The recent integration of novel therapeutics into the management of multiple myeloma (MM) has improved outcomes substantially for both newly diagnosed patients and for those with recurrent or refractory disease, according to Kenneth C. Anderson, MD, Kraft Family Professor of Medicine, Harvard Medical School, and Director of the Jerome Lipper Multiple Myeloma Center and Lebow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Four new drugs—lenalidomide (Revlimid), bortezomib (Velcade), thalidomide (Thalomid), and pegylated liposomal doxorubicin (Doxil)—initially used to treat advanced disease are now being incorporated into first-line therapy of MM, based on data from recent clinical trials.
The Eastern Cooperative Oncology Group (ECOG) trial E4A03 evaluated lenalidomide plus high- or low-dose dexamethasone in 445 newly diagnosed MM patients (Rajkumar SV et al. J Clin Oncol 2007;25[18S]:LBA8025; Rajkkumar SV et al. Blood 2007;110[11]:74). Although response rates were 10% lower in the low-dose arm, the low-dose regimen actually improved survival at 1 year (96% vs 86%) and 2 years (87% vs 75%), probably because of the greater toxicity of the high-dose dexamethasone regimen. “Lenalidomide and low-dose dexamethasone, therefore, in the context of this trial, has moved into the initial management of myeloma,” Dr. Anderson said.
The proteosome inhibitor bortezomib was included in the initial management paradigm largely based on the results of the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial (San Miguel et al. Blood 2007;110[11]:76). VISTA was an international randomized phase III trial of bortezomib, melphalan, and prednisone versus melphalan and prednisone alone in 682 newly diagnosed patients ineligible for transplantation. The addition of bortezomib resulted in highly significant increases in time to disease progression, progression-free survival, overall survival, time to next treatment, and complete response (CR).
“There was a remarkable 35% CR rate when they added bortezomib to melphalan and prednisone, which is a rate that is typically not achieved short of high-dose treatment and transplantation,” Dr. Anderson noted.
Importantly, adverse cytogenetics, advanced age, and renal function had no impact on the efficacy of the bortezomib-containing regimen, which was well tolerated. “The adverse features that confer poor prognosis to conventional and high-dose therapy did not impact response and do not seem to apply in the world of new drugs. This study is evidence of that,” Dr. Anderson observed.
Phase I/II trials have shown that 98% of newly diagnosed MM patients respond to combined bortezomib-lenalidomide therapy, with more than half of the patients experiencing a CR or a very good partial response (VGPR). Responses have also been seen in 58% of patients refractory to treatment with either agent alone. Dr. Anderson and his colleagues have been studying combined bortezomib-lenalidomide therapy in previously untreated MM patients. Response rates have reached 98%, including 52% with a CR, near CR (nCR), or VGPR. The combination has not adversely affected stem cell harvesting, he added.
In patients with relapsed or refractory myeloma, lenalidomide plus dexamethasone has been compared with dexamethasone alone in two phase III trials (Dimopoulos M et al. N Engl J Med 2007;357:2123–2132; Weber DM et al. N Engl J Med 2007;357:2133–2142). Overall response and response duration favored the lenalidomide-dexamethasone arm, with a response duration of 16–17 months versus 5–8 months for dexamethasone alone. Time to disease progression was approximately 11 months in the combination arm versus less than 5 months for dexamethasone alone (P < 0.001).
“[The combination of] lenalidomide and dexamethasone was superior to dexamethasone alone, regardless of whether the patient had received prior treatment with thalidomide, with a time to progression that was almost threefold higher and an overall survival advantage,” Dr. Anderson reported. Pooled survival data showed a median survival of 35 months with the lenalidomide-dexamethasone combination versus 31 months with dexamethasone alone, which included 47% of patients crossing over to receive the combination (Dimopoulos M et al. Haematologica 2007;92[suppl 2]:171). However, venous thromboembolism and infection were common in patients receiving combined therapy.
Adverse prognostic features had a minor impact on lenalidomide/dexamethasone outcomes in this study; the combination still produced the better outcomes. Furthermore, it seemed to overcome the poor prognosis conferred by cytogenetic abnormalities (Bahlis N et al. Blood 2006;108[11]:3557).
Bortezomib also is effective in the relapse setting, based on data from the phase III APEX study, which compared single-agent bortezomib with high-dose dexamethasone. In an updated efficacy analysis (Richardson PG et al. Blood 2007;110:3557–3560), the response rate was 43% with bortezomib versus 18% for dexamethasone (P < 0.0001). A CR or nCR was observed in 16% versus 0% of relapsed patients, respectively. Median overall survival was 29.8 months with bortezomib and 23.7 months with dexamethasone, despite nearly two thirds of patients crossing over to bortezomib. One-year survival rates were 80% and 67%, respectively (P = 0.00002).
Patients with poor prognostic factors benefited as well from bortezomib. Deletion of chromosome 13 did make a difference in patients treated with dexamethasone, as it was associated with poorer survival, but it had no impact in bortezomib-treated patients (Jagannath S et al. Leukemia 2007;21:151–157). “This [study] further highlights the need to redefine high-risk myeloma in the new world,” Dr. Anderson commented.
“We now have category 1 evidence for both of the new drugs, lenalidomide and bortezomib, in relapsed myeloma,” he said. Bortezomib can be used in patients with renal failure, including those on dialysis, “which makes it the drug of choice in this population.” It also stimulates osteoblast production and function and inhibits osteoclast function, thus exerting a clinical benefit on bone formation. Lenalidomide also can be used in patients with renal compromise, though dosing should be reduced, Dr. Anderson cautioned.
