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Keywords:

  • myeloma;
  • clinical practice guidelines;
  • chemotherapy;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

Purpose and basic procedure of the study:  The availability of new targeted therapies has revolutionised the treatment of multiple myeloma (MM), for both the newly diagnosed and the relapsed and refractory settings. A panel of Italian experts provided guidelines for optimal clinical practice in the treatment of MM.

Main findings and conclusions:  The panel recommended that treatment should only be initiated in symptomatic patients. Autologous stem cell transplantation (ASCT) with melphalan is the treatment of choice in patients younger than 65 yr, and induction therapy including new drugs seems the most suitable preparatory regimen before ASCT. In patients who fail to achieve at least a very good partial response (VGPR) after transplant, a consolidation with a second transplant is of clinical benefit. Also, there is evidence that maintenance with thalidomide after ASCT in young patients failing to reach at least VGPR could prolong survival. In elderly patients, the combination of an alkylating drug with a novel agent should be considered as standard approach. Relapsed MM should be retreated after the reappearance of symptoms and signs of organ and tissue damage. Salvage regimens should include corticosteroids plus bortezomib, thalidomide or lenalidomide.

Multiple myeloma (MM) is a common haematological disease, accounting for about 20% of deaths from haematological cancers (1–3), which is incurable despite conventional and high-dose chemotherapy (2). Novel immunomodulating therapy has doubled median survival for MM patients to approximately 5 yr, and patients now have a 50% chance of complete response (CR) to treatment with improved 10-yr survival rates (4). The advent of new targeted therapies has galvanised a re-imagining of MM treatment regimens, both in the newly diagnosed or in the relapsed and refractory setting. To provide a standardisation of the best patient care, we describe below guidelines for optimal clinical practice in the treatment of MM.

Design and methods

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

An expert opinion meeting was held in Rome, Italy on 26 and 27 February, 2008. This meeting brought together an Italian faculty with extensive clinical and scientific experience in MM. Four consensus panels co-ordinated by a chairman were convened to define four specific areas: (1) Recommendations for up-front treatment in young patients (chairman: Michele Cavo); (2) Recommendations for up-front treatment in elderly patients (chairman: Antonio Palumbo); (3) Recommendations for the treatment and management of relapsed and refractory patients (chairman: Mario Boccadoro); (4) Management of side-effects from novel drugs (chairman: Maria Teresa Petrucci). First, the experts reviewed the scientific evidences published in the literature in their specific field; then, they expressed the recommendations on the basis of both scientific evidence and clinical practice. The expert panel based all the recommendations on the results of at least one large prospective randomised trial. If phase 3 studies have not yet been conducted in a specific area, the expert panel expressed some suggestions based on the results of prospective non-randomised studies and clearly indicated the need of further data in that field. Therefore, these recommendations should not be regarded as evidence-based official guidelines. However, the statements of the experts indicated how scientific results are perceived by medical practitioners and how they are applied in daily clinical practice.

Clinical consideration for initiation of therapy in multiple myeloma

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

Smoldering or asymptomatic MM accounts for about 15% of all cases with newly diagnosed MM and is defined by a serum monoclonal protein level of ≥3 g/dL, ≥10% plasma cells, or both in absence of end-organ damage (5). The overall risk of progression to symptomatic or active MM reaches a 78% probability at 20 yr (6) A few small, randomised trials in the early 1990s observed no difference in overall survival (OS) between melphalan plus prednisone (MP) chemotherapy and observation (7), and established the current standard of care based on a close follow-up every few months without any drug therapy (8). The rationale for this approach is to delay treatment, which has not been proven to prevent progression to active MM, and to spare toxicities to patients who may not progress for months to years without any therapy. Recently, at least two considerations have challenged this paradigm. First, some studies identified a specific subset of patients at highest risk of progression carrying adverse prognostic factors such as elevated serum M protein, high bone marrow plasma cell labelling index, abnormal appearance of the spine in magnetic resonance imaging (MRI) and abnormal serum free light chain ratio (9–11). Secondly, novel biological agents that are much more active than alkylating agents are now available for MM therapy. Ongoing studies are testing the use of bisphosphonates, interleukin inhibitors, clarithromycin and dehydroepiandrosterone (12–15). Thalidomide has also been studied in the treatment of smoldering MM in an attempt to delay progression to active MM (16). At present, only preliminary data are available, and the appropriate approach is to start therapy only in presence of target organ damage according to the CRAB (calcium elevation, renal insufficiency, anaemia and bone abnormalities) criteria (17).

