New treatment options for patients with myeloma have helped to change the natural history of this disease, even in the context of relapsed disease. For standard-risk patients, doublet-based therapy may offer benefit, whereas for patients with aggressive or genetically high-risk disease combinations of agents are needed for adequate disease control. Second-generation agents offer significant activity for patients with refractory myeloma, and new categories of agents provide new targets for future study and clinical use. Combinations of these agents in selected patient populations represent the next stage in the quest to cure myeloma.
Key points
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Complete remission is becoming a crucial end point for longer survival in relapsed/refractory patients, especially for those not heavily pretreated.
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Disease-related and patient-related conditions should be considered in the management of relapsed and refractory multiple myeloma (RRMM), but the therapeutic choices presented by cytogenetic abnormalities are still untimely.
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Response to previous therapy may also contribute in deciding the treatment approach at the time of relapse, but no conclusive data outlining the most appropriate sequence of treatment of patients with RRMM exist.
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Carfilzomib and pomalidomide seem more effective and safer than their predecessors, and they may soon become the new standard in the treatment of multiple myeloma.
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Emerging agents with innovative mechanisms of action, like histone deacetylase inhibitors, monoclonal antibodies, and kinesin spindle protein inhibitors, are already proving to be effective in the relapsed setting.
Introduction
Improvements in treatment options over the last decade have contributed to a doubling in the median overall survival (OS) for patients with myeloma. Despite this progress, in large part because of the use of high-dose therapy (HDT) and autologous transplant as well as new drugs such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI), multiple myeloma (MM) remains a disease of which few patients are cured, and most patients relapse and require additional therapy.
In 2006, the International Myeloma Working Group (IMWG) modified the definition of relapse/refractory disease within the context of new response criteria for MM. The definition of relapsed myeloma is now based on laboratory or imaging criteria (25% increase from nadir in the serum or urine monoclonal protein, or difference between involved and uninvolved serum-free light chain levels), whereas the need to initiate therapy for a relapsed patient requires the development of symptomatic relapse such as the appearance of at least 1 clinical manifestation of organ damage summarized by the CRAB (increased calcium, renal failure, anemia, and bone disease) symptoms. For patients with nonsecretory myeloma, an increase in marrow plasma cells or bone disease is used to define progression, whereas symptomatic relapse is defined the same way as for patients with secretory myeloma. Refractory disease is defined as progression on therapy, or within 60 days from the last treatment. Patients who never achieve at least a minimal response (MR) to initial antimyeloma therapy and progress on therapy are defined as primary refractory patients with MM.
Important advances have been made recently in understanding the biology and pathogenesis of the disease. The genomic instability of the myeloma cell predisposes patients to acquire new mutations or genetic events resulting in numerical and structural chromosomal abnormalities. The clinical heterogeneity of MM is caused by numerous different types of myeloma guided by different underlying genetic changes. Although on pathology plasma cells may look similar, using gene expression profiling or routine fluorescent in situ hybridization and cytogenetics, there are differences in disease biology between patients with hyperdiploid myeloma and with patients who harbor the t (4:14) or deletion of 17p. In addition to interpatient differences in disease biology, within a single patient there may be different clones of cells that harbor different mutational profiles resulting in disease evolution over time. The clinical significance of these different clones identified by whole-genome sequencing is currently under intense study; however, the sequence in which therapies are delivered may create new selective pressures and induce different biological responses in the different clones. If the disease is to be cured, aggressive therapy with the goal of eradication of all clones of disease to prevent emergence of more resistance subclones should remain a high priority.
Introduction
Improvements in treatment options over the last decade have contributed to a doubling in the median overall survival (OS) for patients with myeloma. Despite this progress, in large part because of the use of high-dose therapy (HDT) and autologous transplant as well as new drugs such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI), multiple myeloma (MM) remains a disease of which few patients are cured, and most patients relapse and require additional therapy.
In 2006, the International Myeloma Working Group (IMWG) modified the definition of relapse/refractory disease within the context of new response criteria for MM. The definition of relapsed myeloma is now based on laboratory or imaging criteria (25% increase from nadir in the serum or urine monoclonal protein, or difference between involved and uninvolved serum-free light chain levels), whereas the need to initiate therapy for a relapsed patient requires the development of symptomatic relapse such as the appearance of at least 1 clinical manifestation of organ damage summarized by the CRAB (increased calcium, renal failure, anemia, and bone disease) symptoms. For patients with nonsecretory myeloma, an increase in marrow plasma cells or bone disease is used to define progression, whereas symptomatic relapse is defined the same way as for patients with secretory myeloma. Refractory disease is defined as progression on therapy, or within 60 days from the last treatment. Patients who never achieve at least a minimal response (MR) to initial antimyeloma therapy and progress on therapy are defined as primary refractory patients with MM.
