BY RAVI VIJ, MD, Associate Professor of Medicine, Section of Stem Cell Transplant and Leukemia, Washington University School of Medicine, St. Louis
The literature on multiple myeloma in 2013 provided us with ample evidence that the relentless march of advances in this disease continues. The articles published ran the spectrum from treatment for smoldering multiple myeloma, data on the new immunomodulatory drug pomalidomide, the novel proteasome inhibitor carfilzomib, the histone deacetylase inhibitors (HDACs) vorinostat and panobinostat, the value of stringent CR (sCR) and minimal residual disease (MRD) as endpoints, and recommendations on treatment- or myeloma-related bone disease.
While no brief review can do justice to the area, here I seek to highlight a few of the key topics to provide a flavor for the year past.
I: Treat It While It Smolders?
The publication by Mateos et al—“Lenalidomide Plus Dexamethasone for High-risk Smoldering Myeloma,” (NEJM Aug 1 2013; 369:438-447)—certainly generated much debate. In a randomized Phase III study, 119 patients with high-risk smoldering myeloma were randomized to either treatment with lenalidomide and dexamethasone or observation. The results at a median of 14 months of follow-up showed that the median time to progression (TTP) was significantly longer in the treatment group than in the observation group (not reached versus 21 months p < 0.001). The three-year survival rate was also higher in the treatment group (94% versus 80%, p= 0.003).
However, several questions have been raised regarding the clinical relevance of this study. The definition of high-risk population in this trial was nonstandard, with high-risk disease defined as a plasma cell bone marrow infiltration of at least 10 percent and a monoclonal component or only one of the two criteria plus at least 95 percent phenotypically apparent plasma cells in the bone marrow cell component with reductions in one or two uninvolved immunoglobulins.
Another issue with the trial design pertains to the fact that dexamethasone was added for patients in whom asymptomatic biological progression occurred during the maintenance phase, but in the observation arm evidence of end-organ dysfunction was required for patients to receive anti-myeloma therapy. Twenty-four of 57 patients (42%) in the intervention group had asymptomatic biological progression and 18 had dexamethasone added.
Also, lenalidomide and dexamethasone were not used consistently as salvage therapy for the observation group on disease progression. Therefore, this study is not informative on the issue of early treatment with lenalidomide and dexamethasone versus treatment with lenalidomide and dexamethasone deferred until time of progression of disease.
In addition, the 20 percent three-year mortality rate observed in the observation group is relatively high compared with historical data, which may have magnified the magnitude of benefit in the intervention arm of the study.
Since 40 percent of the patients in the trial were included on the basis of flow cytometric criteria which are not widely available and reproducible, the relevance of these results through general practice at this time is questionable. Hopefully, ongoing trials will clarify the issue in the future.
II: How Deep Do We Aim?
In multiple myeloma, as the capability of our therapies to deliver greater depths of response improves, the bar for definition of complete remission continues to be raised. Certainly, nobody today would accept the old SWOG definition of a 75 percent reduction in paraprotein as evidence of complete remission. The International Myeloma Working Group criteria define complete remission as absence of paraprotein on SPEP (serum protein electrophoresis) with a negative immunofixation. However, now there is great interest in pursuing even greater reductions in disease burden to define complete remission.
Kapoor et al in their publication—“Importance of Achieving Stringent Complete Response After Autologous Stem Cell Transplantation in Multiple Myeloma,” JCO 2013;31:4529-4535—studied the impact of achieving sCR after autologous stem cell transplantation in patients with multiple myeloma. In this study, sCR was defined as normalization of the serum free light chain ratio in absence of monoclonal bone marrow plasmacytosis and negative serum immunofixation studies.
Of 445 consecutive patients who underwent autologous stem cell transplantation (ASCT) within 12 months of diagnosis of myeloma, 109 patients (25%) achieved sCR after ASCT. The median overall survival (OS) rate from the time of transplantation for patients achieving a sCR was not reached, in contrast to 81 months for those achieving conventional complete response (CR) and 60 months for patients with near CR (nCR) (p< 0.001). Five-year OS rates were 80, 53, and 47 percent for sCR, CR, and nCR, respectively. The median TTP from ASCT of patients achieving sCR was 50 months compared with 20 months for those achieving conventional CR and 19 months for patients in nCR.
In another publication, Rawstron et al (“Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact On Outcome In the Medical Research Council Myeloma IX Study,” JCO 2013; 31:2540-2547) investigated the prognostic value of MRD assessment in patients with multiple myeloma treated on the Medical Research Council (MRC) Myeloma IX trial. That was a multicenter randomized Phase III study with patients initially assigned to either intensive or non-intensive pathway treatment, and thereafter randomly assigned to maintenance thalidomide or no further therapy.
A six-color panel of antibodies was used to define MRD by multiparameter flow cytometry. MRD was assessed after induction therapy in 378 patients, at day 100 after autologous stem cell transplant, and at the end of induction therapy in 245 non-intensive pathway patients.
In intensive pathway patients, absence of MRD at day 100 was highly predictive of improvement in progression-free survival (PFS) (p< 0.001) and OS (p= 0.183). The shortest PFS was demonstrated in those MRD-positive patients who did not receive maintenance and the longest in those who are MRD negative and did receive thalidomide (p< 0.001). MRD assessment after induction therapy in the non-intensive pathway patients did not seem to be predictive of outcome.
Certainly this endpoint is being incorporated increasingly into the design of prospective clinical trials in multiple myeloma. As more labs in the country develop the capability to perform multiparameter flow cytometry, MRD- negative status may become a goal of future studies and may serve as a surrogate for overall survival if validated in future studies.
