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New agents for the treatment of multiple myeloma

In 2013 American Society of Hematology ( ASH ) Annual Meeting data on several compounds in development for the treatment of multiple myeloma were presented.

Alternating vs sequential regimens

In 231 newly diagnosed elderly patients, researchers evaluated sequential versus alternating use of VMP ( Bortezomib [ Velcade ], Melphalan, and Prednisone ) and Rd ( Lenalidomide [ Revlimid ] plus low-dose Dexamethasone ) in the GEM2010MAS65 trial.
The sequential treatment scheme was nine consecutive cycles of VMP followed by nine consecutive cycles of Rd. Patients treated with the alternating scheme either started with one cycle of VMP and alternated with one cycle of Rd, or started with one cycle of Rd and alternated with one cycle of VMP, each for up to 18 cycles.

After 9 months of treatment, response rates were higher for the alternating scheme ( 93% vs 89% with sequential treatment ), and the proportion of patients achieving a very good partial response or greater was 78% vs 56%, respectively ( P = 0.004 ).
At 20 months, the alternating group also had numerical improvements in progression-free survival ( 84% vs 80% ) and overall survival ( 92% vs 88% ), but the differences were not statistically significant.

The study also established the benefit of achieving a stringent complete response or complete response. In this group, progression-free survival was 96% in the alternating arm and 92% in the sequential arm, which was significantly better than those with less than a very good partial response, whose progression-free survival rates at 20 months were 78% and 62%, respectively.

Doublets as good as triplets

In a community-based population, triplet alkylating combinations did not lead to improved progression-free survival or overall survival benefits over doublet therapy.
The study compared Rd ( Lenalidomide plus low-dose Dexamethasone, n=211 ) versus the alkylating-based regimens MPR ( Melphalan, Prednisone, Lenalidomide, n=210 ) and CPR ( Cyclophosphamide, Prednisone, Lenalidomide, n=220 ) in elderly, transplant-ineligible, newly diagnosed myeloma patients.
After a median of nine cycles, all patients received maintenance Lenalidomide until disease progression.

A partial response or better was achieved by 74% of the Rd group, 73% of the MPR group, and 72% of the CPR group.
At a median follow-up of 26 months, progression-free survival was 22 months, 27 months, and 24 months, respectively, and overall survival was 80%, 81%, and 84%. None of the differences were statistically significant.
MPR was associated with significantly more neutropenia ( P less than 0.0001 ), thrombocytopenia ( P less than 0.003 ), and anemia ( P less than 0.0001 ), and required significantly more dose reductions ( P less than 0.0001 ) than the other regimens. CPR may be a good regimen for fit patients, Rd may be good for unfit patients, and a lower-dose regimen of Lenalidomide at 15 mg plus Dexamethasone at 10 mg may be best for frail patients.

Ixazomib citrate

In newly diagnosed patients, the oral proteasome inhibitor Ixazomib citrate ( formerly known as MLN9708 ) combined with Lenalidomide and Dexamethasone, led to high response rates and increased depth of response with extended treatment duration.

Ixazomib was given twice weekly with Lenalidomide / Dexamethasone to 71 treatment-naive patients, mostly at a dose of 3.0 mg. Patients received up to 16 cycles of the triplet.

The overall response rate was 94%, and the rate of complete response plus very good partial response was 76%. A stringent complete response was reached in 75% of complete responders.
Responses appeared to deepen over the course of treatment, with 93% of patients responding after 4 cycles ( at least a very good partial response in 61% ) and 95% responding after both 8 and 16 cycles ( at least a very good partial response in 71% ).

Drug-related serious adverse events were seen in 28% of patients, grade 3 drug-related adverse events were reported in 58%, and there were no grade 4 events.

These data suggest that twice-weekly oral Ixazomib plus Lenalidomide and Dexamethasone is feasible and active in patients with newly diagnosed multiple myeloma. However, rates of rash, peripheral neuropathy, and dose reductions appear higher than in the parallel study using weekly Ixazomib, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase III trials.


An updated analysis of the phase II PANORAMA 2 trial of the oral histone deacetylase inhibitor Panobinostat paired with Bortezomib and Dexamethasone in 55 patients with relapsed and Bortezomib-refractory disease was presented.
Patients showing clinical benefit by eight cycles continued on treatment. The median duration of exposure was about 5 months.
The objective response rate was 35% ( with very good partial responses in 5.5% ), and the clinical benefit rate was 53%, with a median duration of response of 6 months.
High-risk cytogenetics did not negatively impact response rates; in this subset, the response rate was 42.9% and the clinical benefit rate was 71.4%.
For all patients, median progression-free survival was 5.4 months and median overall survival was 17.5 months.

Another multicenter dose-finding phase II study evaluated in combination with the proteasome inhibitor Carfilzomib ( Kyprolis ) in 44 patients with relapsed/refractory myeloma.
Median progression-free survival was 6.8 months, the 12-month progression-free survival rate was 41%, the 12-month overall survival rate was 85%, overall response rate was 64%, and clinical benefit rate was 76%.

Other emerging agents

Several monoclonal antibodies are in various stages of development in myeloma. One that targets CD38, Daratumumab, is considered promising and received Breakthrough Therapy designation from the FDA ( Food and Drug Administration ) in 2013. Data on 11 patients who relapsed after at least two prior lines of therapy were presented. Eight achieved at least a partial response after treatment with Daratumumab ( up to 16 mg/kg ), in combination with Lenalidomide and Dexamethasone, including complete responses in three and very good partial responses in two.
No patients had disease progression, and the treatment was well tolerated.

A new class of agents that target the kinesin spindle protein is also being tested in myeloma. One such kinesin spindle protein inhibitor is Filanesib ( ARRY-520 ). Mature data from a phase II trial of this agent in 87 heavily pretreated patients ( median, 6 prior therapies ) found response rates to be 16% for the single agent, and 15% for Filanesib plus Dexamethasone, which was administered to patients who were dual-refractory to both Bortezomib and Lenalidomide.
In addition, the retrospective use of AAG ( acute phase protein alpha-1-acidic glycoprotein ) levels as a biomarker improved predictive outcomes. In patients with low AAG levels, the response rate was 24% for single-agent Filanesib and 19% for Filanesib plus Dexamethasone in dual-refractory patients. The median overall survival in AAG-low patients receiving the single agent was 23.3 months, and was 11 months in dual-refractory patients with low AAG levels, compared to 4.5 months and 2.9 months, respectively, for patients with high AAG levels in these treatment arms. ( Xagena2014 )

Source: ASCO Post, 2014