The diagnosis of active MM requires the presence of a monoclonal protein in serum and urine, plasma cells in the bone marrow or plasmacytomas and signs of organ damage that are defined as hypercalcaemia, renal insufficiency, anaemia, bone lesions (CRAB) or recurrent bacterial infections (5). In the initial work-up of active MM, standard radiological skeletal survey is the ‘gold standard’ for baseline evaluation of bone involvement. Spine MRI is used to assess a variety of clinical problems, including cord compression, osteopenia and uncertain staging, and to delineate areas requiring radiation therapy or surgical intervention (18). Moreover, spine MRI can detect an abnormal marrow pattern in up to 50% of patients with negative X-ray (19). Whole body positron emission tomography–computed tomography was superior to planar radiographs, identifying both extramedullary and medullary lesions in 19% of patients with negative X-rays (20). On the basis of these results, the number of focal areas identified by these technologies is integrated in the recently proposed Durie and Salmon PLUS staging system with conventional clinical and biohumoral risk factors, leading a potential change in staging and treatment in 15–25% of cases (21).

Among the prognostic factors, serum beta-2-microglobulin was recognised as the single most powerful prognostic factor since 1980. A combination of serum beta-2-microglobulin and serum albumin provided the simplest, more powerful and reproducible three-stage International Staging System classification (22). Chromosome 13 deletion, deletion of 17p13, and translocation t(4;14), t(14;16) and t(14;20) were associated with shorter survival in several large series of patients (23). The effect of deletion 13 on prognosis is, however, greater when deletion 13 is detected by karyotype than when it is detected by interphase fluorescence in situ hybridisation (FISH) (23). Some authors have proposed a basic panel to assess the cytogenetic risk (24); however, there is no consensus on the validity of this evaluation on newly diagnosed patients, since standardised bone marrow cytogenetics testing is not universally available, and because there are no specific alternative therapies in patients with chromosomal abnormalities (21). The panel provided recommendations to define the appropriate time and examinations for the beginning of therapy in newly diagnosed MM.

Recommendations

Therapy should be initiated only in symptomatic patients. Some examinations are considered mandatory in all newly diagnosed MM patients (Table 1), whereas others are recommended in particular circumstances (Table 2). Bone marrow FISH or cytogenetic data should not be used for the decision of the time and appropriate choice of treatment and should be limited to cases enrolled in clinical studies. Bone disease should be routinely studied by X-ray survey. Osteoporosis cannot be considered a sign of bone disease that requires treatment unless it causes bone deformation such as vertebral collapse. Spinal MRI should be restricted to symptomatic patients with negative X-ray and in cases of clinical suspicion of spinal cord compression or solitary plasmacytoma.

Table 1.   Mandatory examinations needed in all newly diagnosed multiple myeloma patients
Mandatory examinations
  1. PEP, protein electrophoresis; Ig, immunoglobulin; LDH, lactate dehydrogenase.

Blood count
Serum PEP
Quantitative Ig immunofixation
Urine PEP
24 h total urine protein
Creatinine clearance
Calcium
Albumin
LDH
Beta-2-microglobulin
Marrow aspirate
Marrow biopsy
Bone X-ray
Table 2.   Exams recommended in particular circumstances
CircumstanceRecommended examination
  1. MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; FISH, fluorescence in situ hybridisation; FLC, free light chain.

Suspicion of cord compression Suspicion of solitary plasmacytoma Symptomatic patients with negative X-ray Inside controlled protocolsSpine and pelvis MRI
Inside controlled protocolsPET-CT
Inside controlled protocolsFISH for: del(13), t(4;14), t(14;16), del p17
Non-secretory myeloma Bence Jones myelomaFLC

The significant improvement of the prognosis obtained by treatment with high-dose chemotherapy and/or novel agents in recent years should question an earlier initiation of treatment in specific subsets of asymptomatic patients. Since sufficient clinical data are not yet available, prospective trials aimed at addressing this issue are strongly encouraged.

Up-front treatment for young patients

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

The role of autologous stem cell transplantation

In the late 1990s, several randomised trials have shown the superiority of autologous stem cell transplantation (ASCT) compared with conventional therapy in patients younger than 65 yr. A benefit in response rate and event-free survival (EFS) was observed in all the trials (25–28), but only two of them showed a significant prolongation of OS (25, 26). These studies established a strong relationship between quality of response and survival (29): patients achieving CR, or at least very good partial response (VGPR), had a longer OS than patients with only partial response (PR). Therefore, CR or at least VGPR (30) achievement is now considered an objective of high-dose treatment.

