BY RAVI VIJ, MD
As 2014 winds down it is once again time to review what the motley crew of authors, reviewers, and editors thought fit to consign to print in their various esteemed journals this year.
I. Myeloma Redefined
Perhaps the manuscript with the greatest impact in the years to come may be the one just published by Vincent Rajkumar et al (Lancet Oncology 2014;15:e538-548) in the waning months of the year, which lays out the International Myeloma Working Group (IMWG) consensus to update the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of end-organ dysfunction.
The rationale for updating the diagnostic criteria is that currently the definition of myeloma needs a clinical manifestation of serious end-organ damage before the diagnosis can be made. This definition prevents patients from getting early therapy to prevent organ damage from occurring in the first place. However, with the availability of less toxic and more effective treatment options, some of which have data to show a possible improvement with early intervention at a stage when patients are currently diagnosed to have smoldering myeloma, it is felt that a revision of the definition is warranted. Also, advances in laboratory and imaging techniques have meant that an update on diagnostic criteria is due.
The IMWG reached a consensus that if reliable biomarkers could be identified for patients with smoldering myeloma that predicted for 80 percent probability of progression to myeloma within two years, then such patients should be redefined as having multiple myeloma and be offered therapy.
With this goal in mind, the panel after data mining and reviewing published data came up with the following recommendations/modifications:
- Diagnostic for M-protein as part of diagnostic criteria is not mandatory;
- Clonal bone marrow plasma cells ≥ 10% should be established by showing kappa/lambda restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen and in case of disparity between the aspirated core biopsy, the highest value should be used;
- Renal insufficiency should be defined as a creatinine clearance < 40 mL/minute or a creatinine of > 2 mg/dL; and
- Bone lesions should be defined as one or more osteolytic lesions seen not only on skeletal survey, but also if detected by CT or CT PET scanning.
In addition, the definition of multiple myeloma has been modified to include one or more of the following biomarkers of malignancy:
- Clonal bone marrow plasmacytosis > 60%;
- Involved to uninvolved serum free light chain ratio ≥ 100 (the involved free light chain must be ≥ 100 mg/L); and
- More than one focal lesion on MRI studies with each being at least 5 mm or more in size.
These diagnostic criteria remove the need for documented end-organ damage as a mandatory requirement for definition of malignancy.
This redefinition is certainly going to mean that more patients with plasma cell dyscrasia are going to be treated now instead of being observed as smoldering myeloma. Hopefully, this will cut down on the situations where previous recommendations to wait and watch led to the occasional patient ending up with acute renal failure or other adverse consequence, which subsequently led one to regret the decision to have adopted a wait and watch policy.
It is likely that there will be situations in the immediate future where one may be hesitant to use the expanded definition to treat a totally asymptomatic patient now newly classified as having myeloma based on CT/PET and MRI or serum free light ratio value. However, as these more expanded criteria are adopted as entry criteria into clinical trials it is likely that with the passage of time conformity will ensue.
II. Randomized Phase III Trials with Conventional Therapy
Lotfi Benboubker et al (NEJM 2014:371:906-917) published results of the FIRST trial, which randomly assigned 1,623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression, the same combination for 72 weeks or to melphalan, prednisone, and thalidomide (MPT) for 72 weeks. The primary end-point was comparison of progression-free survival with continuous lenalidomide and dexamethasone versus MPT.
The median progression-free survival was 25.5 months with continuous lenalidomide and dexamethasone, 20.7 months with 18 cycles of lenalidomide and dexamethasone, and 21.2 months with MPT (p < 0.001 for both comparisons). Overall survival at four years was 59 percent with continuous lenalidomide and dexamethasone, which was statistically significantly improved compared with the 51 percent with MPT, but not when compared with the 56 percent with 18 cycles of lenalidomide and dexamethasone. Grade 3-4 adverse events were somewhat less frequent with lenalidomide and dexamethasone than with MPT (70% versus 78%).
Though this trial is likely to have little practice-changing impact here in the United States, it is hoped that it will lead to the approval of lenalidomide and dexamethasone for front-line therapy, which could be important in other areas of the world like Europe where the use of Revlimid and dexamethasone is still restricted to patients with relapsed and refractory disease.
Jesus San-Miguel et al (Lancet Oncology 2014;15:1195-1206) published results of the PANORAMA-1 study. This multicenter randomized double-blind Phase III study of panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed and refractory multiple myeloma randomized patients to receive 21-day cycles of placebo or panobinostat, both in combination with bortezomib and dexamethasone.
768 patients were enrolled. The median progression-free survival was significantly lower in the panobinostat group (11.99 months) than in the placebo group (8.08 months) (p< 0.0001). Median overall survival was 33.64 months for the panobinostat group and 30.39 months for the placebo group (p = 0.26).