In a recent phase III trial (Orlowski RZ et al. J Clin Oncol 2007;25:3892–3901), the addition of pegylated liposomal doxorubicin to bortezomib improved response rates and survival, increased the median time to disease progression from 6.5 months to 9.3 months, and prolonged the duration of response by 3.2 months. As a result of these findings, the US Food and Drug Administration (FDA) approved this combination in 2007 for relapsed myeloma, and the regimen is now included in the National Comprehensive Cancer Network (NCCN) Multiple Myeloma guidelines.
“New drugs are achieving high response rates and overall survival that we have not seen before,” Dr. Anderson concluded. “We are using science to inform the design of clinical trials whose results are positive in the majority of patients. This is refreshing—we are getting drugs to the patients who urgently need them.”
Autologous stem cell transplantation (ASCT) is still considered important therapy for eligible MM patients because of its high response rates, low mortality (3%), and lack of donor limitation, commented William Bensinger, MD, Professor of Medicine and Director of the Autologous Stem Cell Transplantation Program at the Fred Hutchinson Cancer Research Center in Seattle. Some trials have documented a survival benefit as well, but ASCT is still not curative for most patients, Dr. Bensinger asserted.
Response rate is a surrogate endpoint for outcome. The International Myeloma Foundation pooled data from 99 trials involving 849 patients to examine the prognostic impact of CR and VGPR post transplant. At a median follow-up of 47 months, overall event-free survival was 39 months, and 5-year survival was 62%. The degree of response was clearly important, as was event-free and overall survival. The 5-year survival rate of patients with CR was 77%. For patients with VGPR and PR, the 5-year survival rates were 68% and 55%, respectively. “Survival [rate] was far superior for CR versus a partial response,” Dr. Bensinger observed, “and for this reason we consider response [rate] to be important.”
The recommendation for high-dose ASCT over conventional chemotherapy for newly diagnosed myeloma is based on studies showing benefits in response, event-free survival, and overall survival. “Importantly, these trials predate the development of novel drugs we are incorporating now,” Dr. Bensinger emphasized. “So, the transplant paradigm may be changing as we learn more with these new agents.”
The question of single versus double autografts has been answered by several studies showing that the attainment of a CR or nCR is important for a survival benefit, but patients who achieve a CR or nCR after one autograft do not benefit from a second autograft. Benefit appears to be restricted to patients with less than a VGPR after the first transplant, Dr. Bensinger noted.
“This was the genesis for the [NCCN’s] guidelines. After initial treatment, we recommend that all patients have stem cells stored to preserve the possibility of a future transplant,” he said. “We recognize that some patients do not want a transplant up front. Some trials show equivalent survival between up-front and salvage transplant; therefore, we believe a delayed approach is acceptable.” Allogeneic stem cell transplantation is an acceptable option, mainly for high-risk patients, but should only be performed in a clinical trial setting, he added.
Does transplantation benefit all myeloma patients? “We think it improves outcomes for patients with partial responses, minimal disease, stable disease, or primary resistant disease following induction,” he said, “but patients already in a CR after the first transplant do not appear to benefit from the second transplant. Its impact is less clear for patients with a CR following induction with conventional therapy, because until recently we had few agents that could achieve a CR. And we also know it is less effective in patients with certain high-risk features, such as deletion 17p, t(4;14), and elevated b2-microglobulin.” In a recent study, no differences were observed in progression-free or overall survival between patients achieving CRs before or after transplant (Dingli D et al. J Clin Oncol 2007;25:4933–4937).
With relapsed disease occurring after induction therapy, transplantation is an acceptable form of salvage therapy. Patients relapsing after autologous transplant can be salvaged with a second autologous transplant or an allogeneic transplant on trial. For patients who respond with less than a CR, a tandem transplant is an acceptable option. For those who have a CR or nCR, observation or placement on maintenance therapy in a clinical trial should be considered, Dr. Bensinger commented.
Novel agents also are being employed in induction regimens. Harousseau and colleagues (Blood 2007;110[11]:450) compared induction therapy with bortezomib plus dexamethasone with conventional combination chemotherapy. After transplant, 62% of patients treated with bortezomib/dexamethasone had a VGPR or better, and 35% had a CR or nCR and did not need a second autologous transplant. As with other studies of bortezomib in MM, adverse cytogenetics and other risk factors did not affect the efficacy of the regimen.
Cavo et al (Blood 2007;110[11]:73) compared thalidomide induction with the same regimen plus ortezomib. The addition of bortezomib significantly improved CR, nCR, and VGPR rates and upgraded responses post transplant. Fifty-seven percent of patients receiving bortezomib had a CR or nCR versus 28% for those who received thalidomide plus dexamethasone alone. The percentage of patients who achieved a VGPR or better response was 77% versus 54%, respectively.
“These findings suggested that a single transplant was additive,” Dr. Bensinger said. There was more neuropathy and skin rash with bortezomib, but more deep vein thrombosis without it. The trial is ongoing. In the meanwhile, the NCCN guidelines have added the bortezomib-thalidomide-dexamethasone regimen to its primary induction therapy options.
Maintenance therapy after transplant also is being evaluated. Attal et al (Blood 2005;106:[11]:1148) have found that thalidomide confers a survival benefit in patients without a deletion 13. Barlogie and coworkers (N Engl J Med 2006;354:1021) showed that adding thalidomide to a complex induction regimen, performing tandem transplants, and giving thalidomide as maintenance therapy for 1 year improved response rates and event-free survival but not overall survival. At relapse, patients receiving thalidomide had worse outcomes than control patients.
“We still need to learn how to use these novel agents. Thalidomide may not be best used from beginning to end, since it does not improve survival,” Dr. Bensinger offered. Other maintenance therapy studies are ongoing.