This month we will be focusing on data from the recent 12th International Myeloma Workshop (IMW) 2009. This meeting was held on February 26 - March 1, 2009 in Washington, DC. A large amount of information from that meeting was covered for you during our Best of the Day program from the IMW. I would encourage you to view those interviews to gain the perspective of a number of the national thought leaders in multiple myeloma.

“Best of the Day^SM from the 12th International Myeloma Workshop”

Therapy for Transplant Ineligible Patients

As with induction therapy for younger patients, the treatment for transplant ineligible patients has also undergone significant evolution over the past decade. Melphalan-prednisone (MP) had been the standard for many years, but high quality responses to MP were uncommon, absorption of oral melphalan was variable, and the potential for myelodysplastic syndrome (MDS) was worrisome. With the emergence of impressive data regarding thalidomide from several centers, many community oncologists began to switch therapy for this group of older patients with myeloma to thalidomide and dexamethasone.

Then at the American Society of Clinical Oncology (ASCO) Annual Meeting 2006, abstract number 1 from the French IFM group reported the results of the IFM 99-06 trial, a phase III trial comparing MP versus MPT versus VAD following by Mel100 and ASCT. There was a significant improvement in CR rate, VGPR rate and overall response rate (ORR) for MPT compared to the other 2 arms. Progression-free survival and OS were also significantly better for the MPT arm. Since then, the value of MPT has been confirmed in some additional trials and MPT has become one of the standards for front-line therapy of older transplant ineligible patients.

At the IMW this year the HOVON-49 trial was updated (Abstract 116). This trial randomized patients >65 years old to MP versus MPT for 8 cycles. Maintenance thalidomide was given to the MPT group at 50 mg/day until disease progression (PD). The ORR, VGPR rate and PR rates were all significantly greater for MPT although the CR rate was only 2% for both groups. The PFS was also significantly greater for MPT at 14 months compared to 10 months for MP. However, the difference in OS was not significant at 37 versus 30 months

At the 2007 ASH meeting, Dr Jesus San Miguel gave the first presentation of the results of the VISTA trial comparing MP with MP-bortezomib (VMP). VMP was statistically superior across all endpoints including TTP, PFS, time to next treatment (TTNT), CR rate and ORR. In addition, OS rate at 2 years was significantly better for VMP versus MP in patients both younger than 75 years and those older than 75 years.

At the IMW this year Dr San Miguel updated those VISTA results (Abstract 232) with a median follow-up of 26 months. Three-year OS was 72% versus 59%. Time to next treatment was longer at 28 months versus 19 months. In addition, fewer patients in the VMP arm required subsequent therapy.

Overall survival was not affected by baseline renal function. Peripheral neuropathy seen in the VMP arm improved in 79% of patients with a median time to improvement of less than 2 months, with complete resolution of symptoms in 60% of patients over a median of 5.7 months.

A subsequent presentation (Abstract 235) by Dr Jean Luc Harousseau regarding the VISTA trial reported on the relationship between length of treatment and the quality of response. Responses (ORR = 71% for VMP, 35% for MP) were more rapid in onset with VMP, as were complete responses. The median times to first response, best response and CR for VMP were 1.4, 2.3 and 4.2 months indicating that response quality improved with prolonged treatment. Twenty-eight percent of the CRs occurred during cycles 5-9. In addition, CR was associated with longer response duration than that seen for either VGPR or PR.

An additional report from the VISTA trial (Abstract 172) concerned the incidence of peripheral neuropathy (PN) with VMP. The overall incidence of PN was 47%, with 19% grade 2, and 13% >grade 3. The median accumulative dose of bortezomib to first onset of PN was 32.6 mg/m² and PN rate reached a plateau at the cumulative dose of 45 mg/m². Seventy-nine percent of patients improved by 1 grade or more in 1.9 months. Baseline diabetes, age, gender, ISS stage, Karnofsky performance status (KPS) and creatinine clearance (CrCl) did not affect the PN rate. The authors concluded that the rate and degree of PN seen with VMP did not differ from that seen with bortezomib alone, and thus was not affected by the addition of MP.

Finally the VISTA group evaluated the effects of VMP in renally impaired patients with myeloma (Abstract 166). Superiority of VMP was not affected by creatinine clearance with approximately 5% having CrCL <30 mL/min, 50% having CrCl between 30-60 mL/min and 45% have CrCL >60 mL/min. Improvement in CrCl from <50mL/min to >60 ml/min occurred in 44% of VMP patients compared to 34% of MP patients. Time to improvement in renal function was also shorter in the VMP arm.

As previously mentioned previously, the GEM/PETHEMA group (Abstract 154) compared VMP with VTP in 167 evaluable newly diagnosed patients with myeloma. There were no significant differences in ORR or CR rate. But there were significant differences in the adverse event profiles. VMP was associated with worse neutropenia and thrombocytopenia as well as PN. But VTP was associated with a significant incidence of >grade 3 cardiac toxicity and DVT/PE. The authors concluded that thalidomide might not be the best partner for bortezomib.

The Italian Myeloma Network (Abstract 092) reported the results of a phase II trial evaluating the 4 drug combination of MPT plus lenalidomide (RMPT). This double IMiD^® combination includes lenalidomide and thalidomide in addition to the MP backbone. Forty-four patients were treated, although 26 of those received RMPT as second-line therapy. The ORR was 75.8% including 30% VGPR. One-year PFS was 48.6%, and 1-year OS was 90%. The main toxicities were hematologic with no incidences of DVT reported.

Another interesting phase III trial presented at this year’s IMW by Dr Antonio Palumbo was the comparison of VMP with the 4-drug VMPT regimen in newly diagnosed patients (Abstract 117). This trial randomized 393 newly diagnosed patients with myeloma older than 65 years to VMP versus VMPT for nine 6-week cycles. Later the schedule was changed to administer bortezomib on a weekly schedule in both arms with a planned course of nine 5-week cycles. The VGPR rate was 55% for VMPT versus 42% for VMP. There were no significant differences in PFS or 3-year OS between the 2 study arms. Changing the bortezomib schedule to weekly dosing significantly reduced the incidence of peripheral neuropathy.

In an interesting debate on sequential versus combination therapy Dr Joan Blade provide his owned tailored recommendations for older patients:

OncoFacts™ Editor:

James Epstein, MD

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