Serious adverse events were recorded in 60 percent of patients in the panobinostat group and 42 percent in the placebo group. Common grade 3/4 laboratory abnormalities included thrombocytopenia (67% in the panobinostat group versus 31% in the placebo group); lymphopenia (53% versus 40%); diarrhea (36% versus 8%); ischemia or fatigue (24% versus 12%); and peripheral neuropathy (18% versus 15%).
On November 6 the Oncologic Drugs Advisory Committee (ODAC) of the FDA voted 5 to 2 against recommending approval of the drug, as they felt that the benefits of panobinostat as potential treatment for myeloma outweighed its risks. A final FDA decision on the application for approval of panobinostat based on this trial is still pending.
III. Autologous Stem Cell Transplantation for Multiple Myeloma
Antonio Palumbo et al (NEJM 2014;371:895-905) reported on an open-label randomized Phase III study comparing melphalan at a dose of 200 mg/m² plus autologous stem cell transplantation with melphalan, prednisone, and lenalidomide and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.
273 patients 65 years of age of younger, were randomized to high-dose melphalan plus stem cell transplantation on melphalan, prednisone, and lenalidomide consolidation after induction and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end-point was progression-free survival.
After a median follow up of 51.2 months, both progression-free and overall survival were significantly longer with high-dose melphalan plus stem cell transplantation than with melphalan, prednisone, and lenalidomide--43 months versus 22.4 months (p < 0.001) and four-year overall survival--81.6 percent versus 65.3 percent (p value =0.002).
Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance, 41.9 versus 21.6 months (p < 0.001). However, three-year overall survival was not significantly prolonged 88 versus 79.2 percent (p = 0.14).
This trial once again reaffirmed the role of autologous stem cell transplantation for patients with myeloma even in the era of novel drugs.
Gordon Cook et al (Lancet Oncology 2014;15:874-885) reported on the first randomized open-label Phase III trial to study the role of high-dose chemotherapy with autologous stem cell transplantation in patients with relapse multiple myeloma after a previous autologous stem cell transplant (NCRI myeloma X relapse intensive trial).
This multicenter trial recruited patients who had needed treatment for first progressive or relapse disease at least 18 months after previous autologous stem cell transplantation from 51 centers across the United Kingdom. Before randomization patients received bortezomib, doxorubicin, and dexamethasone induction, and eligible patients were randomized 1:1 to either high-dose melphalan 200 mg/m² with salvage ASCT or oral cyclophosphamide (400 mg/m² per week for 12 weeks).
Between April 2008 and November 2012, a total of 297 patients were registered, of whom 293 received induction therapy; 174 patients were randomized to ASCT or cyclophosphamide.
After a median follow-up of 31 months, the median time to progression was significantly longer in the salvage ASCT cohort (19 months) than in the cyclophosphamide group (11 months) (p < 0.0001).
Though the choice of therapy in the control arm could be questioned, this study provides evidence for the efficacy of high-dose melphalan and salvage ASCT in the management of patients with relapsed multiple myeloma eligible for intensive therapy.
IV. ‘Next-gen Duo’
2014 saw additional publications on pomalidomide and carfilzomib for patients with relapsed disease:
Paul Richardson et al (Blood 2014;123:1461-1469) reported on the results of the MM-002 randomized Phase II study of pomalidomide alone or in combination with low-dose dexamethasone in relapsed of relapsed/refractory multiple myeloma. The primary endpoint was progression-free survival.
A total of 221 patients were randomized with a median follow-up of 14.2 months. The median progression-free survival was 4.2 and 2.7 months (p = 0.003), and overall response rates were 33 and 18 percent (p = 0.013). The median response duration was 8.3 and 10.7 months, and the median overall survival was 16.5 and 13.6 months, respectively. Refractoriness to lenalidomide or the resistance to both lenalidomide and bortezomib did not affect outcomes with pomalidomide and dexamethasone.
Nikoletta Lendvai et al (Blood 2014;124:899-906) reported on a Phase II single-center study of carfilzomib given at an escalated dose of 56 mg/m² with or without low-dose dexamethasone in relapsed multiple myeloma. At time of enrollment, all patients had received prior bortezomib and immunomodulatory drugs with a median of five prior regimens. Of the 42 response-evaluable patients, 55 percent achieved at least a partial response.
Median duration of response and progression-free and overall survival were 11.7, 4.1, and 20.3 months, respectively. Of six patients who responded, progressed, and had dexamethasone added, four achieved at least stable disease. Grade 3/4 adverse events possibly related to carfilzomib included lymphopenia (43%), thrombocytopenia (32%), hypertension (25%), pneumonia (18%), and heart failure (11%). Seven patients (16%) discontinued treatment due to adverse events.
This dose of carfilzomib is being compared head to head to bortezomib in the randomized Phase III ENDEAVOR trial.
V. Coming Down the Pike: Ixazomib
The year saw the publication of several Phase I/II studies of ixazomib, an orally bioavailable small molecule inhibitor of the 20S proteasome. Ixazomib has been shown to have similar selectivity and potency to bortezomib, but a shorter disassociation half-life. Ixazomib has been shown to have preclinical activity and antitumeric activity in xenograft models of myeloma, some of which were bortezomib resistant.
