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In the 21st Century, melphalan-prednisone can no longer be regarded as the standard treatment of multiple myeloma patients not eligible for high-dose melphalan followed by autologous stem cell transplantation. The introduction of thalidomide, lenalidomide and bortezomib has improved the arsenal of therapeutic options in multiple myeloma. Indeed, randomized studies have shown that melphalan-prednisone-thalidomide and melphalan-prednisone-bortezomib are superior to melphalan-prednisone alone. Additionally, other combinations, including lenalidomide are under study. In this review we discuss the role of novel therapies in multiple myeloma in elderly multiple myeloma patients. Important aspects, such as toxicity and the role of prognostic factors, are also addressed.
Multiple myeloma is a malignant B-cell disorder characterized by a monoclonal proliferation of plasma cells in the bone marrow.(1, 2) In a recent prospective cancer screening study including 77,469 healthy subjects, among who 71 developed multiple myeloma during the course of the study, multiple myeloma was consistently preceded by the precursor condition monoclonal gammopathy of undetermined significance (MGUS). (3) Multiple myeloma accounts for about 10% of hematological malignancies.(4, 5) The median age at diagnosis is about 65-70 years and is only occasionally diagnosed in patients below 40 years of age.(4-6) Males are affected more commonly than females (7); compared to Caucasians, Blacks have higher rates of both MGUS and multiple myeloma (8). MGUS and multiple myeloma are 2- to 3-fold more common among blood relatives of MGUS/multiple myeloma patients (9-11). In the Western world, the annual age-adjusted incidence for multiple myeloma is 4.8-8 per 100,000.(5)
In multiple myeloma, the proliferation of B-cells commonly results in overproduction of monoclonal immunoglobulins, termed M-proteins. Approximately 8% of all patients are asymptomatic at diagnosis.(12) Clinical signs and symptoms may be caused by direct tumor growth or the monoclonal products. The malignant proliferation of plasma cells produces skeletal destruction that leads to bone pain and pathologic fractures. The M-protein may lead to renal failure, hyperviscosity syndrome, or through suppression of uninvolved immunoglobulins result in recurrent infections. Anemia and hypercalcemia are common complications.(13)
A number of prognostic factors have bee identified in various multiple myeloma patient populations and following different therapies. Today, the International Staging System (ISS) is the most widely used prognostic scoring system, and provides a simple and reproducible three-stage classification: stage I is characterized by β2-microglobulin less than 3.5 mg/L and serum albumin higher than 3.5 g per 100 mL and had a median survival of 62 months; stage II is represented by neither stage I nor III and showed a median survival of 44 months; and stage III is defined by β2-microglobulin above 5.5 mg/L with a median survival of 29 months (Table 1).(14)
Patients with symptomatic multiple myeloma may be classified into high-risk or standard-risk disease (Table 2).(15, 16) Acquired chromosomal abnormalities significantly impact survival in myeloma patients. In current clinical practice, poor prognosis is associated with the presence of immunoglobulin heavy chain translocations t(4;14), t(14;16), t(14;20), deletion 17p13 or deletion 13. By contrast, a favorable prognosis has been observed in the presence of t(11;14), t(6;14) or hyperdiploidy. (17-20) In research settings, gene expression profiling (GEP) has become an increasingly powerful tool with the aim to characterize prognostic profiles (21), and define distinct multiple myeloma subtypes.(22, 23)
It must be noted that the ISS and the adverse impact of cytogenetic abnormalities, as well as by GEP, are established in the context of conventional therapies but not with novel treatments. Also other factors, such as age at diagnosis, performance status, and response to therapy are of importance in the prognosis of multiple myeloma patients.(24, 25)
At this time, there are no data to support that asymptomatic multiple myeloma patients benefit from early treatment.(26) Therefore therapy shall not be given to asymptomatic multiple myeloma patients in clinical practice. However, clinical trials are currently ongoing in order to determine if new agents can delay progression from asymptomatic to symptomatic myeloma, and thereby prolong survival.