Important advances have been made recently in understanding the biology and pathogenesis of the disease. The genomic instability of the myeloma cell predisposes patients to acquire new mutations or genetic events resulting in numerical and structural chromosomal abnormalities. The clinical heterogeneity of MM is caused by numerous different types of myeloma guided by different underlying genetic changes. Although on pathology plasma cells may look similar, using gene expression profiling or routine fluorescent in situ hybridization and cytogenetics, there are differences in disease biology between patients with hyperdiploid myeloma and with patients who harbor the t (4:14) or deletion of 17p. In addition to interpatient differences in disease biology, within a single patient there may be different clones of cells that harbor different mutational profiles resulting in disease evolution over time. The clinical significance of these different clones identified by whole-genome sequencing is currently under intense study; however, the sequence in which therapies are delivered may create new selective pressures and induce different biological responses in the different clones. If the disease is to be cured, aggressive therapy with the goal of eradication of all clones of disease to prevent emergence of more resistance subclones should remain a high priority.
The achievement of complete remission
Although there is growing evidence that a deeper quality of response is associated with prolonged OS in newly diagnosed MM (NDMM), in the relapsed setting the impact of complete response (CR) on survival is still under debate.
Emerging data in the early relapse setting (1–3 prior lines) suggests that a depth of response seen with 3 agents rather than 2 may predict longer OS, but additional studies are needed to confirm this benefit. Niesvizky and colleagues analyzed the impact of quality of response on clinical benefit for patients who received bortezomib within the context of the phase III Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial. Although median OS was not reached in the various response cohorts, it was observed that patients achieving CR had a substantially longer median treatment-free interval (24.1 months) compared with patients attaining very good partial remission (VGPR) (13.6 months) or partial remission (PR) (6.4 months). Furthermore, in this study the best outcomes were noted in the patients who experienced a MR to bortezomib compared with nonresponders in terms of time to progression (TTP) (4.9 vs 2.8 months) and OS (24.9 vs 18.7 months). Another study reported that a bortezomib-based regimen led to a trend toward an OS benefit in patients attaining at least a VGPR compared with those who reached only a PR, and event-free survival (EFS) was significantly longer in the first group (1-year EFS, 83% vs 16% respectively; P = .02). The beneficial impact of CR was observed with 4-drug combination thalidomide-doxil-dexamethasone-bortezomib (ThaDD-V), which led to a longer TTP in patients obtaining CR (3-year TTP, 67%) compared with those achieving lower response (3-year TTP, 10%; P <.001). A pooled analysis from 2 randomized phase III trials (MM-009 and MM-010) showed that response to lenalidomide plus dexamethasone improved over time, with better quality of response associated with improved clinical outcomes. With a follow-up of 48 months, median TTP and OS were longer in patients who achieved CR/VGPR compared with patients who obtained a PR (TTP, 27.7 vs 12.0 months; P <.001; OS, not yet reached vs 44.2 months; P <.021), regardless of when high-quality response was achieved.
In the context of refractory or late relapse, the opposite situation is the case, because patients with MR seem to have a similar progression-free survival (PFS) and OS when treated with either carfilzomib or pomalidomide in the refractory setting. Whether this discordance is a consequence of poor performance status and tolerance of therapy at the end stages of treatment or disease biology is unknown. Nonetheless, the impact of CR on outcomes in the late relapse setting seems to be less important.
Prognostic factors
Among relapsed patients, the challenge is to select the best approach for each patient while balancing efficacy and toxicity. At present there are limited biomarker-driven approaches by which clinicians can optimally select the choice of salvage therapy. In practice, the decision of what to use in the relapsed setting is likely influenced by patient-related features (ie, preexisting toxicities, quality of life, age, performance status, and comorbidities), disease-related factors such as cytogenetic abnormalities, and treatment-related features such as the impact of previous therapies.
Impact of Cytogenetic Abnormalities
The prognostic value of chromosomal abnormalities such as del (13q), t (4;14), del (17p), or gain of 1q21 have not been well assessed in relapsed and refractory multiple myeloma (RRMM) in a prospective fashion because these data are often collected at individual sites, rather than through central review allowing standardization of methodology. Retrospective analysis of phase II-III trials including patients receiving single agents or new drug combinations often show benefit for new drugs to overcome poor-risk genetics; however, patients with poor-risk genetics who are enrolled in clinical trials of new drugs often have a different natural history because they are able to make it onto these trials. As such, these data should be viewed as retrospective and potentially limited in terms of broad applicability.