Shaji Kumar et al (Blood 2014;124:1047-1055) reported on a Phase I study of weekly dosing with ixazomib in relapsed and refractory multiple myeloma. The maximum tolerated dose (MTD) was determined to be 2.97 mg/m². Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in two patients and grade 3 skin rash in one patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). Peripheral neuropathy was seen in 20 percent of patients, with only one grade 3 event reported. The overall response rates were 18 percent and 27 percent at the MTD.
Richardson et al (Blood 2014;124:1038-1046) reported Phase I study of twice-weekly ixazomib in relapsed/refractory multiple myeloma patients. The MTD was 2 mg/m² with dose-limiting toxicities (grade 3 rash and grade 4 thrombocytopenia). Adverse events included nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%). Grade 1/2 drug-related peripheral neuropathy occurred in 12 percent of patients, and no neuropathy of grade 3 or higher was seen. Fifteen percent of patients achieved a partial response or better.
Based on these two Phase I studies, it was decided to pursue once-weekly dosing of ixazomib for future development.
Kumar et al (Lancet Oncology 2014;15:1503-1512) reported the results of an open-label Phase I/II study on the safety and tolerability of ixazomib in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma. The MTD of ixazomib was established at 2.79 mg/m², which was converted to a 4 mg fixed dose based on population pharmacokinetics.
Grade 3 or higher events included skin rash (17%), neutropenia (12%), thrombocytopenia (8%), and peripheral neuropathy (6%). A very good partial response rate or better was seen in 58 percent of patients.
This three-drug combination has now moved into a pivotal Phase III randomized clinical trial, where the three-drug combination will be compared with lenalidomide and dexamethasone.
VI. Minimal Residual Disease (MRD) Monitoring
Minimal residual disease monitoring is emerging as a difficult topic as we aim for deeper responses in multiple myeloma made possible by the incorporation of immunomodulating drugs and proteasome inhibitors. To date, most of the literature in this arena lately has been based on multi-perimeter flow cytometry to define MRD.
Joaquin Martinez-Lopez et al (Blood 2014;123:3073-3079) reported on a next generation sequencing-based platform to define the value of MRD.
A total of 133 multiple myeloma patients in at least very good partial response after front-line therapy were identified and MRD was assessed using IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multi-perimeter flow cytometry (MFC) and specific eukaryotic type polymerase chain reaction (ASO-PCR). Concordance between sequencing and MFC and ASO-PCR was 83 percent and 85 percent, respectively.
Patients who were MRD-negative by sequencing had significantly longer time to progression (median 81 versus 31 months; p <0.0001) and overall survival (median not reached versus 81 months; p = 0.02) compared with patients who were MRD-positive.
In complete response patients, the time to progression remained significantly longer for MRD-negative compared with MRD-positive patients (131 vs. 35 months; p = 0.0009).
The next generation sequencing-based assay has a sensitivity of 1 in 10-6 and is currently offered as the ClonoSIGHT assay by Sequenta, Inc.
Going forth, we now have two competing technologies for assessment of minimal residual disease. This adds to the urgency of reaching a consensus around the definition of minimal residual disease. Publications looking at flow cytometry to date have used a variety of assays, from four-color to eight-color assays for the sensitivity of about one cell in 10-4. This assay can be affected by the number of events studied and the threshold used to define MRD positivity.
The genetic heterogeneity of multiple myeloma was confirmed in two high-profile publications using next- generation sequencing technology to sequence large cohorts of patients.
Jens Lohr et al (Cancer Cell 2014;25:91-101) reported on massive barrow sequencing of paired/normal samples from 200 multiple myeloma patients. Frequent mutations in KRAS, NRAS, BRAF, FAM46C, TP53, and DIS3 were observed. Mutations were often present in subclonal populations, and multiple mutations within the same pathway were observed in the same patient.
Niccolò Bolli et al (Nature Communications 2014;5:2997) used whole exome sequencing, copy number profiling, and cytogenetics to analyze 84 multiple myeloma samples. Most cases were found to have a complex subclonal structure with clusters of subclonal variants including subclonal driver mutations. Serial sampling revealed diverse patterns of clonal evolution including linear evolution, differential clonal response, and branching evolution. There was heterogeneity in the mutational spectrum across samples with few recurrent genes.
Both of these publications complement earlier reports using next-gen sequencing technologies that have made it difficult to identify “targets” for those of us wishing to give up AK-47s and become snipers.
These publications are testament to the fact that basic science researchers and clinical trialists continue to successfully chip away at this edifice and hope that those from the dawning age of personalized and precision medicine will help in the future to deliver a fatal blow.
RAVI VIJ, MD, is Associate Professor of Medicine at Washington University School of Medicine in the Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology, in St. Louis, Missouri.