Patients with a diagnosis of multiple myeloma and with symptomatic disease are in need of therapy. Based on our overall aim to improve and develop new therapeutic strategies and novel drugs, we are in strong support of clinical trials in multiple myeloma. For patients that are not eligible for clinical trials, or if clinical trials are not available, in a standard clinical setting , one may separate multiple myeloma patients into those who are eligible versus those who are ineligible for high-dose melphalan therapy followed by an autologous stem cell transplant (16). In most institutions, patients considered ineligible for autologous stem cell transplantation are those greater than 65-70 years of age, with a serum creatinine >2.5 mg/dL, ECOG performance status 3 or 4, or New York Heart Association functional status class III or IV, or a combination. Patients with renal failure may be transplanted, but the morbidity and mortality is higher.(27). Given the high median age at diagnosis and concurrent morbidity, the majority of all multiple myeloma patients are not eligible for autologous stem cell transplantation.
Since the 1960s, oral melphalan and prednisone (MP) has been the standard of therapy for patients not eligible for autologous stem cell transplantation.(28, 29) Until recently, MP was considered standard of care for symptomatic patients older than 65-70 years. Based on several clinical trials, the response rate with MP is only 50-60% and complete remissions (CR) are rare. This is reflected in a median overall survival of 24 to 48 months.(28, 29) Consequently, through the years, many clinical trials have been conducted to develop treatment regimens with higher response rates and improved overall survival compared to MP. In a large meta-analysis of 4,930 symptomatic myeloma patients in 20 prospective trials, the response rate was 60% for combination chemotherapy compared to 53% for MP (p < 0.001). However, there was no difference in survival. Also the meta-analysis failed to identify a subset of patients who benefited from additional combinations of chemotherapy (28).
The discovery of novel therapies, including thalidomide, bortezomib and lenalidomide, targeting both myeloma cells and the bone marrow microenvironment, has changed the paradigm of myeloma therapy, especially for the elderly population. Thalidomide and lenalidomide have been found to have anti-angiogenesis properties, stimulate T- and natural killer cells and interfere with cytokines. They suppress growth factors such as interleukin-6, tumor necrosis factor-α, inhibit myeloma cell adhesion and blood vessel growth cytokines such as vascular endothelial growth factor.(30, 31)
Bortezomib, a proteasome inhibitor, specifically interferes with the 26S proteasome, which is responsible for degrading protein that control transcription, the cell-proliferation cycle and metabolism.(32) Interestingly, although the initial rationale for its use in multiple myeloma was inhibition of NF-kappa-B activity by blocking proteasomal degradation of I-kappa-B-alpha, recent work indicates that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in multiple myeloma. (33)
Combinations of novel agents with steroids, alkylating agents or anthracyclines have significantly improved response rates, progression-free survival (PFS), and overall survival in multiple myeloma.(34-40) There is also evidence that novel agents may overcome the poor prognosis induced by chromosomal abnormalities and ISS score. Below we review and discuss results and toxicities from major studies based on novel multiple myeloma drugs.
Recently, MP has been combined with thalidomide (MPT) in five different randomized studies (Table 3). Palumbo et al. reported a randomized trial (GIMEMA trial) comparing MPT with MP in 255 patients with newly-diagnosed myeloma aged 65 to 85 years who were considered ineligible for an autologous stem cell transplant.(41) The patients were randomized to six 4 week cycles of melphalan (4 mg/m2 on days 1-7) and prednisone (40 mg/m2 on days 1-7) or MP plus thalidomide 100 mg daily (MPT) during the six cycles and then as maintenance until sign of relapse or progressive disease. The response rate was 76% and CR 16% in the MPT regimen, compared to 48% and 2%, respectively, for MP. The two-year event-free survival was 54% vs. 27%, while the three-year survival was 80% vs. 64%, favoring the MPT regimen, although not significantly (41). In a recent update of that trial, after a median follow-up of 38 months there was still a significantly superior PFS in the MPT arm. However the median overall survival was similar, 45 months in the MPT group and 47.6 in the MP group.(42)
Grade 3-4 adverse events occurred in 48% with the MPT regimen, compared to 25% for MP. The risk of thromboembolic phenomena (12% vs. 2%) was significantly increased in the MPT group. Because of that the protocol was amended and enoxaparin 40 mg per day was given, during the first four cycles as anticoagulation prophylaxis, with a reduction in the number of events. Additionally infections (10% vs. 2%), peripheral neuropathy (8% vs. 0%), and constipation (6% vs. 0%) were greater in MPT compared to MP.