A Canadian group reported that amplification of 1q21 in patients with RRMM who received bortezomib-based therapy was associated with a significantly worse outcome (median PFS, 2.3 months vs 7.3 months for patients with 1q21 gains vs those who lacked this; P = .003; median OS, 5.3 months vs 24.6 months for patients with +1q21 and without +1q21; P = .0006), whereas no statistically significant difference in OS was observed for patients with other genetic risk factors like del (13q), t (4;14), del (17p), or del (1p21). In a post-hoc subanalysis of an expanded access program, treatment with lenalidomide-dexamethasone (RD) overcame the poor prognosis conferred by deletions of chromosome 13q or t (4;14) with similar median TTP and OS to patients without these cytogenetic abnormalities. However, Avet-Loiseau and colleagues found that the patients with t (4;14) had a shorter survival compared with those without this translocation (median PFS, 5.5 months vs 10.6 months; P <.01; median OS, 9.4 months vs 15.4 months; P = .005). With another lenalidomide-based combination, the overall response rate (ORR) was similar for patients with or without del (13q) or t (4;14), but the presence of del (17p) was associated with a significantly poorer response (20% vs 87%; P = .001) and a significantly shorter median TTP (20 vs 45.5 weeks; P = .025) than in patients without this cytogenetic abnormality. In the MM-016 study, the association RD similarly had poor activity in patients with RRMM and del (17p13), with significantly shorter median TTP (2.2 months; P <.001) and OS (4.7 months; P <.001) relative to patients without this cytogenetic abnormality.
In a prospective study, Dimopoulos and colleagues showed that the negative impact on outcome of +1(q21) was evident in the RD group ( P = .032) but not in the VRD group ( P = .121); the patients carrying del13q had shorter survivals in both arms, although it was more pronounced in the RD group, and the presence of t (4;14) was not associated with poor OS regardless of the use of bortezomib. However, despite the addition of bortezomib to lenalidomide-dexamethasone, the investigators found that del (17p) remained one of the most important negative prognostic factor for achieving a deeper response and longer survival.
In a recent study evaluating the impact of genetics on responses with carfilzomib, Jakubowiak and colleagues found that carfilzomib as single agent was not able to overcome the poor prognosis associated with high-risk cytogenetics, with a significantly shorter OS in patients with del (17p), t (4;14), or t (14;16) compared with those with normal karyotypes (median OS, 9.3 months vs 19 months respectively; P = .0003). A phase III trial evaluated the combination of pomalidomide and low-dose dexamethasone versus high-dose dexamethasone revealed a substantially greater benefit in terms of response for patients with t (4;14) and del (17p) in the pomalidomide arm relative to those in steroid group (ORR, 23% vs 6% respectively; P = .032) and outcome (median PFS, 3.8 months vs 1.1 mo; hazard ratio [HR], 0.46; P <.001).
In conclusion, at the moment there are conflicting data for overcoming poor-risk cytogenetics in the relapsed setting. It is likely that combination therapy is needed, in addition to long-term therapy. In a prospective study pomalidomide had activity among 17p-deleted patients, and perhaps combinations of pomalidomide and PI represent the current best approach for high-risk myeloma in the relapsed setting. Additional information is needed to use genetics more accurately to guide the choice of salvage therapy.
Impact of Previous Therapy, Retreatment, and Sequence of Drugs
Most NDMM are currently treated with combinations containing at least 1 new drug. There is concern that use of novel agents as part of induction may limit postrelapse survival because most data series suggest that, with each successive relapse, duration of response shortens progressively. However, the duration of therapy with 1 or more novel agents does not limit practical options for management in the relapsed setting because most younger patients receive 4 cycles of induction followed by HDT consolidation. Krejci and colleagues retrospectively compared outcomes following the use of thalidomide or bortezomib following induction, and at the time of first relapse they did not find significant differences between 2 treatment groups, suggesting that choice of induction, when used for a limited duration, does not affect the success of therapy in the early relapse setting.
In the refractory disease setting, In the MM-003 trial of pomalidomide and low-dose dexamethasone versus dexamethasone alone, pomalidomide/dexamethasone prolonged survival regardless of type or number of previous therapies, although the magnitude of OS benefit was greatest among patients who had received fewer than 3 prior regimens.
