From ASH 2014: What’s New in the Myeloma Treatment Arsenal?


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Meletios A. Dimopoulos, MD

Martha Q. Lacy, MD

Maria-Victoria Mateos, MD

Antonio Palumbo, MD

Ravi Vij, MD

Jatin Shah, MD

Carl June, MD

Patients with high- or intermediate-risk disease were just as likely to respond as patients with low-risk disease…. PVD [pomalidomide/bortezomib/dexamethasone] is a highly attractive option for patients with relapsed and refractory myeloma.

—Martha Q. Lacy, MD

At the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, attendance at many multiple myeloma sessions outnumbered the room size, as data from studies of novel agents, such as the monoclonal antibodies, and from key trials, such as ASPIRE, drew crowds. The ASCO Post covered these key developments, but our coverage did not end there. Here is our roundup of other newsworthy presentations about antimyeloma drugs.

Sequencing or Alternating Bortezomib and Lenalidomide

Outcomes are comparable, whether bortezomib (Velcade)– and lenalidomide (Revlimid)–based regimens are alternated or sequenced, according to a study by the Spanish Myeloma Group comparing these approaches in newly diagnosed elderly patients.1

The investigators hypothesized that an alternating scheme would be more efficacious and less toxic; however, this hypothesis was not confirmed, said
Maria-Victoria Mateos, MD, of the University Hospital of Salamanca in Spain. “So far, both schemes yielded similar results,” she said. 

The GEM2010MAS65 trial of 250 patients evaluated a “total therapy” approach that included bortezomib/melphalan/prednisone (VMP) and ­lenalidomide/low-dose dexamethasone (Rd). Patients were treated with both regimens. One cohort received them in an alternating fashion—one cycle with one, one with another, and so on for 18 cycles. The other received the regimens sequentially, with one given for nine cycles and then the next for nine cycles. 

The investigators predicted, she said, that the alternating scheme would offer less probability of cell-tumor escape and lower cumulative toxicity, but after a median of 18 cycles, the overall response rate was 77% in the sequential arm and 80% in the alternating arm.

Rates of complete and near-complete responses were also similar, approximately 41%. The median progression-free survival was 32 months in the sequential arm and 34 months in the alternating arm. Overall survival at 3 years was 73% and 71%, respectively, and toxicity profiles were also similar. 

“This fixed total therapy (18 cycles) regimen, including VMP and Rd, resulted in impressive results in those patients who completed the 18 planned cycles,” Dr. Mateos indicated.

Pomalidomide Activity as Single Agent or in Combination

In reportedly the largest study yet in a heavily pretreated relapsed/refractory myeloma population, the European phase IIIb STRATUS (MM-010) trial evaluated single-agent pomalidomide (Pomalyst) with low-dose dexamethasone according to the current indication—ie, after failure with both an immunomodulatory drug and a proteasome inhibitor.2

The overall response rate was 35%, which was maintained in patients refractory to both lenalidomide and bortezomib. The median progression-free survival was 4.2 months. The safety profile was consistent with previous studies. The most frequent grade 3/4 adverse events were hematologic, but there was a low incidence of febrile neutropenia or discontinuation of treatment. The efficacy in STRATUS confirmed the clinical benefit observed in previous trials, said Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

A regimen of pomalidomide/bortezomib/dexamethasone (PVD) achieved a response rate of 85% and a 12-month event-free survival of 94% in patients refractory to lenalidomide, in a small phase II trial reported by Martha Q. Lacy, MD, of the Mayo Clinic, Rochester, Minnesota.3

“Patients with high- or intermediate-risk disease were just as likely to respond as patients with low-risk disease…. PVD is a highly attractive option for patients with relapsed and refractory myeloma,” Dr. Lacy said.

She reported these findings in 47 patients who had received up to four prior regimens and were resistant to lenalidomide. They received a median of eight cycles of PVD and were followed for a median of 12 months. Of 40 patients who responded, 21 had very good partial responses or better. The median progression-free survival was 10.7 months, and the median duration of response was 13.7 months.

Weekly Dosing for Carfilzomib

Weekly administration of carfilzomib (Kyprolis) may be equivalent to the current practice of twice-weekly injections, according to Antonio Palumbo,
MD
, of the University of Turin, Italy, who presented data from a phase I/II study in elderly newly diagnosed patients.4

“With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy,” Dr. Palumbo said in an interview.

To evaluate once-weekly carfilzomib, Dr. Palumbo and colleagues enrolled 12 patients in a dose-finding phase, then added 18 patients for phase II. Escalating doses started at 45 mg/ m2, with a maximal planned dose of 70 mg/ m2. Carfilzomib was given along with oral cyclophosphamide and oral dexamethasone on days 1, 8, and 15. Of 30 patients, 21 patients received the maximum tolerated dose (70 mg/ m2). After completion of nine cycles, patients received 28-day maintenance cycles with carfilzomib at the maximum tolerated dose until disease progression or ­intolerance.

“Grade 3/4 adverse events were very rare, very low,” he said, with once-weekly higher-dose carfilzomib and were not increased over what has been observed with twice-weekly dosing. Dose reductions also appeared to be required less frequently (10%) than with twice-weekly dosing (21%).