In the second study, the IFM 99-06, the French Myeloma Group reported on 447 previously-untreated patients with myeloma aged 65 to 70 years who were ineligible for autologous stem cell transplantation.(43) They were randomized to 12 cycles of 6-weeks melphalan (0.25 mg/kg) and prednisone (2mg/kg) (days 1-4) and thalidomide (given in an increasing dosage to a maximum of 400 mg daily if tolerated during the cycles and then stopped); or melphalan and prednisone in the same dosage and schedule; or VAD followed by melphalan 100 mg/m2 × 2 followed by stem cell rescue. A higher partial response (PR) rate was seen in the MPT and in the melphalan 100 mg/m2 groups, compared with MP (76 vs. 65 vs. 35%, respectively). Similarly, the CR rates were significantly higher with MPT (13%) and intermediate-dose melphalan (18%) compared with MP (2%). Median PFS was 27.5 months in the MPT patients and 17.8 months in the MP group (P<0.0001), and median overall survival was significantly better in the MPT group compared to the MP group (51.6 and 33.2 months, respectively (P<0.001) and the melphalan 100 mg/m2 group (P=0.027).(43)
Compared to the MP group, MPT was associated with higher rates of grade 3 or 4 neutropenia (48%), constipation (10%), and somnolence, fatigue/dizziness (8%). Patients did not receive anticoagulation, and 12% of the patients in the MPT arm developed venous thromboembolism.
In another French study (IFM 01-01), 229 patients with previously untreated multiple myeloma who were greater than 75 years of age, were randomized to melphalan 0.2 mg/kg plus prednisone 2 mg/kg days 1-4 every 6 weeks for 12 cycles or melphalan and prednisone in the same dosage plus thalidomide 100 mg daily (MPT) without maintenance.(44) The PR rate was 62% in the MPT group and 31% in the MP group, and CR was observed in 7% and 1% respectively. Median PFS was 24.1 months for MPT and 19.0 months for MP (P=0.001), and median overall survival was 45.3 months for MPT and 27.7 months for MP (P=0.03).(44)
Toxicity in this elderly population was similar to that observed in earlier trials. Peripheral neuropathy was seen in 39% in the MPT group compared to 21% in the MP group. Grade 3-4 neutropenia was greater in the MPT arm. No anticoagulation was prospectively planned, and no significant difference was observed in thrombosis complication between the arms, possibly related to more frequent use of anti-thrombotic treatments for other co-morbidity in this age group.(44)
In a study by the Nordic Myeloma Study Group, 362 patients with a mean age of 75 years (range, 49–92) were randomized to receive melphalan (0.25 mg/kg) and prednisone (100 mg) for four days every 6 weeks until plateau phase.(45) The MPT arm received additionally thalidomide at a starting dose of 200 mg, escalating to 400 mg if possible, and then given as maintenance as 200 mg in plateau phase. Results of an interim analysis showed better PR (27% vs. 22%) and CR/nCR (6% v. 3%) in the MPT group compared to MP. No difference was observed in PFS or overall survival (29 vs. 33 months) in this study. Furthermore in patients above 75 years there was a tendency to higher early mortality in the MPT group.