When evaluating a similar question with second autologous transplant as the relapse therapy choice, Olin and colleagues showed that the number of prior therapies (≥5 vs <5 lines) was the strongest predictor of poor PFS and OS after salvage transplantation. This finding has recently been corroborated by a second group, with poorer outcomes among patients with more prior therapy (HR, 5.1; 95% confidence interval [CI], 1.1–22.1; P = .04).
When evaluating the response rate and duration of response for the novel agents in the early relapsed setting, Vogl and colleagues reported a poorer overall response among patients treated with bortezomib alone as salvage therapy after previous therapy with thalidomide relative to thalidomide-naive patients (ORR, 30% vs 46% respectively; P <.005) and this was associated with a shorter TTP ( P = .04) and OS ( P <.001), whereas this disparity was lost when the choice of salvage therapy was bortezomib plus pegylated liposomal doxorubicin. Given the different mechanisms of action of IMiDs and PI, this difference is likely a line of therapy issue rather than the effect of induced drug resistance.
In a pooled analysis from the MM-009/MM-010 trials comparing lenalidomide and dexamethasone versus dexamethasone alone, the ORR was significantly higher among thalidomide-naive patients treated with lenalidomide and dexamethasone than among previously thalidomide-exposed patients (65% vs 54%; P = .04), as was the median TTP (13.9 months vs 8.4 months; P = .004) and PFS (13.2 months vs 8.4 months; P = .02). This difference did not translate into a difference in OS. Patients receiving combination salvage therapy, such as the use of bortezomib, lenalidomide, and dexamethasone (VRD); bortezomib, thalidomide, and dexamethasone (VTD); or bortezomib, dexamethasone, and cyclophosphamide (VCD), showed improved responses if patients had not received prior treatment with or were resistant to thalidomide.
Several studies have reported that prior bortezomib exposure is associated with a poorer outcome for patients receiving lenalidomide-dexamethasone at relapse. However, results from the recent update analysis of the VISTA trial using bortezomib as part of induction showed no impact of bortezomib exposure as the response to either lenalidomide-thalidomide–based or bortezomib-based therapy in the relapsed setting.
Although carfilzomib has shown significant clinical benefit among heavily pretreated patients, because of similar mechanism of action, better responses may be expected among bortezomib-naive or bortezomib-sensitive patients. A recent analysis suggests an improved response rate among patients who were bortezomib naive (ORR, 52%) relative to those who were bortezomib exposed (ORR, 17.1%).
At present, no conclusive data outlining the most appropriate sequence of treatments for patients with RRMM exist. If the relapse occurs earlier (6–12 months) or while the patient is still undergoing treatment, the use of an alternative regimen should be considered, but, if the treatment-free period was greater than 6 months to 1 year, the National Comprehensive Cancer Network (NCCN) guidelines suggest that the agent can be used again. If relapse occurs following single-agent or doublet therapy, the addition of a novel agent can overcome the previous resistance, acting synergistically.
Studies have specifically addressed the issue of bortezomib retreatment in RRMM, confirming that it is feasible, without evidence of cumulative toxicity. In a retrospective multicenter survey of RRMM that responded to initial bortezomib treatment, toxicity with bortezomib retreatment was commonly identified, and efficacy data showed that 63% of patients responded to retreatment, with a median TTP of 9.3 months. A recent prospective phase 2 trial showed an ORR of 40% in patients who received bortezomib as retreatment and a median duration of response (DOR) and TTP of 6.5 months and 8.4 months, respectively, after achieving at least a PR. The investigators noted a decrease in ORR with increasing number of prior therapies and also reported a trend for higher overall rates for bortezomib retreatment among patients who achieved a CR, rather than PR, following prior bortezomib therapy.
Current treatment options for RRMM
Thalidomide
Thalidomide was the first novel agent to be evaluated in RRMM, and since then many studies have shown its activity as a single agent or in combination. A systematic review of 42 clinical studies published by Glasmacher and colleagues reported that thalidomide monotherapy produced at least a PR in 30% of RRMM, with a median OS of 14 months. The most frequent grade 3 or 4 toxicities were constipation (16%), sedation (11%), peripheral neuropathy (PN) (6%), and increased risk of venous thromboembolism (VTE) (3%). The neuropathy occurred more frequently if the daily dose exceeded 200 mg or particularly after prolonged exposure; 70% of patients treated for 12 months experienced at least mild PN.