III: The New Kids On the Block
2013 certainly saw the publication of a number of studies with the immunomodulatory drug pomalidomide, which was granted accelerated approval by the FDA earlier in the year. This approval was based on the MM-002 randomized Phase II study of patients with relapse and refractory multiple myeloma treated with pomalidomide alone or in combination with low-dose dexamethasone.
In October 2013, Sam Miguel et al published the results of a randomized open Phase III study (MM-003) comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (Lancet Oncology 2013;14:1055-1066). This study led to the approval of pomalidomide by the European Medicines Agency (EMA).
In this study, the patients were randomly assigned in a 2:1 fashion to receive either pomalidomide plus low-dose dexamethasone (n= 302) or high-dose dexamethasone (n= to 153). The patients were eligible if they had failed to respond to at least two previous treatments of bortezomib and lenalidomide.
After a median follow-up of 10 months, the median PFS with pomalidomide plus low-dose dexamethasone was four months versus 1.9 months for those receiving high-dose Dexamethasone (P < 0.0001). Median OS was also significantly longer in the pomalidomide plus low-dose dexamethasone group compared with the high-dose dexamethasone group (12.7 months versus 8.1 months, P= 0.00285).
Although the clinical relevance of the high-dose dexamethasone comparator in this highly refractory population of patients may be questioned, the OS of 12.7 months reported with pomalidomide and low-dose dexamethasone seemed to be superior to the median nine month survival reported by Kumar et al in the multicenter International Myeloma Working Group study (Leukemia 2012;26:149-157).
A Phase III study to compare the efficacy of pomalidomide, bortezomib, and low-dose dexamethasone versus bortezomib and low-dose dexamethasone in individuals with relapsed and refractory myeloma (OPTIMISMM) is now accruing patients. This study is being done to support the full approval of pomalidomide in the United States.
2013 also witnessed the publication of several articles on carfilzomib: For example, Wang et al (“Phase II Dose Expansion Study, PX-171-006, of Carfilzomib, Lenalidomide, and Low-dose Dexamethasone in Relapsed or Progressive Multiple Myeloma,” Blood 2013;122: 3122-3128) reported that the combination of carfilzomib, lenalidomide, and low-dose dexamethasone produced an overall response rate (ORR) of 76.9 percent and a median PFS of 15.4 months. The ORR was 69.2 percent in bortezomib-refractory patients and 69.6 percent in lenalidomide-refractory patients, with median durations of response (DOR) of 22.1 and 10.8 months, respectively.
This regimen is being compared with Revlimid and dexamethasone in a Phase III study (ASPIRE) for full approval of carfilzomib in the United States and has the potential to become a widely used regimen for patients with myeloma.
IV: Is There a Future for HDACs?
The year also saw the publication of several studies seeking to incorporate histone deacetylase inhibitors for the treatment of patients with relapsed and refractory multiple myeloma.
Dimopoulos et al published the results of VANTAGE 088, a multicenter randomized double blind study of vorinostat or placebo in combination with bortezomib in patients with multiple myeloma; 317 eligible patients were assigned to the vorinostat group and 320 to the placebo group.
This study met its primary endpoint, showing an improvement in PFS for the addition of vorinostat (7.63 months versus 6.83 months, p= 0.0100). However, despite the statistically positive results, it was felt that the study had little clinical meaningful benefit and has not been put forward to the FDA for seeking approval of vorinostat for the treatment of patients with relapsed and refractory multiple myeloma.
One now awaits with great anticipation the results of the PANORAMA I study comparing the combination of panobinostat with bortezomib and dexamethasone with bortezomib and dexamethasone alone in patients with relapsed and refractory multiple myeloma. A news release in December 2013 stated that the study had met its primary endpoint, but actual data on this trial have yet to be released.
However, in 2013, results of the PANORAMA II study combining panobinostat with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma were published by Richardson et al (Blood 2013;122: 2331-2337). In that study, 55 heavily pretreated patients (median of four prior regimens including a median of two prior bortezomib-containing regimens) were enrolled, and the ORR was 34.5 percent with a clinical benefit rate of 52.7 percent. Median PFS was 5.4 months with a median DOR of six months.
Certainly if the PANORAMA I study shows clinically meaningful benefit, we could possibly have a new drug class approved for patients with this disease, and this would provide a boost to other HDAC inhibitors including the HDAC 6 inhibitor ACY-1215, which is currently in clinical trials and is felt to have a much better efficacy-to-toxicity ratio.
V: Building Bones
The year also saw the release of the International Myeloma Working Group recommendations for the treatment of myeloma-related bone disease (Terpos et al: JCO 2013; 31:2347-2357). These guidelines recommended that bisphosphonates be considered in all patients with multiple myeloma receiving front line anti-myeloma therapy regardless of the presence of osteolytic bone lesions on conventional radiography.
Both intravenous zoledronic acid and pamidronate were felt to be appropriate therapies. Zoledronic acid is to be preferred over oral clodronate because of its potential anti-myeloma activity and survival benefits. It is recommended that bisphosphonate be administered until disease progression in patients not achieving CR or very good partial response (VGPR) and further continued at relapse. For patients in CR or VGPR, the optimal duration of bisphosphonates should be at least 12 months and up to 24 months and then at the physician's discretion.
The guidelines recommend that kyphoplasty be considered for symptomatic vertebral compression fractures and that low-dose radiation therapy be used for palliation of uncontrolled pain, impending pathological fracture, or spinal cord compression.
Going forward, it is hoped that a lot of the promising research with several novel agents in development, including monoclonal antibodies to CD38, which have been presented at international symposia, will start to appear in peer- reviewed literature, making for even more excitement in 2014.
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