No thrombosis prophylaxis was given and there was no difference in the incidence of thromboembolic complications, however approximately 30% of the patients had anti-thrombotic treatment for other reasons.(45)
In the HOVON study, 344 patients age 65 years and older were randomized to receive eight 4-week cycles of melphalan (0.25 mg/kg days 1-5), prednisone (1 mg/kg days 1-5) with or without 200 mg of thalidomide, until plateau.(46) The MPT arm additionally received thalidomide as maintenance, 50 mg per day. The overall response rates were higher in MPT group (66% vs. 47%) and CR was 2% in both arms. The PFS was significantly improved in the MPT group (P<0.001). Median overall survival was 37 months in the MPT group compared to 30 months in MP (not significant).
Grade 2-4 toxicity was seen in 60% of the patients in the MP arm and in 88% of the MPT patients, and was mainly due to peripheral neuropathy. No differences between the two arms were seen for other toxicities.(46)
Taken together, results from these five randomized studies have been consistent with regards to response rate being superior in the MPT arms compared to MP, however all but one have shown an improvement in PFS. Only the two French studies have shown a survival benefit. Comparisons between different studies are difficult to make because of differences in patient populations, duration of treatment and use of maintenance regimens. Despite these differences, data strongly support the MPT regimen as the new standard of care for elderly myeloma patients. In all studies, the MPT patients showed a higher incidence of extra-hematological toxicities compared with the MP regimen, especially neurological adverse events, infections, and thromboembolism. Anti-thrombotic prophylaxis is recommended when using MPT, and aspirin seems to be a safe option.(24) The higher toxicity rate significantly reduced the efficacy of the MPT combination. Randomized studies that used more strict inclusion criteria showed better outcome. In the French studies, a higher incidence of grades 3–4 hematological toxicity (neutropenia and thrombocytopenia) was also observed, probably due to a higher number of MP cycles administered (12 cycles) and a higher dose of thalidomide (median dose 200 mg). The duration of MP treatment may also be reduced from 12 cycles to 6 cycles, as prolonged melphalan exposure induces thrombocytopenia that hampers the delivery of subsequent effective salvage regimens.
In younger patients, Thal/Dex significantly improves PFS in comparison with high-dose dexamethasone alone.(34) In 289 elderly patients, Thal/Dex was compared with MP in a randomized study. Patients in the Thal/Dex arm had a significantly higher response rate but failed to show any advantage in PFS. In fact, overall survival was inferior with Thal/Dex compared with MP (P=0.024).(47) Patients on Thal/Dex experienced more grades 2–3 neuropathy (25%) and skin toxicity (12%) compared with those on MP (8 vs. 3%, respectively), particularly in patients older than 75 years with poor performance status. Thromboembolic complications were seen in 8% of patients receiving Thal/Dex and in 3% of patients receiving MP. The higher toxicity rate of Thal/Dex regimen can explain the lower efficacy of Thal/Dex in the elderly population.
In the Medical Research Council Myeloma IX trial, cyclophosphamide, thalidomide and dexamethasone (CTD) was been compared with MP in 900 patients. In the CTD group, the PR rate (82 vs. 49%) and the CR rates (23 vs 6%) were significantly superior in the CTD group.(48) Data on remission durations are not available, and mature survival data are needed on this trial prior to making recommendations for clinical practice.