Many studies have shown that ORR can be significantly enhanced (to 50%) with the addition of concomitant dexamethasone. Because thalidomide is not myelotoxic and potentiates the apoptotic activity of other agents, several conventional cytotoxic agents have been combined with thalidomide-dexamethasone (TD) in order to increase the depth and extent of response. One of the largest data sets of combination therapy has combined cyclophosphamide with TD, with high ORR; (57%–84%). The use of thalidomide with continuous low-dose cyclophosphamide alone was also effective with 64% of patients reaching at least PR. Other combinations containing thalidomide in RRMM include melphalan with or without prednisone or dexamethasone, liposomal doxorubicin (pegylated liposomal doxorubicin [PLD]), PLD-vincristine-dexamethasone, bendamustine-prednisolone, or dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide (DT-PACE) ( Table 1 ).
| Study | Phase | N | Regimen | Schedule | Prior Treatment | ORR (%) | CR (%) | TTE | Key Toxicities (% of Patients) |
|---|---|---|---|---|---|---|---|---|---|
| Garcia-Sanz et al, 2004 | II | 71 | CTD | C: 50 mg continuously for 28-d cycle T: 200–800 mg (median dose 600 mg) continuously D: 40 mg days 1–4, 15–18 | 52% ≥2 | 55 a | 2 a | 2-y PFS: 57% 2-y OS: 66% | Grade ≥3 neutropenia: 10 Grade ≥3 infection: 7 Grade ≥2 PN: 6 Grade ≥3 venous thromboembolism: 7 Grade ≥2 constipation: 24 |
| Kyriakou et al, 2005 | II | 52 | CTD | C: 300 mg/m 2 days 1, 8, 15, 22 of 28-d cycle T: 50–300 mg continuously D: 40 mg days 1–4 | Median: 2 | 78.8 | 17.3 | 2-y EFS: 34% 2-y OS: 73% | All grade neutropenia: 38.5 Grade ≥3 infections: 19 Grade ≥3 PN: 0 Grade ≥3 venous thromboembolism: 7.5 |
| Kropff et al, 2003 | II | 60 | CTD | C: 300 mg/m 2 days 1–8 of 28-d cycle T: 100–400 mg continuously D: 20 mg/m 2 days 1–4, 9–12, 17–20 | Median: 2 | 72 | 4 | Median EFS: 11 mo Median OS: 19 mo | Grade ≥3 neutropenia: 67 Grade ≥3 infection: 23 Grade ≥3 PN: 16 |
| Palumbo et al, 2006 | I/II | 24 | MPT | M: 20 mg/m 2 days 1 every fourth month P: 12.5–50 mg every other day T: 100–400 mg continuously | Median: 3 T: 66% | 41.7 | 0 | Median PFS: 9 mo Median OS: 14 mo | Grade ≥3 neutropenia: 42 Grade ≥3 thrombocytopenia: 21 Grade ≥3 infection: 8 Grade ≥3 PN: 8 |
| Offidani et al, 2006 | II | 50 | PLD-TD | PLD: 40 mg/m 2 day 1 of 28-day cycle T: 100 mg continuously D: 40 mg days 1–4, 9–12 | 54% >2 | 76 | 26 | Median EFS: 17 mo Median PFS: 22 mo Median OS: NR | Grade ≥3 neutropenia: 16 Grade ≥3 infections: 16 Grade ≥3 PN: 2 |
| Pönish et al, 2008 | I | 28 | BT-PNL | MTD: NR; highest dose level: B: 60 mg/m 2 days 1, 8, 15 of 28-d cycle T: 50–200 mg continuously PNL: 100 mg days 1, 8, 15, 22 | Median: 2 T: 14% V: 28% | 85.7 | 14.3 | Median PFS: 11 mo Median OS: 19 mo | Grade ≥3 neutropenia: 43 Grade ≥3 thrombocytopenia: 7 Grade ≥3 infections: 21.5 Grade ≥3 PN: 0 |
a Responses available in 66 patients after 3 months of therapy.
The risk of VTE with thalidomide as a single agent is low but increases when it is used in combination with dexamethasone or anthracyclines. For this reason the IMWG has recommended low-molecular-weight heparins (LMWH), to patients receiving high-dose dexamethasone or doxorubicin regardless of the number of myeloma-related risk factors.
The NCCN guidelines recommend thalidomide monotherapy for patients who are corticosteroid intolerant and consider TD and DT-PACE as category 2A options (uniform NCCN consensus that the intervention is appropriate based on low-level evidence) for RRMM.
Bortezomib
Bortezomib (BTZ) is a first-in-class proteasome inhibitor that blocks the 26S proteasome, with potent antimyeloma activity when used as a single agent and in combinations with other agents.
