2015 was a very exciting year for us myelomatologists. The FDA approved four new agents for multiple myeloma (panobinostat, daratumumab, ixazomib, and elotuzumab). In 2016 we will have to begin the task of determining the most appropriate combinations and sequencing of agents. This is a review of some of the key manuscripts published this year of relevance to the practicing oncologist.
Workup and Staging
2014 gave us revised criteria for the diagnosis of multiple myeloma; and in 2015 we now had several important manuscripts providing guidance on the diagnostic workup and prognostication for the disease.
Dimopoulos et al (JCO 2015; 33:657-664) reported a consensus statement from the International Myeloma Working Group (IMWG) on the use of magnetic resonance imaging (MRI) in multiple myeloma. The authors concluded that MRI was the gold standard for imaging of the axial skeleton, for evaluation of painful lesions, and for distinguishing benign from malignant osteoporotic vertebral fractures.
The authors recommended that in addition to visualization of the spinal cord or nerve compression and the presence of soft tissue masses that MRI be used for the workup of solitary bone plasmacytoma and that all patients with smoldering myeloma undergo full body MRI or spinal and pelvic MRI if whole body MRI is not available. If these patients have more than one focal lesion of greater than 5 mm in diameter, they should be considered to have symptomatic disease for consideration of therapy.
In cases of equivocal or small lesions, a second MRI should be performed after three to six months and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. For patients with an established diagnosis of multiple myeloma, an MRI at diagnosis and after treatment, especially autologous stem cell transplantation, was thought to provide prognostic information, but to date does not change treatment selection.
Palumbo et al (JCO 2015: 33:2863-2869) published a revised international staging system for multiple myeloma on behalf of IMWG. Clinical and laboratory data from 4,445 patients with newly diagnosed myeloma enrolled into 11 international trials were pulled together, and this revised international staging system combined the exiting international staging system with chromosomal abnormalities detected by interphase fluorescence in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate prognosis:
- Revised ISS I: ISS stage I, no high-risk cytogenetic abnormalities (deletion 17p, t(4;14) and/or t(14;16)) and normal LDH with a five-year overall survival (OS) of 82 percent and five-year progression-free survival (PFS) of 55 percent;
- Revised ISS 2: Not R-ISS I or III with five-year OS of 62 percent and five-year PFS of 36 percent;
- Revised ISS stage III: Including ISS stage III and high-risk cytogenetics or high LDH level with five-year OS of 40 percent and five-year PFS of 24 percent.
Recently, next-generation sequencing (NGS) technologies have defined for us the mutational spectrum of patients with multiple myeloma and the clonal heterogeneity that characterizes this disease like several other hematological neoplasms. However, past publications did not establish the clinical relevance of these mutations.
Walker et al (JCO 2015; 33:3911-3920) performed whole exome sequencing for 463 patients with newly diagnosed multiple myeloma who are enrolled onto the National Cancer Research Institute Myeloma-XI Trial for whom complete molecular cytogenetic and clinical outcome data were available.
The researchers identified 15 significantly mutated genes. The mutational spectrum was dominated by mutations in RAS (43%) and nuclear factor kappa B (17%) pathways. Though prognostically neutral, these could be potentially targeted therapeutically.
Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) were associated with a negative impact on survival. In contrast, IRF4 and EGR1 mutations were associated with favorable overall survival. The authors combined these known mutation risk factors with recurrent molecular adverse features and the international staging system to generate a prognostic score that could identify high-risk populations.
Though exome sequencing is not yet a clinical standard, one could imagine a not too distant future where this may become mainstream, and such a prognostic system could then become clinically useful.
2015 saw the promise of monoclonal antibody therapy in multiple myeloma become a reality, and two seminal papers in the New England Journal of Medicine attested to the dawn of a new era.
Lonial et al (NEJM 2015; 373:621-631) reported on a Phase III study with patients randomly assigned to receive either elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAM F7), plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone.