Novel agents have been evaluated either prior to or after ASCT. The thalidomide-dexamethasone (TD) regimen did not increase the CR rate prior or after ASCT in comparison with dexamethasone alone or vincristine, doxorubicin and dexamethasone (VAD) (31–33). Preliminary results from non-randomised studies employing bortezomib combined with dexamethasone, or included in multi-agent combinations, showed the highest CR + VGPR rates observed to date prior to ASCT of 30–60% (34–37). These were confirmed by the recent preliminary analysis of the randomised trial of the Italian Myeloma Network GIMEMA comparing bortezomib-thalidomide-dexamethasone (VTD) vs. TD as induction prior to ASCT (38) Overall, response rates are consistently superior after ASCT with bortezomib, challenged by data using thalidomide in the cyclophosphamide-thalidomide-dexamethasone (CTD) or thalidomide-adriamycin-dexamethasone combinations (39, 40). The MRC Myeloma IX trial comparing CTD vs. cyclophosphamide-VAD regimens for instance showed CR + near CR rates of 58% vs. 41% (39) It is, however, too early to clearly state which is the preferred regimen, as longer follow-up is awaited to show whether increased and enhanced responses translate into improved survival.

Recommendations

Autologous stem cell transplantation with melphalan 200 mg/m2 is the treatment of choice in patients younger than 65 yr. Induction therapy including new drugs seems the most suitable preparatory regimen before ASCT, as it allows the highest probability of obtaining a CR before transplant. Among all the data available, bortezomib-based regimens are the most extensively studied and seem to improve CR not only before, but also after ASCT. It is recommended to evaluate response at the end of induction therapy and every 3 months after transplant. CR criteria according to International Myeloma Working Group (IMWG) are the reference definition (17), but it is conceivable that the different depth of response after ASCT (VGPR, CR, stringent CR and molecular CR) can influence the final outcome of ASCT.

The role of double ASCT, consolidation and maintenance

The Inter-groupe Francophone du Myelome (IFM) was the first to conduct a randomised trial comparing single and double ASCT and showed significant improvement in both EFS and OS in the double ASCT arm (41). The benefit in EFS, but not in OS, was confirmed by two other randomised studies (42, 43). The French and the Italian studies established that the benefit from the double ASCT was dependent on the response to the first ASCT: patients with <90% reduction of their M-component after one ASCT had a longer OS in the double-ASCT arm, whereas patients experiencing CR or VGPR had the same OS regardless of a second transplant (41, 42). Novel agents were evaluated as maintenance after ASCT. Two randomised trials showed a benefit in the thalidomide arm in terms of CR, EFS and OS in comparison with the control arm (44, 45). A Tunisian study showed that a single ASCT followed by 6 months of thalidomide maintenance therapy was significantly superior to tandem ASCT without maintenance therapy in terms of OS and EFS (46). The Arkansas group confirmed a higher CR rate and longer EFS, but did not show a difference in the 5-yr OS because of a shorter survival after relapse (47). Bortezomib has also been used as part of a consolidation regimen with thalidomide and dexamethasone (VTD) (48). VTD was started within 6 months from ASCT to induce further cytoreduction and to achieve molecular remission. VTD consolidation allowed some CR/VGPR patients to enter molecular remission. This study demonstrated that new non-chemotherapeutic agents have activity on minimal residual disease persisting following ASCT and indicated that molecular remission is also an achievable goal outside the allogeneic transplantation setting (48). Pegylated lyposomal doxorubicin and dexamethasone (PAD) as induction pre-ASCT followed by lenalidomide plus prednisone as consolidation induced a high response rate with a 56% CR rate recorded at the end of a reduced intensity ASCT regimen for elderly patients (49).

Recommendations

In patients who fail to achieve VGPR or CR after transplant, a consolidation with a second transplant is of clinical benefit. There is evidence that maintenance with thalidomide after ASCT in young patients failing to reach at least VGPR could prolong OS. The role of a long-term treatment with novel agents at low doses until progression (maintenance) is currently still undefined. Given the toxicity related to the long-term use of thalidomide or bortezomib, a treatment for a limited period of time after ASCT (consolidation treatment) rather than maintenance until progression could be suggested. Future studies are needed to assess the efficacy of lenalidomide as maintenance.