In the large randomized APEX trial, BTZ showed superiority compared with pulsed high-dose dexamethasone in 669 patients with myeloma who had received no more than 3 prior treatment regimens. Patients treated with bortezomib had higher ORRs (38% vs 18%; CR, 6% vs <1%; both P <.001), better TTP (6.2 months vs 3.5 months; P <.001), and longer 1-year OS (80% vs 66%; P = .003). After an extended median follow-up period of 22 months, the ORR was 43% with BTZ and the data confirmed a survival benefit of 6 months for patients who received PI (29.8 months) compared with steroid (23.7 months), despite a 62% crossover of patients from the dexamethasone to the bortezomib arm. The addition of dexamethasone for patients with a suboptimal response or progression disease (PD) to BTZ alone, led to an improvement in the degree of response in 18% to 39% of patients, whereas this association from the onset of therapy produces ORRs ranging from 54% to 74% and did not seem to alter the safety profile of BTZ.
Based on the results of a phase 1 study, a large randomized trial comparing single-agent bortezomib with bortezomib plus PLD showed an improvement with this combination in terms of longer median TTP (6.5 months vs 9.3 months) and 15-month OS (65% vs 76%). A study has also reported an improved response rate (ORR, 67%) with the addition of low-dose dexamethasone to bortezomib plus doxorubicin.
Based on the manageable toxicity profile of bortezomib and its synergistic activity with the other drugs characterized by different modes of action, multiple combinations have been evaluated in phase I to II trials, including bortezomib in combination with melphalan, dexamethasone-melphalan, low-dose cyclophosphamide-dexamethasone (VCD), or prednisone (VCP) and bendamustine-dexamethasone, showing high ORRs (60.9% to 82%) with promising DOR and OS ( Table 2 ).
| Study | Phase | N | Regimen | Schedule | Prior Treatment | ORR (%) | CR (%) | TTE | Key Toxicities (% of Patients) |
|---|---|---|---|---|---|---|---|---|---|
| Orlowski et al, 2007 | III | 324 | PLD-V | PLD: 30 mg/m 2 day 4 of 21-d cycle V: 1.3 mg/m 2 days 1, 4, 8, 11 | 66% ≥2 T and L: 40% V: 0% | 44 | 4 | Median TTP: 9.3 mo 15-mo OS: 76% | Grade ≥3 neutropenia: 29 Grade ≥3 thrombocytopenia: 23 Grade ≥3 febrile neutropenia: 3 Grade ≥3 PN: 4 |
| Palumbo et al, 2008 | II | 64 | V-DOX-D | V: 1.3 mg/m 2 days 1, 4, 8, 11 of 28-d cycle DOX: 20 mg/m 2 days 1, 4, or PLD 30 mg/m 2 day 1 D: 40 mg days 1–4 | Median: 2 T: 75% V: 27% | 67 | 9 | 1-y EFS: 34% 1-y OS: 66% | Grade ≥3 neutropenia: 36 Grade ≥3 thrombocytopenia: 48 Grade ≥3 infection: 15 Grade ≥3 PN: 10 |
| Popat et al, 2009 | I/II | 53 | VMD | MTD: V: 1.3 mg/m 2 days 1, 4, 8, 11 of 28-day cycle M: 7.5 mg/m 2 day 2 D: 20 mg days 1–2, 4–5, 8–9, 11–12 in case of PD or SD after 2 or 4 cycles, respectively | Median: 3 T: 64% V: 9% | 68 | 19 | Median PFS: 10 mo Median OS: 28 mo | Grade ≥3 neutropenia: 57 Grade ≥3 thrombocytopenia: 62 Grade ≥3 infection: 21 Grade ≥3 PN: 15 |
| Kropff et al, 2007 | II | 54 | VCD | V: 1.3 mg/m 2 days 1, 4, 8, 11 of 21-d cycle for the first 8 cycles, then same dose days 1, 8, 15, 22 of 35-d cycle for 3 cycles C: 50 mg/m 2 continuously D: 20 mg days 1–2, 4–5, 8–9, 11–12 for the first 8 cycles, then same dose days 1–2, 8–8, 15–16, 22–23 | Median: 2 T: 30% V: 0% | 82 | 16 | Median EFS: 12 mo Median OS: 22 mo | Grade ≥3 leukopenia: 57 Grade ≥3 thrombocytopenia: 53 Grade ≥3 infection: 38 Grade ≥3 PN: 21 Grade ≥3 fatigue: 15 |
| Reece et al, 2008 | I/II | 37 | VCP | MTD: NR; highest dose level: V: 1.5 mg/m 2 days 1, 8, 15 of 28-d cycle C: 300 mg/m 2 days 1, 8, 15, 22 P: 100 mg every 2 d | Median: 2 T: 38% V: 3% L: 3% | 68 | 32 a | Median PFS: 15 mo Median OS: 24 mo | Grade ≥3 neutropenia: 13 Grade ≥3 thrombocytopenia: 70 Grade ≥3 infection: 13 Grade ≥3 PN: 8 |
