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PRIORITY PRESS - 15th Congress of the European Hematology Association

Barcelona, Spain / June 10-13, 2010

The era of novel agents for the treatment of multiple myeloma (MM) has dramatically improved outcomes for newly diagnosed patients but treatment choice is still highly dependent on individual patient characteristics including age, the presence of high-risk cytogenetics and comorbidities.

“In the past, achievement of a complete remission (CR) was rare,” Dr. Maria-Victoria Mateos, consultant physician, University Hospital, Salamanca, Spain, told EHA delegates here. Today, CR is an important objective for all patients with MM, she added, as time to progression (TTP), progression-free survival (PFS) and overall survival (OS) are all significantly attenuated among those who achieve a near CR (nCR) or who are left with minimal residual disease, both in the post-transplant and non-transplant setting.

VISTA Results

The depth and duration of CR is also a strong determinant of outcome: the deeper and longer the maintenance of CR, the longer the TTP, treatment-free interval (TFI) and OS, Dr. Mateos noted. In the phase III VISTA (Velcade as Initial Standard Therapy in multiple myelomA) study, for example, the TFI among those who achieved a CR was 17.6 months in the bortezomib/melphalan/prednisone (VMP) arm compared with 8.4 months for the MP arm (P<0.001).

VISTA patients achieving a CR in the VMP arm were significantly more likely to have a longer TFI than patients who achieved a partial response (PR) on the same triple regimen (P<0.0001). At three years, 68.5% of patients treated with the VMP regimen were still alive compared with 54% of those in the MP arm, a 35% reduction in mortality risk with VMP compared with MP.

As discussed here at the EHA by Prof. Philippe Moreau, Head of Hematology, CHU-Nantes, France, approximately one-third of patients with MM have poor cytogenetics. In an effort to overcome their inherently poor prognosis, investigators have attempted to use several novel agents as front-line therapy, including thalidomide and lenalidomide, but neither of these immunomodulatory drugs (IMiDs) has been shown to improve outcomes in this patient group, Prof. Moreau noted.

In contrast, the CR rate and TTP were very similar between standard-risk and high-risk cytogenetic patients in the VISTA trial treated with the VMP regimen. At a median follow-up of 36.7 months, median OS has not yet been reached in the VMP arm whereas median OS was 40 months among the small group of high-risk cytogenetic patients treated with the same regimen.

Renal Effects

Renal impairment and failure occur in approximately 40% of MM patients, Prof. Moreau continued, “and we have to act rapidly to remove disease burden and improve renal function.” Here again, results from the VISTA study indicated that VMP is more effective than MP in patients with renal impairment in terms of CR rates, time to first response, duration of response and TTP. More importantly, efficacy and safety profiles were comparable among VISTA patients with an estimated glomerular filtration rate (GFR) of =50 mL/min and those with a GFR in excess of 50 mL/min. Some 44% of patients on VMP also had an improvement in GFR from <50 mL/min at baseline to >60 mL/min on treatment compared with 34% of those on MP.

According to a recent study by Roussou et al. (Leuk Res 2010, in press), significantly more patients with newly diagnosed MM and renal impairment (creatinine clearance [CrCl] <50 mL/min) at baseline achieved a renal CR at 71% when treated with a bortezomib-based regimen compared with either an IMiD-based regimen (45%) or conventional chemotherapy (41%). The median time to a major renal response in the same study was also much shorter for those treated with bortezomib at 0.69 months compared with 1.6 months for the IMiD group and 1.8 months for the conventional chemotherapy group. Rapid improvement of renal function (one month or less) was also associated with a trend towards longer survival, as Prof. Moreau observed.

High-dose Therapy

As speakers here noted, patients with MM are diagnosed at a median of 70 years of age; thus, over half of those with newly diagnosed MM are not eligible for high-dose therapy. For those who are eligible, high-dose therapy with autologous stem-cell transplantation (ASCT) is still considered standard of care. As discussed by Dr. Meletios Dimopoulos, Professor and Chair of Clinical Therapeutics, University of Athens School of Medicine, Greece, data no longer support the use of “traditional” vincristine/doxorubicin/dexamethasone (VAD) and cyclophosphamide/dexamethasone (CyDex) but rather a triple-drug induction regimen that contains at least one novel agent, followed by stem-cell harvest, high-dose melphalan and stem-cell infusion.

Response to transplantation is again highly critical for patient survival, as pointed out by Dr. Laura Rosiñol, hematology specialist, Hospital Clinic, Barcelona, Spain. She told EHA delegates that median reported survival approaches 10 years in patients who achieve a CR to transplant vs. a median of four years for those who achieve a PR. Both pre-ASCT and post-ASCT CR rates are exceptional relative to historical controls. For example, bortezomib/thalidomide/dexamethasone (VTD) induction regimens lead to pre-ASCT CR rates in 31% of patients and in 52% of patients post-ASCT, according to Dr. Rosiñol’s own data (ASH 2009, Abstract 130). “Unprecedented” CR rates have also been reported with novel agents added to the MP backbone in non-transplant candidates, be they thalidomide (15%), lenalidomide (13 to 18%) or bortezomib (30% based on VISTA data).

Retreatment Feasible

As was originally observed by VISTA investigators, salvage therapies appeared to be similarly effective in both treatment arms, indicating that the use of bortezomib upfront does not preclude the successful use of novel agents at relapse. Indeed, findings presented here suggest that bortezomib itself may be used following relapse from initial bortezomib treatment.

As presented here at the EHA by Dr. Maria Teresa Petrucci, La Sapienza University of Rome, Italy, 126 evaluable patients who had relapsed six months or more after their last dose of bortezomib were retreated with the standard regimen of eight three-week cycles, with dosing on days 1, 4, 8 and 11. The last tolerated dose given during the initial course of treatment was used as the starting dose for retreatment; most patients (72%) received additional dexamethasone.

“Results were good because 40% of patients responded to retreatment,” Dr. Petrucci related in an interview during the EHA sessions. At a median of 5.7 months, the TFI had not yet been reached in patients who responded to treatment, while the median TTP was 8.4 months. Grades 3 and 4 thrombocytopenia occurred in about one-third of patients and grade 3 peripheral neuropathy occurred in 9% of the group.

A once-weekly infusion schedule appears to significantly reduce the incidence of peripheral neuropathy. As reported here by Dr. Sarah Bringhen, University of Turin, Italy, a total of 369 patients over the age of 65 with newly diagnosed MM were treated with once-weekly bortezomib and 134 with a twice-weekly infusion. The actual dose delivered was virtually identical in both arms at approximately 40 mg/m², as Dr. Bringhen noted, which may explain the similar CR rates of 29% vs. 35% for the once- vs. twice-weekly groups, as well as PR rates of 85% and 86%, respectively. PFS and OS at three years were also virtually identical at 50% and 47% for the once- vs. twice-weekly regimen and OS at 88% vs. 89%, respectively. In contrast, the incidence of peripheral neuropathy was significantly reduced from 16% in the twice-weekly group to 3% in the once-weekly group, with less frequent need to reduce the dose or discontinue treatment altogether, thereby prolonging time on therapy.

Summary

Rapid incorporation of novel agents into the treatment algorithm for MM has dramatically improved patient outcomes. Trials such as VISTA confirm that upfront use of such agents confers a significant survival advantage relatively independent of patient or disease characteristics. This portends well for MM patients, who because of the aging population, could soon represent an important proportion of hematological care.