The drug pipeline for multiple myeloma is full of promise, based on data from a variety of new classes of agents and improvements upon established classes—often in patients with disease refractory to conventional therapies. The following drugs are currently considered the most promising, having proceeded to phase 3 clinical trials or according to data presented at recent oncology conferences.
Ixazomib (MLN9708) is the first oral proteasome inhibitor to enter clinical trials in patients with myeloma. It is a reversible inhibitor of the 20S proteasome that has similar selectivity and potency as bortezomib (Velcade), but with less peripheral neurotoxicity.
The final results of the phase 1 trial of ixazomib as a single agent were reported at the 2013 American Society of Clinical Oncology (ASCO) annual meeting.1 The study included 32 patients with myeloma in the dose-escalation phase (≥2 previous treatments), and 31 patients in the expansion cohort. The average patient had received 4 previous treatments, usually including bortezomib and/or lenalidomide (Revlimid), and 15% of the patients received carfilzomib (Kyprolis). The overall response rate with ixazomib was 18%, and 4 of 10 responders were previously exposed to another proteasome inhibitor. Among the patients who were optimally dosed, the response rate was 26%. The international phase 3 TOURMALINE-MM1 trial will assess ixazomib, given once weekly with lenalidomide and dexamethasone, in patients with relapsed and/or refractory myeloma.
Daratumumab is an investigational human CD38 monoclonal antibody that in May 2013 received “breakthrough therapy” designation from the US Food and Drug Administration for patients who had received at least 3 previous lines of therapy or whose disease is “double refractory” to a proteasome inhibitor, as well as to an immunomodulatory agent. A phase 1/2 dose-escalation study reported at the 2013 ASCO annual meeting involved 32 patients with relapsed disease. Of the 12 patients who received ≥4 mg/kg of daratumumab, 8 patients achieved at least a minimal response, and 7 of them had a 50% to 100% concomitant reduction in bone marrow plasma cells. The patients receiving ≥4 mg/kg of daratumumab had not reached the median progression-free survival (PFS) by a data cutoff of 3.8 months, and no major safety issues were identified.2
Elotuzumab is a monoclonal antibody that targets a cell-surface receptor called CS1, which is highly expressed on myeloma cells. This action is believed to facilitate the efficacy of other antimyeloma drugs, such as lenalidomide and bortezomib. Elotuzumab, given with lenalidomide and dexamethasone, was evaluated in a phase 2 clinical trial of 73 patients with myeloma who had received a median of 2 previous lines of therapy.3 The overall response rate was 84%, with 92% response rate with the 10-mg/kg dose and 76% response rate with the 20- mg/kg dose. At a median follow-up of 20.8 months, the median PFS was 18.6 months in the 20-mg/kg group and was not reached by the 10-mg/kg group.
Elotuzumab is currently being evaluated in 2 phase 3 clinical trials in combination with dexamethasone and lenalidomide—ELOQUENT-1, which is being investigated in the first-line setting, and ELOQUENT-2, in the relapsed disease setting. Moreover, the combination of bortezomib and dexamethasone is being evaluated with or without elotuzumab in a phase 2 trial in patients with relapsed and/or refractory myeloma.
Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit the aggresome and proteasome pathways. The phase 2 clinical trial PANORAMA 2 investigated panobinostat, in combination with bortezomib and dexamethasone, in 55 patients with relapsed and with bortezomib-refractory multiple myeloma.4 The overall response rate was 34.5%, and an additional 10 patients achieved a minimal response, for a total clinical benefit rate of 52.7%; the median PFS was 5.4 months. Responders were stable for a median of 6 months. Grade ≥3 peripheral neuropathy was rare (seen in only 1 patient). Phase 3 clinical trials of panobinostat are ongoing.
Two other oral histone deacetylase inhibitors include quisinostat, which is in phase 2 clinical trials, and vorinostat; however, vorinostat has demonstrated little clinical benefit so far.
ARRY-520 is a potent, highly selective inhibitor of the kinesin spindle protein inhibitor. In a phase 2 clinical trial reported at the 2012 American Society of Hematology annual meeting, the overall response to ARRY-520, given with lenalidomide plus dexamethasone, was 22% (28%, when counting minor responses) and the median response duration was 5.4 months. Most of the patients had disease refractory to bortezomib and to lenalidomide.5 Of note, ARRY-520 has also shown activity as a single agent.
Plitidepsin is a compound originally isolated from the sea squirt, a marine organism. A phase 2 clinical trial in 47 patients with relapsed and/or refractory myeloma showed positive activity, with an overall response rate of 22% when plitidepsin was combined with dexamethasone. Plitidepsin is currently being evaluated in combination with dexamethasone in the international phase 3 clinical trial ADMYRE in patients with relapsed and/or refractory myeloma.6
Other Promising Agents in Early Development
According to the Multiple Myeloma Research Foundation, other promising drugs in phase 2 clinical trials include AT7519, siltuximab, and PD0332991.
Encouraging compounds in phase 1 trials include ABT-199, ganetespib, GSK2110183, MLN128, marizomib, OSI006, SAR650984, TG02, and TKI258.7
- Kumar S, Bensinger W, Zimmerman TM, et al. Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): results from a phase I study after full enrollment. J Clin Oncol. 2013;31(15 suppl). Abstract 8514.
- Lokhorst HM, Plesner T, Gimsing P, et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2013;31(15 suppl). Abstract 8512.
- Lonial S, Jagannath S, Moreau P, et al; for the 1703 Study Investigators. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): updated ph II results and ph I/II long-term safety. J Clin Oncol. 2013;31(15 suppl). Abstract 8542.
- Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. Epub 2013, August 15.
- Shah JJ, Zonder JA, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 449.
- Multiple Myeloma Research Foundation. Relapsed/refractory patients: treatment options—Aplidin. www.themmrf.org/living-with-multiple-myeloma/relapsed-refractory-patients/treatment-options/aplidin.html. Accessed September 19, 2013.
- Multiple Myeloma Research Foundation. Results: pipeline. www.themmrf.org/about-the-mmrf/results/pipeline.html. Accessed September 19, 2013.