Among the myeloma news that caught my attention at the ASH Annual Meeting were new immune modulating agents (IMiDs), new proteasome inhibitors, and myriad possible combinations, some now capable of achieving minimal residual disease (MRD) status. In addition, agents with totally different mechanisms of action are beginning to make an impact. Major ongoing questions covered in the Educational Session included prognostic risk factors, the role of high-dose therapy with autologous stem cell support (SCT) consolidation of first remission in this era of highly active agents, and the benefits vs. risks of maintenance strategies.
Two familiar trials of initial therapy were updated. Antonio Palumbo (Abstract 200) updated the phase III study comparing bortezomib melphalan-prednisone (VMP) vs VMP with thalidomide (T) followed by VT maintenance in non-transplant eligible patients (more than 95% of whom were over age 64). With four years of follow-up, the four-drug combination improved overall survival (OS) (59% at five years), particularly in those under age 75.
The complete response (CR) rate was higher (40% vs. 28%), and OS was better even when analysis was limited to those achieving CR. Grade 3/4 neuropathy was seven percent with VT maintenance, but no increase in second malignancies has been seen.
In an update of MM-015, in which patients who received MP-lenalidomide (R) followed by lenalidomide maintenance had prolonged PFS compared with MP or MPR without maintenance, Meletios Dimopoulos (Abstract 944) reported that when patients required second-line therapy, prior lenalidomide did not appear to affect the response to re-treatment with lenalidomide-based regimens.
These two trials are reassuring in that we can improve not only progression-free survival (PFS) but also OS and have not “used up” our treatment options.
The other major front-line studies reported are not MP based, either using cyclophosphamide (Cy) or avoiding alkylating agents altogether. Various combinations include a corticosteroid dexamethasone (Dex), almost always now on the weekly schedule, with IMiDs, proteasome inhibitor, and/or the alkylator (Cy).
The irreversible proteasome inhibitor carfilzomib (C), recently approved in the U.S. for use in relapsed myeloma, has rapidly moved into the front-line setting, substituting for bortezomib in many of these. Relatively early data, primarily response rate (RR) and toxicity, from phase II trials were reported of carfilzomib-Dex plus either cyclophosphamide (CCd), thalidomide (CTD), lenalidomide (CRD) and the four-drug CYCLONE regimen (CTD and Cy).
Another study by Palumbo (Abstract 730) reported on 34 newly diagnosed myeloma patients age 65 and older who received CCd as front-line therapy. Carfilzomib is given as usual on two consecutive days for three weeks out of four (i.e., days 1, 2, 8, 9, 15, and 16), with Dex 40 mg orally once weekly and Cy orally on days 1, 8, and 15 of each 28-day cycle. Carfilzomib is given at 20 mg/m2 on days 1 and 2 of cycle 1, and then at 36 mg/m2 subsequently. Maintenance carfilzomib is planned at 36 mg/m2 on two consecutive days every two weeks until disease progression or toxicity.
About 75 percent of patients achieved at least 90 percent reduction in myeloma burden (VGPR), with 40 percent achieving CR/nCR. There was no grade 3 or greater neurotoxicity and no grade 4 thrombocytopenia.
In a younger (age less than 65, median of 58), SCT-eligible population, Pieter Sonneveld (Abstract 333) discussed data from the first 40 patients treated with a planned four cycles of CTD, cyclophosphamide mobilization, and high-dose melphalan autologous SCT, and then additional CTD x 4. Induction RR was almost 90 percent (53% at least VGPR), 35 completed CTD induction, and adequate stem cells were collected in all 34 patients attempted. Post-SCT VGPR was 63 percent in 31 patients.
In a small study of CRD (Abstract 732), 10 of the first 18 patients achieved stringent CR, and these were all negative by flow cytometry for evidence of residual disease—i.e., they achieved MRD status. The CYCLONE regimen (Abstract 445), essentially CCd as above plus continuous thalidomide at 100 mg daily, in 27 SCT-eligible patients (median age 65) treated to date, resulted in a VGPR of 75 percent or better including 29 percent CR.
