ABSTRACT: Responses to treatment of relapsed and refractory multiple myeloma are characteristically short, and median survival is as brief as 6 months. Although prognostic factors in the context of relapsed and refractory disease require further characterization, high-risk patients include those with certain cytogenetic abnormalities, high β2-microglobulin, and low serum albumin. The development of novel therapies targeting disease biology and tumor microenvironment has significantly improved the outlook for patients with relapsed and refractory disease, with bortezomib(Drug information on bortezomib) (Velcade), a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide(Drug information on thalidomide) (Thalomid) and lenalidomide (Revlimid) constituting “backbone” agents in this setting. More recent approaches for treating relapsed and refractory myeloma that are recommended by the National Comprehensive Cancer Network include single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib plus pegylated liposomal doxorubicin(Drug information on doxorubicin), lenalidomide/dexamethasone, and lenalidomide/bortezomib/dexamethasone. Individualized treatment of progressive myeloma should take into account the time to progression and/or the type of prior therapy. Additional clinical challenges discussed in this article are renal dysfunction, extramedullary disease, and advanced bone disease. Finally, participation in clinical trials is especially encouraged in this patient population.
Supported by an educational grant from Millennium Pharmaceuticals, Inc.
Survival in multiple myeloma (MM) has improved significantly since 1990, but the disease remains incurable, with most patients responding to therapy but all eventually relapsing. Some have primary refractory disease and do not respond to initial therapy, and those with relapsed and refractory disease constitute a serious and unmet medical need. Overall, the median survival of patients with relapsed and refractory MM is as short as 6 months.
Patients who have received at least two prior therapies and have progressed on therapy or within 60 days of last treatment are usually defined as having “relapsed and refractory” MM. Clinical considerations in caring for these patients include the number of prior therapies, existing and potential toxicities related to treatment, and disease characteristics (eg, aggressiveness of relapse, relapsed disease emerging from prior remission vs disease that is truly both relapsed and refractory, and other high-risk features). Features associated with poor prognosis are t(4;14) or t(14;16), deletion of chromosomes 17 and/or 13, hypodiploidy, high β2-microglobulin, and low serum albumin. Additional challenging clinical scenarios include patients with light-chain and immunoglobulin A (IgA) isotype, renal failure, extramedullary disease, hyposecretory myeloma, and/or advanced bone disease.
There is no single standard treatment for relapsed and refractory MM; the National Comprehensive Cancer Network (NCCN) recommends a number of agents and combinations as salvage therapy (Table 1). This article reviews recent data on the efficacy and safety of NCCN-recommended therapies that make use of bortezomib and/or lenalidomide, in primarily describing the use of novel agents in the setting.
Clinical Data on NCCN-Recommended Therapies
In 2003, bortezomib (Velcade) was granted accelerated approval by the US Food and Drug Administration (FDA) for treatment of relapsed and refractory MM on the basis of results from the phase II trials SUMMIT (Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of bortezomib in the Treatment of relapsing multiple myeloma).[4,5] Subsequently, the phase III APEX trial (Assessment of Proteasome inhibition for EXtending remissions) showed that in comparison with high-dose dexamethasone(Drug information on dexamethasone), bortezomib improved time to progression (TTP), complete response (CR) rate, and overall survival (OS) (Table 2).[3,6-11] Bortezomib received full FDA approval in 2005. With extended follow-up (median, 22 months), response rates further improved to 43% with bortezomib; moreover, 1-year survival was superior with bortezomib, even though 62% of patients in the control arm crossed over to bortezomib. On subgroup analysis of the APEX trial, bortezomib demonstrated substantial clinical activity in patients ≥ 65 years old and those with more than one prior line of therapy, stage II/III myeloma by the International Staging System, or refractoriness to immediate prior therapy.