The role of allogeneic stem cell transplantation

Compared with the other treatment modalities in MM, allogeneic stem cell transplantation induces the highest rate of clinical CR and molecular responses. However, despite the improvement in supportive care and patient selection, allogeneic transplantation after myeloablative conditioning has a transplant-related mortality (TRM) of 20–30% because of organ toxicities, graft-versus-host disease and infections (50). Therefore, retrospective comparisons between allogeneic transplantation and ASCT were in favour of ASCT (51). The aims of the reduced-intensity conditioning (RIC) transplants introduced in the late 1990s are both the reduction of the toxicity of the preparatory regimens and the maintenance of the immunological effect of donor lymphoid cells (the graft-versus-tumour effect). The application of this approach in relapsed patients was limited by a high rate of disease progression (52) Currently, RIC allogeneic transplants are mostly used after tumour burden reduction with high-dose therapy followed by ASCT. Final results from two randomised prospective trials (53, 54) in newly diagnosed patients, comparing a double ASCT with a single ASCT, followed by a RIC transplant in patients with a human leukocyte antigen matched sibling, are now available and preliminary data of two other trials (55, 56) have been presented. The TRM incidence was low in all the studies, ranging between 10% and 15%. Only in the Italian study were the EFS and OS of the allogeneic arm significantly higher compared with the autologous arm (54). However, in the two more recent trials, the preliminary data showed a survival plateau beyond 3 yr in the allogeneic arm (55, 56) and final results are expected to draw firm conclusions.

Recommendations

Patients with newly diagnosed MM should be treated with allogeneic stem cell transplantation inside clinical trials. At the time of writing, allogeneic stem cell transplantation cannot be recommended as the standard of care because of lack of data; better results seem possible at diagnosis, while in the relapsed setting, these are likely to be achievable only in selected patients.

Up-front treatment for elderly patients

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

The role of novel agents and maintenance

In newly diagnosed elderly patients with MM, a significant improvement of EFS after treatment with MP plus thalidomide (MPT) compared with standard MP was reported in four independent-randomised studies, and a significant prolongation of OS was observed in two of the four studies (57–60). Two trials failed to observe an OS advantage mainly because of an excess of early toxic deaths in the MPT arm (58, 60). Although there were some differences in the median thalidomide doses (ranging between 100 and 200 mg/d) and duration of treatment (6 or 9 months, with or without thalidomide maintenance), these trials showed virtually identical results, and they represent the experimental evidence that supports MPT as a standard of care for elderly patients not eligible for ASCT. The association of standard MP with bortezomib or lenalidomide are promising first-line treatments for elderly MM patients. The data available from the most recent studies suggest that the combinations of MP with thalidomide, bortezomib and lenalidomide has the potential to improve outcome in elderly MM patients. The increased toxicity observed with some of these new combinations can be managed with dose reduction. Further prospective studies are needed to assess the optimal dosages of regimens, including new drugs and combination with conventional chemotherapy. In fact, two phase II studies one using bortezomib plus MP (VMP) (61) and the other MP plus lenalidomide (MPR) (62) showed a further increase in at least VGPR to 30% to nearly 50% and a 1 yr-EFS >90% and are currently under investigation in randomised studies (63, 64). The Velcade as Initial Standard Therapy Assessment trial (63) confirmed the superiority of VMP vs. MP for response and time-to-event end-points, including CR rate, time to progression (TTP), OS and time to next therapy. Moreover, responses to bortezomib and lenalidomide were not significantly affected by cytogenetic abnormalities (62, 64).

Autologous stem cell reinfusion after intermediate-dose melphalan was demonstrated to be inferior in comparison with MPT in the French-randomised trial (57). However, recently, intermediate-dose melphalan after an induction treatment with novel agents obtained a high rate of CR with an acceptable toxicity in elderly patients between 65 and 75 yr and long-term results are awaited (49).

Interferon (IFN) and glucocorticoids were evaluated as maintenance therapy in responding patients treated with standard-dose conventional induction chemotherapy. A prolongation of response duration was observed in a few randomised trials comparing IFN maintenance and observation, without an OS advantage in the majority of them (65, 66). The positive role of glucocorticoids in maintenance was suggested by two large Southwest Oncology Group-randomised trials observing that 50 mg prednisone every other day significantly prolonged both progression-free survival (PFS) and OS in comparison with a lower dose of prednisone, and that the addition of 50 mg prednisone three times weekly to IFN was superior to IFN alone in terms of PFS, but not OS (67, 68). Maintenance with novel drugs need to be tested in randomised trials, length of maintenance as well as different doses should be evaluated.

