111/j.1600-0609.1998.tb01073.x

35 Shipman CM Rogers MJ Apperley JF Russell RG Croucher PI Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity Br J Haematol 1997 98 665 672 9332325 10.1046/j.1365-2141.1997.2713086.x

36 Shipman CM Croucher PI Russell RG Helfrich MH Rogers MJ The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway Cancer Res 1998 58 5294 5297 9850051

37 Takahashi R Shimazaki C Inaba T Okano A Hatsuse M Okamoto A Hirai H Ashihara E Nakagawa M A newly developed bisphosphonate, YM529, is a potent apoptosis inducer of human myeloma cells Leukemia Res 2001 25 77 83 11137564 10.1016/s0145-2126(00)00087-4

38 Mhaskar R Redzepovic J Wheatley K Clark OA Miladinovic B Glasmacher A Kumar A Djulbegovic B Bisphosphonates in multiple myeloma: a network meta-analysis Cochrane Database Syst Rev 2012 5 CD003188 CD003188 22592688 10.1002/14651858.CD003188.pub3

39 Zervas K Verrou E Teleioudis Z Vahtsevanos K Banti A Mihou D Krikelis D Terpos EIncidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients Br J Haematol 2006 134 620 623 16889620 10.1111/j.1365-2141.2006.06230.x

40 Ludwig H Anemia of hematologic malignancies: what are the treatment options? Semin Oncol 2002 29(Suppl 8) 45 54 12082654 10.1053/sonc.2002.33533

41 Ludwig H Fritz E Kotzmann H Höcker P Gisslinger H Barnas U Erythropoietin treatment of anemia associated with multiple myeloma N Engl J Med 1990 322 1693 1699 2342535 10.1056/NEJM199006143222402

42 Littlewood TJ Bajetta E Nortier JW Vercammen E Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial J Clin Oncol 2001 19 2865 2874 11387359 10.1200/JCO.2001.19.11.2865

43 Osterborg A Brandberg Y Molostova V Iosava G Abdulkadyrov K Hedenus M Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies J Clin Oncol 2002 2 2486 2494 12011126 10.1200/JCO.2002.08.131

44 Gabrilove JL Cleeland CS Livingston RB Sarokhan B Winer E Einhorn LH Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing J Clin Oncol 2001 19 2875 2882 11387360 10.1200/JCO.2001.19.11.2875

45 Snowden JA Ahmedzai SH Ashcroft J D’Sa S Littlewood T Low E Lucraft H Maclean R Feyler S Pratt G Guidelines for supportive care in multiple myeloma 2011 Br J Haematol 2011 154 76 103 21517805 10.1111/j.1365-2141.2011.08574.x

46 Rizzo JD Brouwers M Hurley P Seidenfeld J Arcasoy MO Spivak JL Bennett CL Bohlius J Evanchuk D Goode MJ Jakubowski AA Regan DH American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer Blood 2010 116 4045 4059 20974674 10.1182/blood-2010-08-300541

47 Dammacco F Silvestris F Castoldi GL Grassi B Bernasconi C Nadali G Perona G De Laurenzi A Torelli U Ascari E Rossi Ferrini PL Caligaris-Cappio F Pileri A Resegotti L The effectiveness and tolerability of epoetin alfa in patients with multiple myeloma refractory to chemotherapy Int J Clin Lab Res 1998 28 127 134 9689556 10.1007/s005990050032

48 Demetri GD Kris M Wade J Degos L Cella D Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study Procrit Study Group. J Clin Oncol 1998 16 3412 3425 10.1200/JCO.1998.16.10.3412 9779721

49 Leitgeb C Pecherstorfer M Fritz E Ludwig H Quality of life in chronic anemia of cancer during treatment with recombinant human erythropoietin Cancer 1994 73 2535 2542 8174050 10.1002/1097-0142(19940515)73:10<2535::aid-cncr2820731014>3.0.co;2-5