| Ludwig et al, 2014 | II | 79 | BVD | B: 70 mg/m 2 days 1, 4 of 28-d cycle V: 1.3 mg/m 2 days 1, 4, 8, 11 D: 20 mg days 1, 4, 8, 11 | Median: 2 V: 63.3% L: 53.2% | 60.9 | 15 | Median PFS: 9.7 mo Median OS: 25.6 mo | Grade ≥3 leukopenia: 17 Grade ≥3 thrombocytopenia: 38 Grade ≥3 infections: 23 Grade ≥3 PN: 6 |
| Offidani et al, 2013 | II | 75 | BVD | B: 70 mg/m 2 days 1, 8 of 28-d cycle V: 1.3 mg/m 2 days 1, 4, 8, 11 for the first 2 cycles, then same dose days 1, 8, 15, 22 D: 20 mg days 1–2, 4–5, 8–9, 11–12 for the first 2 cycles, then same dose days 1, 8, 15, 22 | Median: 1 T: 57% V: 46.5% L: 54.5% | 77 | 20 | Median PFS: 15.5 mo 1-y OS: 78% | Grade ≥3 neutropenia: 18.5 Grade ≥3 thrombocytopenia: 30.5 Grade ≥3 infections: 12 Grade ≥3 PN: 8 |
Toxicities associated with bortezomib include cyclic transient thrombocytopenia, PN, herpes zoster infection, fatigue, nausea, and diarrhea. The PN occurs in about one-third of patients but it can be effectively managed with dose modifications, especially if associated with pain, and it is generally reversible in more than 50% of cases. The use of bortezomib with weekly dosing or with subcutaneous administration, recently approved by US Food and Drug Administration (FDA), is able to reduce the risk of onset of this side effect. Because of the high rate of varicella zoster virus reactivation, the routine use of antiviral prophylaxis is recommended.
MLN9708 (Ixazomib) is a boronate PI similar to bortezomib and is the first orally available PI to advance into phase III trials. Because of its encouraging results in phase I study in RRMM, a phase III randomized trial in this setting is ongoing comparing lenalidomide and low-dose dexamethasone with or without the addition of ixazomib (TOURMALINE-MM1).
Lenalidomide
Lenalidomide is a more potent derivate of thalidomide that has been found to be less toxic and more active than its older analogue. Single-agent lenalidomide was effective and well tolerated in both phase I and phase II studies with response rates ranging from 29% to 39% in patients with RRMM who had received a median of 3 prior therapeutic regimens. The maximum tolerated dose was 25 mg daily and, unlike thalidomide, no significant neuropathy, somnolence, or constipation were noted.
Two randomized phase III trials (MM-009 and MM-010) compared RD with placebo plus dexamethasone in patients with RRMM who had received a median of 2 previous therapies. Patients receiving lenalidomide-dexamethasone obtained a better quality of response (ORRs, 60% and 61% for RD, compared with 24% and 20% for dexamethasone-monotherapy; CR rate, 16% and 14% for RD, compared with 3.4% and 0.6% for steroid as a single agent) and experienced a significantly longer median TTP (11.3 and 11.1 months in RD group vs 4.7 months in both dexamethasone groups) and prolonged survival (median OS, not reached and 29.6 months for RD, compared with 20.6 and 20.2 for dexamethasone single agent). A pooled analysis of trials with a prolonged median follow-up of 48 months confirmed the significant improvements in ORRs (60.6 vs 21.9; P <.001) and a significantly longer DOR (15.8 vs 7 months; P <.001), which translated into longer TTP (median TTP, 13.4 vs 4.6; P <.001) and improved OS (median OS, 38 vs 31.6; P = .045) in the RD-treated patients, despite a crossover of 41.9% of the patients from the dexamethasone to lenalidomide-based treatment, as happened in the APEX trial.
From these two pivotal phase III studies, RD was approved by the FDA and European Medicines Evaluation Agency for the treatment of patients with MM who had received at least 1 prior therapy, and it is listed in US and European treatment guidelines as a recommended treatment option.