Recommendations

The combination of an alkylating drug with a novel agent should be considered as standard treatment in elderly patients. MPT is the reference combination in elderly patients. VMP should be considered the other standard therapy. MPR will be considered the third after positive results will be available from the ongoing phase III MPR vs. MP study (MM-015). The duration of treatment should be limited to 6–9 months. Longer periods of treatment with melphalan may produce cumulative haematological toxicity without adding significant clinical benefit.

The availability of combination treatment including new agents has significantly reduced the value of ASCT with intermediate dose of melphalan. Further studies are needed to directly compare the best combination vs. the best intermediate dose melphalan in elderly patients.

The evidence of the efficacy of maintenance in patients failing to reach at least VGPR is lacking in elderly patients in whom compliance with prolonged treatment is more difficult. Controlled trials on this issue are also needed.

Is it time to introduce the geriatric assessment in the treatment of elderly patients?

Factors influencing survival time can be related to the disease, the patient and the treatment. Whereas the influence of characteristics of the disease has been extensively studied, in most trials patients’ characteristics, especially in elderly cancer patients, are less well described. Traditionally, the oncologist’s assessments of functional status includes an evaluation of Karnofsky or Eastern Cooperative Oncology Group performance status (PS), whereas the comprehensive geriatric’s assessment (CGA) (69) is the description of patients’ characteristics, and traditionally includes an evaluation of an older individual’s functional status [patient’s ability to complete activities of daily living (ADLs) and instrumental ADLs], comorbid medical conditions, cognition, nutritional status, psychological state, social support and a review of the patient’s medications. The CGA adds further substantial information on the functional assessment of elderly patients who are not included in the definition of PS (70). Therefore, PS cannot be reappraised as a unique marker of functional status among elderly cancer patients. Moreover, recent studies have demonstrated that functional status, cognitive performance and comorbidities significantly and independently impact on morbidity and OS in older patients with breast, colorectal and prostate cancers (71–73). These results should prompt oncologists and haematologists’ co-operative groups to develop a standardised CGA, integrate the CGA into studies that includes a high proportion of older patients, and test the impact of CGA on the outcome of elderly patients. Use of CGA could allow the comparison of study results avoiding a potential confounder because of different cohorts of elderly patients, and the definition of the treatment guidelines that will be applicable in the population.

Recommendations

The panel observed that the introduction of novel agents dramatically changed the objectives of the treatment particularly in elderly patients, moving from palliation to long-term remission. However, novel agents have side-effects that should be recognised and monitored by trained physicians and could limit compliance of elderly patients. The panel agreed that evaluation of comorbidities and geriatric assessment could avoid elderly patients being excluded from potentially effective treatments based on age alone, and the appropriate regimen and dosage could be chosen according to biological age. Some experts encouraged the use of appropriate scales to grade comorbidities, but their validation inside prospective clinical trials is still lacking.

The choice of an appropriate dose of novel agents at the beginning of the treatment, a dose reduction in case of side effects, especially non-haematological, the limitation of the treatment duration, and prophylaxis are all useful modalities to enhance compliance of novel agents in elderly patients.

Treatment of relapsed and refractory multiple myeloma

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

No therapy is curative in the treatment of relapsed MM. Responses to treatment are characteristically short. Moreover, there are no definitive data on the optimal regimen or sequence (74). Bortezomib and the immunomodulatory agents, thalidomide and lenalidomide, now constitute the ‘backbone’ agents in this setting. The international, randomised phase III APEX trial compared bortezomib single agent with high-dose dexamethasone and demonstrated the superiority of bortezomib in terms of response rate, median TTP and survival, leading to European Medical agency (EMEA) approval in 2005 as second-line treatment of MM patients (75). Another recent, large, phase III trial reported further improvement of the TTP with a combination of pegylated liposomal doxorubicin and bortezomib compared with bortezomib alone (76). Moreover, phase II trials demonstrated that the addition of dexamethasone for the suboptimal response to bortezomib alone improved the response rate from 18% to 33%.

Other promising associations tested in phase II trials are bortezomib and thalidomide, bortezomib and lenalidomide, and bortezomib and melphalan. Two large phase III trials demonstrated a significantly delayed TTP after lenalidomide plus dexamethasone in comparison with dexamethasone alone; therefore, the association was approved by the EMEA in 2008 (77, 78). These two key phase III trials in relapsed or refractory MM patients (MM-009 and MM-010) showed that lenalidomide combined with dexamethasone produced an overall response rate of approximately 60% (61% in MM-009 and 60% in MM-010), a CR rate of about 15% (14% and 16%), and a median TTP of at least 11.1 months (77, 78). Phase II data is available on the clinical efficacy of thalidomide plus dexamethasone in relapsed patients, but has not been proven in phase III studies (79–81). Response rates of about 50% were measured with a median dose of 200–400 mg/d and a median duration of response of about 12 months; therefore, this treatment is not FDA- or EMEA-approved for this indication.