The Spanish cooperative group conducted a large phase I/II trial of melphalan, prednisone, and bortezomib, (MPV), with encouraging results.(49) This study formed the basis for the VISTA trial, where 682 patients, median age 71 years (range 48-91), where randomized to receive 9 six-week cycles of bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11, 22, 25, 29, 32 during cycles 1-4 and bortezomib 1.3 mg/m2 on days 1, 8, 22, and 29 during cycles 5-9 plus melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 of each cycle (MPV) or to MP in the same dosage and schedule.(50) The response rates were better in the MPV arm, both PR (71% vs. 4%) and, importantly a very high CR was observed in the MPV arm (30% vs. 4%). Median survival was not reached in either group but at 16 months the survival was significantly improved in the MPV arm (P=0.008). Furthermore, the efficacy seemed not to be influenced by poor prognostic factors, including ISS stage, renal failure, and high risk cytogenetic profiles.(50)
As expected, neutropenia, thrombocytopenia, anemia, and gastrointestinal symptoms were more common with the MPV regimen. Peripheral neuropathy occurred in 44% of the MPV group and in 5% with MP; This included 13% risk of grade 3 neuropathy in the MPV arm. The peripheral neuropathy resolved or improved in 74% of patients within a median of two months.(50) Pre-existing neuropathy or previous neurotoxic therapy increases the risk of peripheral neuropathy, which can be reduced or resolved by prompt dose reduction of the drug. The incidence of neuropathy can also be reduced greatly by once weekly administration of bortezomib instead of the twice-weekly schedule. There is an increased risk of herpes zoster infection with MPV, and prophylactic antiviral medications are recommended. There was no difference in the incidence of venous thromboembolism between the groups.
The Italian group evaluated in a phase I/II trial, dosing, safety and efficacy of melphalan plus prednisone and lenalidomide (MPR) in newly diagnosed elderly myeloma patients.(51) The maximum tolerated dose was considered to be melphalan at 0.18 mg/kg on days 1–4, prednisone at a 2-mg/kg dose on days 1–4 and lenalidomide at 10 mg on days 1–21, every 28 days for nine cycles. Aspirin was given as a prophylaxis for thrombosis. Eighty-five percent of patients achieved at least a PR, and 23.8% achieved immunofixation-negative CR. The 1-year event-free and overall survival was 92 and 100%, respectively. Preliminary results showed that the event-free survival of patients with deletion of chromosome 13 or chromosomal translocation (4;14) was not significantly different from those who did not have such abnormalities.(51) The results of an international phase III study comparing MP vs MPR are awaited. An Eastern Cooperative Oncology Group (ECOG) study comparing MPT versus MPR is ongoing.
Grades 3–4 adverse events in the Italian study were mainly related to hematologic toxicities (neutropenia 66%). Severe non-hematologic side effects were less frequent and included febrile neutropenia (8%), cutaneous rash (10%) and thromboembolism. Neutropenia and DVT are the major complications with lenalidomide, although the addition of aspirin markedly reduced the risk of thromboembolic events in newly diagnosed patients treated with lenalidomide in association with dexamethasone or chemotherapy.(51) Recommendations for thrombo-prophylaxis in patients treated with thalidomide or lenalidomide have been published, and aspirin seems to be the preferred choice in the absence of additional risks of thromboembolism.(24) The addition of granulocyte-colony stimulating factor is recommended in case of neutropenia, and melphalan dose reduction (from 0.18 to 0.13 mg/kg) should be applied in the presence of severe neutropenia despite granulocyte-colony stimulating factor.
A randomized trial from the ECOG group studied 445 previously untreated symptomatic multiple myeloma. Patients were assigned to lenalidomide (25 mg daily days 1 to 21) plus high-dose dexamethasone (40 mg daily on days 1 to 4, 9 to 12, and 17 to 20) or to lenalidomide in the same dose and schedule plus dexamethasone 40 mg given weekly for each 28-day cycle.(52) The median age was 66 years, and included 233 patients older than 65 years. Among all patients preliminary results show that the one-year survival was 96% for lenalidomide/low-dose dexamethasone compared to 88% for lenalidomide plus high-dose dexamethasone. Early deaths were more common in the high-dose arm. The two-year survival probability was 87% and 75%, respectively.(52). Among elderly patients the 2-year survival was also superior in the low-dose group.