As observed in SUMMIT and CREST, bortezomib-associated thrombocytopenia and neutropenia in APEX were transient and cyclical, with rapid recovery during the treatment-free period in each dosing cycle. Although the rate of grade 3/4 thrombocytopenia was higher with bortezomib than with dexamethasone (30% vs 6%), the incidence of significant bleeding events was comparable in the two treatment groups. Bortezomib-associated thrombocytopenia may not require treatment delays or dose reductions, except in instances of grade 4 toxicity or any situation involving bleeding. In most instances, it can be managed with platelet transfusions as needed to maximize dosing and response to therapy. Similarly, bortezomib-associated neutropenia can typically be managed with growth factor support, with dose delay reserved for patients with febrile neutropenia, which occurred in only 0.3% of bortezomib-treated patients in the APEX, SUMMIT, and CREST studies.
Bortezomib-associated peripheral neuropathy (PN) was the most important toxicity, but proved generally reversible in the APEX trial, using a dose-modification guideline that now appears in the bortezomib prescribing information. Overall, 91 of 331 (27%) patients in the bortezomib arm had treatment-emergent PN of grade ≥ 2. Of those, 64% experienced improvement or resolution to baseline at a median of 110 days, and improvement/resolution was more likely for patients who had dose modification. Grade ≥ 2 PN and dose modification did not appear to adversely affect bortezomib efficacy. Fourteen patients discontinued bortezomib due to grade ≥ 2 PN, and of these, 45% did so within the first three cycles. Close monitoring during initial treatment and, if required, prompt dose modification are necessary to prevent progressive PN and aid reversibility.
Experience outside clinical trials has confirmed the tolerability and efficacy of bortezomib in relapsed and refractory MM. At one center, among 65 patients who received bortezomib with or without a corticosteroid, the overall response rate (ORR) was 64% among patients with relapsed and refractory MM, and the response rate was even higher (82%) among those with primary refractory disease. Response was better in patients who received bortezomib at first or second relapse than in those treated at later points in the disease course. Four patients developed acute renal failure requiring dialysis, two of them following grade 3 diarrhea, and both of the latter patients subsequently died. Grade 3 PN occurred in 13% of patients, grade 3/4 thrombocytopenia in 42%, and grade 3/4 neutropenia in 31%.
In a separate study, investigators in Australia and New Zealand evaluated 111 heavily pretreated patients who received bortezomib for relapsed and refractory MM. Among them, 82% had at least three previous lines of therapy and > 40% had at least four. The most common grade 3/4 events were thrombocytopenia (26%), anemia (8%), peripheral neuropathy (7%), and diarrhea (7%). Of 106 patients evaluable for response, 22% achieved CR and 20% achieved partial response (PR), with the median time to best response being 69 days.
The combination of bortezomib and dexamethasone is at least additive. In an extension trial involving 63 patients from SUMMIT and CREST, retreatment with or continuation of bortezomib ± dexamethasone for a total of 7 to 32 cycles was documented to be safe, with no evidence of new cumulative toxicity. In total, 75% (n = 47) of patients received bortezomib plus dexamethasone, with 38% (n = 18) achieving at least PR.
A multicenter, open-label, phase IIIb trial also showed that bortezomib/dexamethasone is safe and effective for heavily pretreated patients with relapsed and refractory MM. The 638 patients (median, three prior therapies) received bortezomib ± dexamethasone for a maximum of eight 3-week cycles (median, five cycles). The ORR was 67%, including 11% CR. Among the 208 patients who received bortezomib/dexamethasone, 70% showed stable disease or improved response compared with their response to bortezomib monotherapy. The most common grade 3/4 adverse events were thrombocytopenia (39% of patients), neutropenia (16%), and anemia (12%). The most common adverse event leading to treatment discontinuation was PN (5%).
Bortezomib was also recently prospectively studied by 14 office-based hematologists. Of 46 evaluable patients with relapsed and refractory MM, 22 received concurrent dexamethasone and 1 received prednisone(Drug information on prednisone). The ORR was 61%, with a median time to best response of three cycles. Response rates were similar for patients ≤ 70 and > 70 years of age, those with and without renal impairment, and those who did or did not receive concurrent steroid medication. Important grade 3/4 adverse events included thrombocytopenia, PN, fatigue and bone pain, and anemia.