Lenalidomide in combination with chemotherapeutics may be able to further improve the outcome of RRMM. The regimens tested in RRMM include lenalidomide in combination with adriamycin-dexamethasone (ORR, 73%), PLD-vincristine-dexamethasone (ORR, 75%), low-dose cyclophosphamide-prednisone (≥MR, 64%–94%), cyclophosphamide-dexamethasone (ORR, 65%–81%), bendamustine-dexamethasone (ORR, 52%), and bendamustine-prednisolone (ORR, 76%) ( Table 3 ).
| Study | Phase | N | Regimen | Schedule | Prior Treatment | ORR (%) | CR (%) | TTE | Key Toxicities (% of Patients) |
|---|---|---|---|---|---|---|---|---|---|
| Dimopoulos et al, 2007 | III | 176 | RD | R: 25 mg days 1–21 of 28-d cycle D: 40 mg on days 1–4, 9–12, 17–20 for the first 4 cycles, then 40 mg days 1–4 | Median: 2 T: 30.1% V: 4.5% | 60.2 | 15.9 | Median TTP: 11.3 mo Median OS: NR | Grade ≥3 neutropenia: 29.5 Grade ≥3 infection: 11.3 Grade ≥3 febrile neutropenia: 3.4 Grade ≥3 venous thromboembolism: 11.4 |
| Weber et al, 2007 | III | 177 | RD | R: 25 mg days 1–21 of 28-d cycle D: 40 mg on days 1–4, 9–12, 17–20 for the first 4 cycles, then 40 mg days 1–4 | Median: 2 T: 41.8% V: 10.7% | 61 | 14.1 | Median TTP: 11.1 mo Median OS: 29.6 mo | Grade ≥3 neutropenia: 41.2 Grade ≥3 thrombocytopenia: 14.7 Grade ≥3 infection: 21.4 Grade ≥3 venous thromboembolism: 14.7 |
| Knop et al, 2009 | I/II | 69 | RAD | MTD: NR; highest dose level: R: 25 mg days 1–21 of 28-d cycle A: 9 mg/m 2 days 1–4 D: 40 mg on days 1–4, 17–20 | Median: 2 T: 20% V: 57% L: 0% | 73 | 15 | Median TTP: 45 wk Median PFS: 40 wk 1-y OS: 88% | Grade ≥3 neutropenia: 48 Grade ≥3 thrombocytopenia: 38 Grade ≥3 infection: 10.5 Grade ≥3 venous thromboembolism: 1.5 |
| Reece et al, 2010 | I/II | 32 | CPR | MTD: NR; highest dose level: C: 300 mg/m 2 days 1, 8, 15 of 28-d cycle R: 25 mg days 1–21 P: 100 mg every other day | Median: 2 T: 29% V: 48% L: 0% | 94 | 19 | 1-y PFS: 78% 1-y OS: 93% | Grade ≥3 neutropenia: 29 Grade ≥3 thrombocytopenia: 22 Grade ≥3 venous thromboembolism: 6 |
| Schey et al, 2010 | I/II | 31 | RCD | MTD: C: 600 mg days 1, 8 of 28-d cycle R: 25 mg days 1–21 D: 20 mg on days 1–4, 8–11 | Median: 3 T: 90% V: 26% L: 0% | 81 | 29 | 2-y PFS: 56% OS at 30 mo: 80% | Grade ≥3 neutropenia: 19 Grade ≥3 infection: 3 Grade ≥3 venous thromboembolism: 6 |
| Lentzsch et al, 2012 | I/II | 29 | BRD | MTD: B: 75 mg/m 2 days 1, 2 of 28-d cycle R: 25 mg days 1–21 D: 40 mg on days 1, 8, 15, 22 | Median: 3 T: 14% V: 66% L: 45% T and L: 38% | 52 | 0 | Median PFS: 6.1 mo 1-y OS: 93% 2-y OS: 62% | Grade ≥3 anemia: 17 Grade ≥3 neutropenia: 62 Grade ≥3 thrombocytopenia: 38 Grade ≥3 febrile neutropenia: 3 Grade ≥3 infection: 3 |
| Pönisch et al, 2013 | I | 21 | BR-PNL | B: 60–75 mg/m 2 days 1, 2 of 28-day cycle R: 10–25 mg days 1–21 PNL: 100 mg days 1–4 | Median: 2 T: 14% V: 67% L: 5% | 76 | 5 | 18-mo PFS: 48% 18-mo OS: 64% | Grade ≥3 anemia: 19 Grade ≥3 neutropenia: 52 Grade ≥3 thrombocytopenia: 19 Grade ≥3 fever: 14 Grade ≥3 infection: 14 |
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