Along with the CRD study above, other studies building upon lenalidomide-Dex (Rd) were also of interest. Shaji Kumar (Abstract 332 ) reported that the reversible boron-based proteasome inhibitor ixazomib (MLN9708) given orally weekly in combination with Rd resulted in VGPR of 44 percent, with 23 percent CR, and only one grade 3 neuropathy. Skin rash and GI toxicities were seen. This is a fully oral regimen that may be comparable in activity to RVD.
In an attempt to improve on RVD, it was found (Jonathan Kaufman, Abstract 336) that the histone deacetylase inhibitor vorinostat could be added at 200 mg daily on days 1-14 of each three-week cycle with a VGPR rate of 52 percent and CR of 29 percent, with CR increasing over time. Elotuzumab with Rd will be discussed below.
Clearly, longer follow-up is necessary to evaluate the durability of the responses in these early trials. Nonetheless, the take-home message is that various combinations of these four drug classes yield high response rates rated as VGPR and better, including significant rates of CR and some patients with MRD, which are expected to provide durable disease control. Cross-trial comparisons cannot be made, and it will be challenging to select a “best” treatment paradigm among these various regimens.
Relapsed Myeloma: Pomalidomide Combinations
Given the rapid adoption of immune modulators and proteasome inhibitors, a major unmet need currently is for therapies that are active in patients previously treated with, and especially refractory to, these agents.
With the recent approval of carfilzomib in this setting, much attention at the meeting involved pomalidomide (POM), the “third-generation” immune modulator. Several reports were instructive about the efficacy and tolerability of POM/Dex.
Martha Lacy (Abstract 201) presented the Mayo clinic experience of 345 patients treated on sequential phase II studies over the past five years dosing at 2 or 4 mg daily, or in the latest cohort, 4 mg for 21 days of a 28-day cycle, all with weekly Dex and daily aspirin.
PR or better was achieved in about one third of these heavily pretreated patients with duration of response of about eight months. Even in bortezomib/lenalidomide refractory patients the response rate was 27 percent. Grade 3 or higher toxicities were neutropenia in about one third of patients, anemia and thrombocytopenia in 10 to 15 percent, fatigue in eight percent, and pneumonia in eight percent; VTE was three percent.
Somewhat similar outcomes of patients with refractory myeloma having had at least two prior treatment regimens, including both bortezomib and lenalidomide, who received POM plus weekly Dex on the MM-002 trial were updated by Sundar Jagannath (Abstract 450). The dose received was 90 percent of that planned, although grade 3 or 4 neutropenia was 41 percent. Grade 3 or 4 anemia, thrombocytopenia, and pneumonia were all about 20 percent, while fatigue was 14 percent. Peripheral neuropathy was seven percent, but none were grade 3 or 4. A PR or better was achieved in 34 percent of patients, with a median duration of response of eight months.
Tomer Mark (Abstract 77) reported the Weill-Cornell experience of POM/Dex with clarithromycin and 81 mg daily aspirin in 100 patients with relapsed myeloma (median three prior regimens, at least one with lenalidomide) with the response rate about 50 percent, VGPR or better was 22 percent, and median PFS of eight months. Grade 3 or 4 neutropenia was 40 percent, anemia was 25 percent, and fatigue was six percent.
These data set the stage for the late-breaking abstract (LBA-6) in which Meletios Dimopoulos presented the randomized trial of POM/Dex compared with the old high-dose DEX regimen in patients with myeloma refractory to both lenalidomide and bortezomib. There was a 2:1 randomization to POM (4 mg daily on days 1-21 of a 28-day cycle) + LoDex (40 mg weekly) or high-dose DEX (40 mg for 4 days on/4 days off x 3 every 28 days).
Patients over age 75 received 20 mg DEX in each arm. Patients (302 POM/Dex; 153 DEX) were heavily pretreated (median of five prior regimens), and 72 percent were refractory to both lenalidomide and bortezomib. With a median follow-up of 18 weeks, for the primary endpoint of PFS, use of POM/Dex resulted in about four months vs two months for DEX.