Cytogenetic abnormalities, high beta-2-microglobulin and low serum albumin levels retain in the context of relapsed/refractory disease the same adverse prognostic value defined in untreated disease. Additional clinical challenges in the relapsed/refractory population include light chain and IgA isotype, renal failure, extramedullary disease, hyposecretory MM and advanced bone disease. Both bortezomib and thalidomide have been shown to be safe and effective in patients with renal impairment. Both bortezomib and lenalidomide have been shown to overcome the poor prognosis conferred by deletion of chromosome 13 and translocation (4;14) (82, 83).

Autologous stem cell transplantation can be an option also for refractory and relapsing patients, although trials in this setting were few. In fact, only one randomised trial designed in 1990 assessed the optimal time of high-dose therapy and ASCT, comparing an early transplant immediately after induction therapy, and a late transplant as a rescue treatment in case of primary resistance to chemotherapy or at relapse in responders. The results showed similar OS in the two groups with a median survival exceeding 5 yr (27). RIC allogeneic transplants allowed MM control depending on disease status at transplant and showed significantly shorter EFS in patients with relapsed/refractory disease in comparison with responsive patients (52).

Recommendations

The panel agreed that relapsed MM should be retreated after the reappearance of symptoms and signs of organ and tissue damage. The quantitative and morphological determination of the plasma cell marrow infiltration should not be used as a criterion for starting treatment. CRAB criteria should be adopted here with the same rules used at diagnosis. The panel agrees that a sharp increase of the M-component at relapse could be used as a signal to retreat the patient, such as doubling of the M-component with in 2 months, but a precise definition of this issue is lacking. Slow increase of M-component should not be used to retreat. A refractory MM patient is defined as a patient who fails to reach at least a PR after three cycles using a new agent. Primary refractory patients need the change of the induction regimen.

Salvage regimens should include bortezomib, thalidomide or lenalidomide in combination with dexamethasone, alkylating agents or doxorubicin. All the experts agreed that the standard combination for all refractory/relapsing patients should include corticosteroids. Dexamethasone at the monthly dose of 160 mg is the reference schedule. The patient could be retreated with a previously administered regimen, if the response duration has reached at least the median EFS observed in the reference publication for that treatment.

The choice of bortezomib, thalidomide or lenalidomide in combination with dexamethasone, alkylating agents or doxorubicin, should be performed with a rotation principle excluding all drugs that have shown in vivo resistance. Criteria to choose the appropriate re-induction therapy should include patient age, renal function, presence of neuropathy, previous haematological toxicity, and the pharmacological characteristics of the available new drugs.

A second re-induction treatment with new drugs could be followed by ASCT. Allogeneic stem cell transplantation should be performed in selected patients achieving a response to re-induction therapy only inside clinical trials. For elderly patients, the choice of a single agent therapy or a combination should include comorbidities assessment and a quality-of-life evaluation.

Palliation should be started after two subsequent ineffective lines of therapy including new drugs. All available tools including radiation, bisphosphonates, corticosteroids and opiates should be used. Low-dose chemotherapy could be administered to relieve symptoms.

Management of the side effects of novel agents

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References

The main side effects after bortezomib in monotherapy or in combinations are thrombocytopenia, peripheral neuropathy, diarrhoea, herpes varicella-zoster (HVZ) infections and cutaneous rash (75). As expected, patient age, pretreatment and drugs associated with bortezomib influence the rate of severe thrombocytopenia reported in the trials ranging between 30% and 51% (64, 75, 84). The kinetics of thrombocytopenia depend on platelet counts prior to bortezomib therapy. Platelet count usually returns to baseline in the 10-d rest period between treatment cycles and progressively increases in patients responsive to treatment (85). The thrombocytopenia associated with bortezomib therapy likely does not occur because of stem cell damage, but rather because the drug inhibits the budding of platelets from precursors cells, possibly via NF-κB inhibition (85).

