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Improving Overall Survival in Multiple Myeloma: Treatment Strategies and Regimens

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 54th Annual Meeting of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2012

Atlanta - New data released at the 2012 American Society of Hematology (ASH) meeting further linked novel combinations with improved survival across multiple stages of multiple myeloma (MM). Given the relapsing/remitting nature of the disease, the improvements in overall survival (OS) across sequential use of multiple lines of therapy have the potential for a substantial cumulative benefit. The OS benefit is further encouraging because many of the agents now included in the emerging standard regimens are well tolerated, permitting extended survival with highly acceptable quality of life. New data suggest that some therapies active in early stages of disease may remain active in later stages when reintroduced with a new relapse. According to new data reported here at the ASH meeting, the progress in therapy for MM is having a meaningful impact on the natural history of this disease even among older individuals who are not candidates for stem cell transplant.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Optimizing Available Therapies

Of all the new multiple myeloma (MM) data, the most significant may be the survival benefit demonstrated with a new regimen over the previous standard in older individuals. The tested regimen was a combination of bortezomib, melphalan, prednisone and thalidomide (VMPT) followed by maintenance bortezomib and thalidomide (VT). In a phase III multicentre trial, it was compared to a previous standard of bortezomib, melphalan and prednisone (VMP) with no additional therapy. While a progression-free survival (PFS) advantage was first reported 2 years ago, longer follow-up has revealed an overall survival (OS) benefit, redefining optimal management.

“In patients 67 to 75 years of age, VMPT-VT reduced the risk of death by 37% and should be considered a new standard of care,” reported Dr. Antonio Palumbo, Myeloma Unit, University of Torino, Italy. In this updated analysis with 4 years of follow-up, VMPT-VT has now been found “superior to VMP for response rate, progression-free survival (PFS), time to next treatment and now survival.”

The study randomized 511 patients ineligible for stem cell transplant (SCT) to 9 cycles of VMPT or VMP. Initially, both regimens were administered in 9 cycles of 6 weeks each but the protocol was amended early in the study so that both regimens were administered in 5-week cycles. At the end of 9 cycles, the VMPT patients went on to a maintenance program of 1.3 mg/m2 bortezomib every 14 days and thalidomide 50 mg per day. Those randomized to VMP received no further therapy.

After a median follow-up of 54 months, the median OS in the VMP arm was 60.6 months but had yet to be reached in the VMPT-VT group (P<0.01). While the OS benefit was consistent when patients were stratified by age, the 5-year survival benefit was more pronounced in patients younger than 75 years of age (67.8% vs. 49.9%, P=0.01) and among patients who achieved a complete response after induction therapy (81.4% vs. 48.2%, P=0.006). The median duration of maintenance therapy was 23.8 months.

Importantly, in regard to the OS benefit, this more ambitious 4-drug regimen plus maintenance was well tolerated. The difference in symptomatic side effects with the addition of thalidomide was modest. Rather, the most significant increase among grade ≥3 adverse events involved neutropenia (38% vs. 28%; P=0.02). An increase in cardiologic events (10% vs. 5%; P=0.04) reached statistical significance but an increase in thromboembolic events (5% vs. 2%; P=0.08) did not. Significant adverse events occurred at low rates with no side effect of grade ≥3 occurring in >10% of patients. Overall, 12% discontinued maintenance therapy for an adverse event.

In MM, particularly among those ineligible for SCT, the goal is to extend the relapse-free interval. The VMP standard was an important step in this direction. The VMPT-VT trial demonstrates that the addition of thalidomide followed by maintenance represents another step forward, providing an opportunity to prolong life in older MM patients.

Exploring Retreatment for Relapsed MM

Due to its exceptional activity against MM cells, bortezomib has been included in first-line therapies for both younger patients eligible for SCT and in patients who are not transplant candidates. It has not been previously known whether it can be re-employed effectively in patients already exposed to this agent. However, a new meta-analysis of 23 retreatment studies supports this activity.

“Retreatment with bortezomib alone or in combination is efficacious and well tolerated in relapsed patients, with an objective response rate of 57%, a median time to progression of 8.5 months and an OS of 19.7 months,” reported Dr. Kevin B. Knopf, California Pacific Medical Center, San Francisco. In heterogeneous populations of transplant-eligible and transplant-ineligible patients, retreatment with the proteasome inhibitor produced activity outcomes that were “generally consistent across groups, although patients with fewer prior therapies (≤4) and relapsed but not refractory patients achieved higher objective response rates.”

The meta-analysis included data on 1051 patients. In 18 of the 23 studies, bortezomib was reintroduced with active chemotherapy. In the remaining studies, the proteasome inhibitor was used alone or with dexamethasone only.

A random-effects meta-regression analysis controlling for number of prior therapies indicated that patients who had become refractory to the initial regimen that contained bortezomib did less well on re-exposure to this agent than patients who achieved a response and then subsequently relapsed, but Dr. Knopf reported that responses were observed in both groups. He also reported a high rate of activity for a repeat course of bortezomib in older individuals.

“In patients with a median age >65 years, a group that contained a lower proportion of patients who had received prior autologous SCT, retreatment remained active with an average pooled OR of 51%, Dr. Knopf reported.

A repeat course of the proteasome inhibitor was not associated with increased adverse events relative to rates of side effects reported with first exposures. Grade ≥3 peripheral neuropathy was reported in only 3% of patients. Rates of thrombocytopenia (35%), neutropenia (15%) and anemia (14%) were comparable to rates reported in first-line use of bortezomib.

Safety and Survival in Renally Impaired Patients

In another study, novel therapies were associated with particular improvement in OS for those presenting with renal impairment. Renal impairment, commonly identified at the MM diagnosis, is a well established risk factor for a poor outcome. Studies have variably estimated the risk of early death in MM patients with renal impairment as 2- to 4-fold higher than in those without renal impairment. According to new data, the introduction of novel therapies for MM, which have improved OS, have been particularly important in those individuals with renal impairment. In the study, OS was compared before and after thalidomide and bortezomib became available.

“After adjusting for the degree of renal impairment in the model, the hazard ratios (HR) for death for patients with severe renal impairment for the period after the availability of thalidomide relative to the prior period was 0.485,” reported Dr. Meletios A. Dimopoulos, Department of Clinical Therapeutics, University of Athens, Greece. This represents a >50% improvement in survival. After bortezomib became available, the risk of death in patients with severe renal impairment fell by >60% (HR 0.387) relative to the period before availability of either thalidomide or bortezomib.

The data were drawn from 1773 MM patients who have been included in the Greek Myeloma Study Group trials. In Greece, thalidomide became available in January 2000 and bortezomib became available in January 2005. Severe renal impairment was defined as an estimated glomerular filtration rate (eGFR) <30 mL/min. It is notable that the incidence of renal impairment has remained unchanged over the nearly 20-year period that data has been collected.

Survival improvements, although less pronounced, were also observed with the introduction of novel MM treatments for those with moderate renal impairment, defined as eGFR 30 mL/min to <59 mL/min. In these patients, the risk for death was reduced by 35% (HR 0.65) after the introduction of thalidomide and 43% (HR 0.57) after the introduction of bortezomib relative to the period when neither drug was available.

Summary

Incremental improvements in OS for patients with MM have been achieved through progress defining the most effective use of novel agents in both older and younger patients. Cure of MM remains elusive, particularly in patients who are transplant ineligible, but the ability to provide prolonged disease-free periods with relatively well tolerated therapies has led to meaningful changes in prognosis. Survival benefits derived from novel first-line therapies have the potential to lead to progress in identifying better second-line strategies for sustaining disease control.  

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