50 Augustson BM Begum G Dunn JA Barth NJ Davies F Morgan G Behrens J Smith A Child JA Drayson MT Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United kingdom Medical Research Council trials between 1980 and 2002--Medical Research Council Adult Leukaemia Working Party J Clin Oncol 2005 23 9219 9226 16275935 10.1200/JCO.2005.03.2086

51 Oken MM Pomeroy C Weisdorf D Bennett JM Prophylactic antibiotics for the prevention of early infection in multiple myeloma Am J Med 1996 100 624 628 8678082 10.1016/s0002-9343(95)00043-7

52 Chapel HM Lee M Hargreaves R Pamphilon DH Prentice AG Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet 1994 343 1059 1063 7909099 10.1016/s0140-6736(94)90180-5

53 Pour L Adam Z Buresova L Krejci M Krivanova A Sandecka V Zahradova L Buchler T Vorlicek J Hajek R Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib Clin Lymphoma Myeloma 2009 9 151 153 19406726 10.3816/CLM.2009.n.036

54 Avilés A Guzmán R García EL Talavera A Díaz-Maqueo JC Results of a randomized trial of granulocyte colony-stimulating factor in patients with infection and severe granulocytopenia Anticancer Drugs 1996 7 392 397 8826606 10.1097/00001813-199606000-00003

55 Cavaletti G Nobile-Orazio E Bortezomib-induced peripheral neurotoxicity: still far from a painless gain Haematologia 2007 92 1308 1310 10.3324/haematol.11752 18024368

56 Richardson PG Briemberg H Jagannath S Wen PY Barlogie B Berenson J Singhal S Siegel DS Irwin D Schuster M Srkalovic G Alexanian R Rajkumar SV Limentani S Alsina M Orlowski RZ Najarian K Esseltine D Anderson KC Amato AA Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib J Clin Oncol 2006 24 3113 3120 16754936 10.1200/JCO.2005.04.7779

57 Rhee F Anaissie E Angtuaco E Bartel T Epstein J Nair B Shaughnessy J Yoccoby S Barlogie B. Williams Kaushansky K Lichtman MA Beutler E Kipps TJ Seligsohn U Prchal J Williams Hematology Myeloma New York McGraw-Hill 2010

58 Dispenzieri A Lacy MQ Greipp PR Greer J Foerster J Rodgers GM Paraskevas F Glader B Arber DA Means RT Wintrobe’s Clinical Oncology Multiple myeloma Philadelphia Lippincott 2009

59 Srkalovic G Cameron MG Rybicki L Deitcher SR Kattke-Marchant K Hussein MA Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease Cancer 2004 101 558 666 15274069 10.1002/cncr.20405

60 Palumbo A Cavo M Bringhen S Zamagni E Romano A Patriarca F Rossi D Gentilini F Crippa C Galli M Nozzoli C Ria R Marasca R Montefusco V Baldini L Elice F Callea V Pulini S Carella AM Zambello R Benevolo G Magarotto V Tacchetti P Pescosta N Cellini C Polloni C Evangelista A Caravita T Morabito F Offidani M Tosi P Boccadoro M Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial J Clin Oncol 2011 29 986 993 21282540 10.1200/JCO.2010.31.6844

61 Palumbo A Rajkumar SV Dimopoulos MA Richardson PG San Miguel J Barlogie B Harousseau J Zonder JA Cavo M Zangari M Attal M Belch A Knop S Joshua D Sezer O Ludwig H Vesole D Bladé J Kyle R Westin J Weber D Bringhen S Niesvizky R Waage A von Lilienfeld-Toal M Lonial S Morgan GJ Orlowski RZ Shimizu K Anderson KC Boccadoro M Durie BG Sonneveld P Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma Leukemia 2008 22 414 423 18094721 10.1038/sj.leu.2405062

62 Morgan G Myeloma: diagnosis complications and supportive care Hematology 2012 17(Suppl 1) 109 111 10.1179/102453312X13336169156177 22507795