Neutropenia and anaemia are a minor concern with bortezomib, with the exception of the VMP combination that was associated with grade III–IV neutropenia of 43% in newly diagnosed elderly patients, probably because of melphalan myelotoxicity (64). Grade III–IV peripheral neuropathy occurs in 8% of patients after bortezomib monotherapy (75) and 13–17% of elderly patients after bortezomib combination therapy with VMP and bortezomib, doxorubicin and dexamethasone (PAD) (49, 63, 64, 76). A striking feature of bortezomib-induced peripheral neurotoxicity is neuropathic pain (86). The adverse effect seems to be dose-related and associated with cumulative increase of prevalence through the first five treatment cycles. The use of bortezomib as first-line therapy does not change the risk of neurotoxicity in comparison with pretreated patients, while age >75 yr may be an additional factor. More than two-thirds of the patients with clinically significant neuropathy experience resolution or improvement in a few months after dose modification or drug withdrawal (86). An excess of HVZ infections up to 13% during bortezomib treatment in comparison with control arm suggests a prophylaxis with either acyclovir or valacyclovir during treatment (74). Cutaneous sides effects are represented by grade III–IV rashes in <10% of patients (61, 75). and by grade III hand and foot diseases in 5% of patients after PAD regimens (76). No excess of thrombosis and cardiac events have been observed in bortezomib regimens in comparison with combinations without bortezomib (75, 76).

The main adverse effects following treatment with thalidomide in monotherapy or in combinations are peripheral neuropathies, constipation and thrombosis. Peripheral neuropathy is mainly sensory and symmetrical and is related to the duration of the treatment, with an incidence up to 75% of patients treated for longer than 12 months (87). Grade III–IV peripheral neurotoxicity develops after administration of thalidomide at the usual doses of 100 or 200 mg/d for a period shorter than 12 months in <10% patients, even if elderly (57, 58). Thalidomide discontinuation increases the probability of recovery, which usually occurs within 3 wk. If treatment is not stopped, the neuropathy progresses and could become irreversible (88). Constipation is a common form of gastrointestinal side-effect toxicity in elderly patients, which is severe in 6–10% of patients (57, 58). The most troublesome toxic effect of thalidomide is venous thromboembolism. The risk of thromboembolism is not increased by treatment of thalidomide alone, but it increases to 20% after thalidomide is associated with dexamethasone, melphalan or doxorubicin, and is higher in newly diagnosed than in pretreated patients (89). Data regarding thromboprophylaxis during thalidomide therapy are very heterogeneous; aspirin, low-fixed-dose and full-dose warfarin and low-molecular-weight heparin were used in non-randomised trials and allow some protection.

Toxic effects related to lenalidomide in association with dexamethasone or other drugs are mainly neutropenia, thrombocytopenia, infections and thrombosis (77, 78, 90). In the MM-009 and MM-010 international trials, incidence of grade III–IV neutropenia and thrombocytopenia were 29–41% and 11–15%, respectively, in heavily pretreated patients receiving lenalidomide and dexamethasone (77, 78) and fell to 12% and 0% in untreated patients (90) Incidences of severe infections are 9–21% in pretreated (77, 78) and 9% in newly diagnosed patients (62). As expected, MPR combination enhances the severe neutropenia rate up to 52%, and the incidence of severe infections to 9% (62). Myelotoxicity of lenalidomide plus dexamethasone and MPR is not cumulative, since both neutrophil and platelets decrease during the first 21 d of each cycle and then recover towards baseline during the 7-d rest period between cycles (91). Given these results, prophylaxis with granulocyte colony-stimulating factor (G-CSF) and broad spectrum antibiotics has been suggested in case of severe myelotoxicity, particularly in the setting of pretreated or elderly patients, or in association with melphalan. Incidence of thrombosis is not increased after treatment of lenalidomide alone, but is increased up to 20% after lenalidomide in association with dexamethasone (89). The incidence of thromboembolism is significantly lower after low-dose dexamethasone (160 mg/month) in comparison with high-dose dexamethasone (480 mg/month). In the reported studies, aspirin has been appropriate prophylaxis in patients who received lenalidomide in combination with low-dose dexamethasone, melphalan or doxorubicin, reducing the incidence of thromboembolism to <10%.

Recommendations

Table 3 shows the adverse effects that are more frequently associated with the administration of novel drugs and their combinations and indicated when dose reductions or interruptions may be required . Moreover, Table 3 showed how we can prevent toxicities by patient clinical monitoring, drug prophylaxis and supportive therapies. Table 4 shows the management of venous thromboembolism during thalidomide or lenalidomide treatment on the basis of a risk-assessment model that takes in account concurrent risk factors related to patient, disease and therapies.

Table 3.   Risk assessment model for the management of adverse events in multiple myeloma patients treated with combinations that include novel-targeted agents
Adverse eventMain antimyeloma agents involvedManagementDrug interruption or reduction
  1. INR, international normalised ratio; LMWH, low-molecular-weight heparin; HVZ, herpes-varicella-zooster; G-CSF, granulocyte colony-stimulating factor.