Grade 3/4 hematologic events were observed in 23% of patients in this study, compared with 27% in studies of twice-weekly (36 mg/m2) carfilzomib. Grade 3/4 nonhematologic events were seen in 30% and 29%, respectively.

The overall response rate was 86%, with 64% having at least a very good partial response and 41% achieving at least a near-complete response. By cycle 9, a very good partial response or better was achieved by 91% receiving weekly carfilzomib, compared with 77% receiving the drug twice-weekly in prior studies. Dr. Palumbo indicated that response rates would continue to improve over time.

Panobinostat Used With a Triplet Regimen

Jatin Shah, MD, of the University of Texas MD Anderson Cancer Center, presented data for panobinostat in combination with bortezomib, lenalidomide, and dexamethasone (VRD).5 The study in 31 newly diagnosed transplant-eligible patients was the first experience reported with panobinostat in combination with subcutaneous bortezomib and offered the first data in combination with these three drugs, he indicated. 

“The combination was highly active, with a high depth of response and rapid disease control after four cycles,” he said. The maximum tolerated doses were determined to be 10 mg for panobinostat, 25 mg for lenalidomide, and 1.3 mg/m2 for bortezomib. The combination was “very well tolerated,” with limited grade 3/4 toxicity. The rate of grade 3/4 diarrhea/constipation was 6%.

Of the 22 patients who completed 4 cycles at the time of analysis, the overall response rate was 95%, of which 50% were complete responses or near-complete responses. This is much higher than the historic complete response rate of 10% to 20% for VRD alone after three to four cycles, according to Dr. Shah. 

Novel Therapies: Ibrutinib, CAR T-Cell Therapy

Could a targeted agent that works in leukemia become a blockbuster in myeloma as well? Perhaps, according to a phase II study of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).6 Ravi Vij, MD, of Washington University School of Medicine, St. Louis, presented preliminary results for 69 relapsed/refractory patients who received escalating doses of ibrutinib with or without dexamethasone. In the highest dose cohort (840 mg orally daily), a clinical benefit rate of 25% was observed, and another 25% of patients had stable disease. The median progression-free survival was 5.6 months in this latter group.

Some patients had prolonged remissions, even after having received at least four prior treatments. Since the time of analysis, further responses have been observed, Dr. Vij said.

Severe adverse events were observed in 57% of patients, and 22% required dose modifications; 10% discontinued treatment. Major hematologic adverse events were limited to grades 1 and 2. Ibrutinib will be studied in combination with proteasome inhibitors and immunomodulatory drugs.

At a special symposium on chimeric antigen receptor (CAR) T-cell therapy, Carl June, MD, of the University of Pennsylvania, described four late-stage myeloma patients treated with CTL019, which has been used primarily in chronic and lymphocytic leukemias.7 In this pilot study, three of four patients achieved at least a very good partial response to CTL019, and two patients have achieved a stringent complete response. ■

Disclosure: Dr. Mateos has received honoraria from and is a member of an entity’s Board of Directors or advisory committees for Celgene and Janssen. Dr. Dimopoulos has served as a consultant for and received honoraria from Janssen, Onyx, and Celgene. Dr. Lacy has received research funding from Celgene. Dr. Palumbo has served as a consultant for and received honoraria from Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Amgen, Genmab A/S, and Bristol-Myers Squibb; he also has received honoraria from Array BioPharma and Sanofi. Dr. Shah has served as a consultant to and received research funding from Onyx Pharmaceuticals, Celgene, Millennium Pharmaceuticals, Novartis, and Array. Dr. Vij reported no potential conflicts of interest. Dr. June has received royalties and research funding from Novartis.

References

1. Mateos M-V, Martinez-Lopez J, Hernandez M-T, et al: Comparison of sequential vs alternating administration of bortezomib, melphalan, prednisone and lenalidomide plus dexamethasone in elderly patients with newly diagnosed multiple myeloma: GEM2010MAS65 trial. 2014 ASH Annual Meeting. Abstract 178. Presented December 7, 2014.

2. Dimopoulos MA, Palumbo A, Weisel K, et al: Safety and efficacy in the Stratus (MM-010) trial, a single-arm phase 3b study evaluating pomalidomide + low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 80. Presented December 7, 2014.

3. Lacy MQ, LaPlant BR, Laumann KM, et al: Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 304. Presented December 8, 2014.

4. Palumbo A, Rossi D, Bringhen S, et al: Weekly carfilzomib, cyclophosphamide, and dexamethasone in newly diagnosed multiple myeloma patients: A phase I-II study. 2014 ASH Annual Meeting. Abstract 175. Presented December 7, 2014.

5. Shah JJ, Feng L, Manasanch EE, et al: Phase I/Ib trial of the efficacy and safety of combination therapy with lenalidomide/bortezomib/dexamethasone and panobinostat in transplant-eligible patients with newly diagnosed multiple myeloma. 2014 ASH Annual Meeting. Abstract 33. Presented December 6, 2014.

6. Vij R, Huff CA, Bensinger WI, et al: Ibrutinib, single agent or in combination with dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma: Preliminary phase 2 results. 2014 ASH Annual Meeting. Abstract 31. Presented December 6, 2014.

7. June C: Therapeutic efficacy of chimeric antigen receptor T cells. 2014 ASH Annual Meeting. Special Scientific Symposium on Chimeric Antigen Receptor T-Cell Therapy. Presented December 7, 2014.



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