A total of 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the PFS at one year in the elotuzumab group was 68 percent compared with 57 percent in the control group, with two-year PFS rates of 41 and 27 percent, respectively. The median PFS in the elotuzumab group was 19.4 months versus 14.9 months in the control group (hazard ratio 0.70; p< 0.001). The overall response rate in the elotuzumab group was 79 percent versus 66 percent in the control group (p< 0.001).
Lokhorst et al (NEJM 2015; 373: 1207-1219) reported on a Phase I/II study of single-agent daratumumab, a CD38 targeting human IgG1 kappa monoclonal antibody in patients with relapsed and/or refractory multiple myeloma. Patients had received a median of four prior treatments.
The overall response rate was 36 percent in the cohort that received the Phase II dose of 16 mg/kg. The median PFS was 5.6 months, and 65 percent of responders did not have progression at 12 months. Infusion-related reactions were mild, and the most common adverse events of grade 3 or 4 severity were pneumonia and thrombocytopenia.
2015 also saw the publication of the ASPIRE trial for patients with relapsed multiple myeloma comparing the regimen of carfilzomib with lenalidomide and dexamethasone with lenalidomide and dexamethasone alone (Stewart et al: NEJM 2015; 142-152).
PFS was significantly improved in the carfilzomib arm (median 26.3 vs. 17.6 months; p=0.0001). The overall rates of response were 87.1 and 66.7 percent, respectively (p< 0.001). A total of 31.8 percent and 9.3 percent of patients in the respective groups had a complete response or better. Grade 3 or higher adverse events and rates of discontinuation owing to adverse events were comparable in the two arms.
Dimopoulos et al reported results of the ENDEAVOR trial (Lancet Oncology, published online: 05 Dec 2015; doi.org/10.1016/S1470-2045(15)00464-7). In this randomized, Phase III, open-label, multicenter study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) to receive carfilzomib with dexamethasone or bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1.3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group).
Median progression-free survival was 18.7 months (95% CI 15.6–not estimable) in the carfilzomib group versus 9.4 months (range of 8.4-10.4 months) in the bortezomib group at a preplanned interim analysis (p<0.0001). On-study death due to adverse events occurred in 18 of 464 patients (4%) in the carfilzomib group and 16 of 465 patients (3%) in the bortezomib group.
Serious adverse events were reported in 224 of 463 patients (48%) in the carfilzomib group and 162 of 456 patients (36%) in the bortezomib group. The most frequent grade 3 or higher adverse events were anemia (67 [14%] of 463 patients in the carfilzomib group vs. 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs. 12 [3%]), thrombocytopenia (39 [8%] vs. 43 [9%]), and pneumonia (32 [7%] vs. 36 [8%]).
The combination of bortezomib, lenalidomide, and dexamethasone has become a popular regimen for the treatment of patients with multiple myeloma. With the approval of the next-generation proteasome inhibitor carfilzomib and the immunomodulatory drug pomalidomide, it makes rational sense to now combine these drugs as well.
Shah et al (Blood 2015; 126: 2284-2290) reported the results of a Phase I/II trial of carfilzomib with pomalidomide and dexamethasone for relapsed or refractory multiple myeloma. The maximally tolerated dose of the regimen was carfilzomib 20/27 mg/m2 on days 1, 2, 8, 9, 15, and 16, pomalidomide 4 mg daily on days 1 through 21, and dexamethasone 40 mg oral or IV on days 1, 8, 15, and 22 of a 28-day cycle. The combination was well tolerated and highly active in patients with relapse/refractory multiple myeloma.
Autologous Stem Cell Transplantation (ASCT)
In the era of proteasome inhibitors and immunomodulatory drugs, the integration of ASCT in the therapeutic armamentarium continues to be validated.
Gay et al (Lancet Oncology 2015; 16:1617-1629) performed an open-label randomized multicenter Phase III study enrolling transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger. Patients received a common induction with four cycles of lenalidomide and dexamethasone followed by chemotherapy with cyclophosphamide and G-CSF for stem cell mobilization and collection.