NeutropeniaLenalidomide and combinationsG-CSF 5 μg/kg/d until neutrophil recovery in case of uncomplicated grade IV adverse events or grade II adverse events complicated by fever or infection≥25% reduction in case of uncomplicated grade IV adverse events or grade II adverse events complicated by fever or infection
ThrombocytopeniaBortezomib and combinations Lenalidomide and combinationsPlatelet transfusion if treatment-related grade IV adverse events≥25% reduction in case of treatment-related grade III–IV adverse event
AnemiaBortezomib and combinations Lenalidomide and combinationsErythropoietin or darbepoietin in case of Hb level ≤10 g/dL ≥25% reduction in case of treatment-related grade III–IV adverse events
InfectionHigh-dose dexamethasone Bortezomib and combinations Lenalidomide and combinations Thalidomide and combinationsTrimetoprin-cotrimoxazole for P. carinii prophylaxis during high-dose dexamethasone Acyclovir or valacyclovir for HVZ prophylaxis during bortezomib and combinationsNone
NeurotoxicityBortezomib and combinations Thalidomide and combinationsEMG and neurological consult before and during treatment Symptomatic treatment with gabapentin, pregabalin, vitamin B complex compounds, amitryptilin or l-carnitina (uncontrolled trials)Definitive interruption in case of ≥ grade III adverse events 50% reduction in case of grade II adverse events
Cutaneous toxicityThalidomide and combinations Liposomal doxorubicin and combinationsSteroids and antihistaminesDefinitive interruption in case of ≥ grade III adverse events 50% reduction in case of grade II adverse events
Gastroenteric toxicityThalidomide and combinations Bortezomib and combinationsAppropriate diet, laxatives, exercise, hydration (for constipation or diarrhoea) oranti-diarrhoeic drugsInterruption in case of ≥ grade III adverse events 50% reduction in case of grade II adverse events
Renal toxicityLenalidomide has renal excretioncorrect potential precipitant factors, such as dehydration, hypercalcemia, hyperuricemia, urinary infections and concomitant use of nephrotoxic drugsUse dexamethasone or thalidomide or bortezomib without dose reduction Reduce lenalidomide dose in case of creatinine clearance <50 mL/min
ThrombosisThalidomide and combinations Lenalidomide and combinationsAspirin 100–325 mg if no or any one individual/myeloma thrombotic risk is present LMWH (equivalent of enoxaparin 40 mg once daily) or full dose warfarin (target INR 2–3) if two or more individual/myeloma risk factors are present and in all patients who receive high-dose dexamethasone or doxorubicin or multi-agent chemotherapy, independent of the presence of additional risk factors)Drug temporary interruption and full anticoagulation, then resume treatment
Table 4.   Risk assessment model for the management of venous thromboembolism in multiple myeloma patients treated with immunomodulatory agents (Source: Palumbo et al., Leukemia 2007;22:414.)
Risk factorsActions
  1. INR, international normalised ratio; LMWH, low-molecular-weight heparin.

  2. 1Obesity was defined as body mass index ≥30 kg/m2.

  3. 2≥480 mg/month.

Individual risk factorsIf no risk factor or any one risk factor is present: aspirin 81–325 mg once daily
 Obesity1
 Previous venous thromboembolism
 Central venous catheter or pacemaker
Associated diseaseIf two or more risk factors are present: LMWH (equivalent of enoxaparin 40 mg once daily)
 Cardiac disease 
 Chronic renal disease 
 DiabetesFull-dose warfarin (target INR 2–3)
 Acute infection 
 Immobilisation 
Surgery 
 General surgery 
 Any anaesthesia 
 Trauma 
Medications 
 Erythropoietin 
 Blood clotting disorders 
Myeloma-related risk factors 
 Diagnosis 
 Hyperviscosity 
Myeloma therapy 
 High-dose dexamethasone2LMWH (equivalent of enoxaparin 40 mg once daily)
 DoxorubicinFull-dose warfarin (target INR 2–3)
 Multi-agent chemotherapy 

References

  1. Top of page
  2. Abstract
  3. Design and methods
  4. Clinical consideration for initiation of therapy in multiple myeloma
  5. Up-front treatment for young patients
  6. Up-front treatment for elderly patients
  7. Treatment of relapsed and refractory multiple myeloma
  8. Management of the side effects of novel agents
  9. References
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