The interim planned overall survival analysis also favored POM/Dex (median not reached) vs DEX (34 weeks). Cross-over to POM was permitted in the original design, and then mandated once the study endpoints were met.
Grade 3 or higher toxicities were neutropenia (42% POM/Dex vs 15%) and febrile neutropenia (7% vs 0%), with nearly equal thrombocytopenia (21% vs 24%) and infections (24 vs 23%). Neuropathy and VTE were rare (1% each).
While the question remains whether high-dose DEX is an appropriate comparator in the current era, we have gained a good picture of expected efficacy and toxicity of POM/DEX from these reports, and it is encouraging to see activity in patients refractory to lenalidomide.
Of course, efforts are already underway to build on POM/DEX. Paul Richardson reported ( Abstract 727) a phase I trial determining that in patients with relapsed myeloma refractory to lenalidomide and exposed to but not refractory to bortezomib, full doses of bortezomib (1.3 mg/m days 1, 4, 8, 11 every 21 days) plus DEX (20 mg day of and day after each bortezomib) can be combined with POM at 4 mg on days 1-14 of each three-week cycle. PR or better was achieved in almost 80 percent of patients. As expected, neutropenia was seen, but VTE seemed uncommon.
Another combination of POM/DEX with a proteasome inhibitor, in this case carfilzomib, was reported by Jatin Shah (Abstract 74). When combined with POM/DEX, the MTD for carfilzomib was 27 mg/m. In a heavily pretreated double-refractory population the response rate was about 50 percent, PFS was 7.4 months, and no grade 3 or 4 neuropathy occurred.
Antonio Palumbo (Abstract 446) also reported data on POM with prednisone as the corticosteroid in combination with cyclophosphamide in patients with relapsed myeloma previously treated with lenalidomide. With cyclophosphamide and prednisone each at 50 mg every other day, POM could be given at 2.5 mg daily and achieved a PR rate about 50 percent. In this study, maintenance POM continued and median PFS so far is 10 months.
Novel ‘Novel Agents’
We may finally, after a period of disappointment, be entering the monoclonal antibody era in myeloma. The plasma cell marker CD38 is an attractive target, and the unlabeled anti-CD38 monoclonal antibody daratumumab had no unexpected toxicities and has already demonstrated activity in a phase I trial in heavily pretreated patients. CS1 is a glycoprotein target expressed on plasma cells and NK cells. While the anti-CS1 antibody elotuzumab had minimal single-agent activity, it is synergistic in combination with lenalidomide, likely by enhancing antibody-dependent cytotoxicity (ADCC).
Paul Richardson (Abstract 202) also presented phase II data for patients with relapsed myeloma (1-3 prior therapies but no prior lenalidomide) who received lenalidomide at 25 mg on days 1-21 of a 28-day cycle with weekly Dex. (Rd) and weekly elotuzumab at either 10 or 20 mg/kg.
The overall response rate was 84 percent, with median PFS over two years, and a trend towards better results in the lower-dose cohort. Phase III trials of this regimen both in the front line and relapsed settings are under way. Tabalumab (A447), a monoclonal antibody against the TNF-family cytokine B cell activating factor (BAFF), has been combined with bortezomib-Dex with promising activity.
Agents with novel mechanisms of action that generated excitement by demonstrating activity in refractory patients included the kinesin spindle protein (KSP) inhibitor ARRY-520 ( Abstract 653), the cyclin dependent kinase (cdk) inhibitor dinaciclib (Abstract 76) and the circularly permuted form of the apoptosis inducing ligand TRAIL ( Abstract 78) that directly signals apoptosis.
Rapid progress continues in developing novel agents and combinations for myeloma therapy, now with the expectation of achieving a deep response with manageable toxicities not only in first-line but also in the relapsed setting. Still unanswered are how many and which drugs are optimal for induction, the role of high-dose chemotherapy with stem cell support to consolidate that remission, and the overall risk-benefit ratio for maintenance therapy. Additional investigation into prognostic factors, which change as therapy improves, and therapy for patients with high-risk disease is required.