Using a 22 factorial design, patients were randomized to either consolidation with chemotherapy (six cycles of cyclophosphamide) or two courses of high-dose melphalan (200 mg/m2) and ASCT. There was a secondary randomization thereafter to maintenance with either lenalidomide alone (10 mg days 1 through 21) or lenalidomide with prednisone (50 mg every other day).
For the 389 patients enrolled, PFS during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28.6 months vs. 43.3 months; P < 0.0001). PFS did not differ between the two maintenance arms (median 37.5 months with lenalidomide and prednisone and 28.6 months with lenalidomide alone; P=0.034).
A key question regarding stem cell transplantation for patients with multiple myeloma is whether patients should move to transplantation after a finite period of therapy or continue with induction chemotherapy until maximum disease response before embarking on autologous stem cell transplantation.
This controversy was sought to be addressed in a CIBMTR analysis (Vij et al: Biology of Blood and Marrow Transplantation 2015; 21:335-341). In this analysis, 324 patients who received additional salvage chemotherapy after failing to achieve a partial response to first-line induction chemotherapy were compared with 215 patients who had no additional salvage chemotherapy immediately before autologous stem cell transplantation.
Though additional pre-transplant chemotherapy resulted in deeper responses in 68 percent of patients, multi-variant analysis showed no impact of pre-transplant salvage therapy on treatment-related mortality risk for relapse, progression-free survival, or overall survival.
The authors concluded that for patients achieving a less than partial response to initial induction therapy including those with novel agent combinations, additional pre-autologous transplant salvage chemotherapy was not associated with a survival benefit. This indirectly seems to suggest that additional therapy to deepen responses may not be of benefit prior to autologous stem cell transplantation.
Duration of Therapy
One of the most vexing questions in the therapeutics for patients with multiple myeloma has been whether continuous therapy has any advantage versus fixed duration therapy in patients with newly diagnosed multiple myeloma. Continuous therapy has been shown to prolong PFS1 (time from random assignment until first progression or death), but chemotherapy-resistant disease and relapse could potentially negatively impact overall survival.
Palumbo et al (JCO 2015; 33:3459-3466) explored whether PFS2 (time from random assignment until second progression or death) presented an additional tool to estimate outcome and evaluate the benefit of novel agent-based continuous therapy versus fixed-duration therapy in patients with newly diagnosed myeloma.
The authors studied the outcome of 604 patients in a pooled analysis of three randomized Phase III studies that randomly assigned patients to novel agent-based continuous therapy versus fixed-duration therapy. After a median follow-up of 52 months, continuous therapy significantly improved PFS1 (median 32 vs. 16 months; p< 0.001), PFS2 (median 55 vs. 40 months; p< 0.001), and OS (median four-year OS of 69% vs. 60%; p= 0.003).
The improvement in PFS2 suggested that the benefit reported during first remission was not negated by a shorter second remission.
However, certainly longer durations of therapy do add to the cost of therapy, which was a subject of much discussion both in the academic and lay press in 2015. In this regard, it is heartening to note that investigators are attempting to study the financial toxicity of therapy in patients with multiple myeloma.
Huntington et al (Lancet Haematology 2015; 2: e408-e416) reported on a cross-sectional survey of individuals receiving treatment for multiple myeloma at a tertiary academic medical center in the United States. Fifty-nine percent of patients reported that treatment costs were higher than expected; 71 percent said they had at least a minor financial burden; 36 percent needed financial assistance; 46 percent had to dip into savings to pay for myeloma treatment; and 21 percent said they had to borrow money to pay for medication.
The manuscripts discussed here offer only a snapshot of the substantial body of literature that accumulated during 2015. However, this is sufficient proof that myelomatologists have been making steady progress against a devastating disease. I have no doubt that they will reap a bumper crop in 2016 as well.
Links to Studies
Access the hyperlinks (shown in grey) for all the abstracts noted by reading this article on our iPad app, or by reading the pdf of the article on oncology-times.com.