There was significantly more grade 3-4 toxicity among patients in the low dose dexamethasone group (34% vs. 52%), including infections, fatigue, venous thrombosis. The risk of deep venous thrombosis was less in the low dexamethasone regimen (6% vs. 25%), as was the incidence of infections (7% vs. 14%).(52) Based on these results, a randomized trial comparing lenalidomide plus low dose dexamethasone and MPT has been initiated, and accrual is ongoing.
There are a few studies on thalidomide maintenance after autologous stem cell transplantation, suggesting that it may improve outcome in a subset of patients with high risk myeloma or a poor response after autologous stem cell transplantation.(36, 53-56) However, there are no studies supporting maintenance therapy after MPT or MPV. Currently, patients are treated for a fixed duration of 18 months with MPT with no maintenance based on the French studies.(43, 44) Similarly, with MPV, the treatment duration is for 12 months followed by no maintenance. Lenalidomide is better suited to maintenance, but little data are available. At Mayo Clinic, if patients are treated with lenalidomide plus low-dose dexamethasone, patients are offered the option of continuing lenalidomide until progression after 12-18 months of treatment.
Similar to historical drugs, the efficacy of novel multiple myeloma regimens have to be balanced against their higher toxicities. At present in elderly patients, MPT, MPV, MPR, and lenalidomide plus low-dose dexamethasone have all shown significant clinical activity. Treatment with MPT and MPV are supported by phase III trials showing superiority in overall survival compared with MP. Lenalidomide and low dose dexamethasone had the advantage of low toxicity. Randomized trials have not compared these regimens, and in the absence of such trials, the choice of regimen should take into account several factors. Although the numbers are small, it appears that MPV overcomes the adverse effect of chromosomal abnormalities (50). Thus in the presence of high risk cytogenetic features (Table 2), as well as in patients at high risk for thromboembolism, and in patients with renal insufficiency, MPV is the preferred option, whereas MPT is preferred for patients with standard risk disease. Lenalidomide plus low dose dexamethasone is a reasonable alternative to MPT. MPR is also an emerging alternative. There is no evidence that continued chemotherapy with melphalan and prednisone is of benefit after achieving a plateau state, and hence treatment with MPT and MPV is given for a fixed duration of time. There is a risk of myelodysplasia from continued treatment with alkylating agents.
Management of complications in patients with multiple myeloma is also important, especially in the elderly with more co-morbidity. Recommendations on the management of complications such as skeletal disease, hypercalcemia, anemia, renal insufficiency, infections and thrombosis have been published.(13, 24, 57)
Results from three population-based studies (one registry-based Swedish study, one registry-based U.S. SEER study, and one hospital-based study from the Mayo Clinic, MN), indicate that survival in multiple myeloma has improved in recent years, after the introduction of the novel agents.(58-60) However, in all the improvement was predominantly observed in the younger patients. A limitation of these investigations is the fact that none of the three studies had detailed information on individual patients' clinical characteristics or therapy. Underlying causes of the absence of improvement in long-term survival among elderly patients remain unclear and are probably multifactorial, including increased co-morbidity among older patients. Early mortality has been reported to be higher among elderly patients.(61) In addition to the fact that patients do not tolerate aggressive treatment such as high dose therapy, it has also been proposed that elderly patients present with a more advanced disease at diagnosis.(62, 63) Results from randomized studies indicate that survival has improved in elderly patients with multiple myeloma with the introduction of novel agents. Innovative agents and procedures suitable for the older patient (>70 years) coupled with better prognostic markers used to guide individualized treatment in multiple myeloma are greatly needed.
In the shorter perspective, a key clinical challenge will be to better define the optimal sequence, combination(s), and use of available novel multiple myeloma drugs. In the future, molecular diagnostics/prognostics together with more targeted designed drugs and integrated molecular monitoring, will likely become increasingly important to explain clinical heterogeneity, to provide more personalized treatment strategies, and thereby improve survival for multiple myeloma patients. (21)
Supported in part by Grants CA62242 and CA107476 from the National Cancer Institute, Bethesda, MD.