Faculty Bibliography

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

BACKGROUND:Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. DESIGN AND METHODS/METHODS:Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. RESULTS:The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44-2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. CONCLUSIONS:The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior in terms of survival outcomes to the standard infusional regimen of cyclophosphamide-vincristine-doxorubicin-dexamethasone. Based on its oral administration and the reduced incidence of infection and cytopenia, cyclophosphamide-thalidomide-dexa-methasone may be considered an effective induction therapy option for patients with newly diagnosed multiple myeloma. (ISRCTN: 68454111).

In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory multiple myeloma (MM; N = 3846), the overall incidence rate (IR, events per 100 patient-years) of second primary malignancies (SPMs) was 3.62. IR of invasive (hematologic and solid tumor) SPMs was 2.08, consistent with the background incidence of developing cancer. In a separate analysis of pooled data from pivotal phase 3 trials of relapsed or refractory MM (N = 703), the overall IR of SPMs was 3.98 (95% confidence interval [CI], 2.51-6.31) with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) with placebo/dexamethasone; IRs of nonmelanoma skin cancers were 2.40 (95% CI, 1.33-4.33) and 0.91 (95% CI, 0.23-3.66), respectively; IRs of invasive SPMs were 1.71 (95% CI, 0.86-3.43) and 0.91 (95% CI, 0.23-3.66), respectively. The risk of SPMs must be taken into account before initiating lenalidomide treatment. In the context of the observed survival benefit in relapsed or refractory MM patients, the benefit/risk profile of lenalidomide/dexamethasone remains positive.

Next generation DNA sequencing (NGS) technologies have revolutionized the pace at which whole genome and exome sequences can be generated. However, despite these advances, many of the methods for targeted resequencing, such as the generation of high-depth exome sequences, are somewhat limited by the relatively large amounts of starting DNA that are normally required. In the case of tumour analysis this is particularly pertinent as many tumour biopsies often return submicrogram quantities of DNA, especially when tumours are microdissected prior to analysis. Here, we present a method for exome capture and resequencing using as little as 50 ng of starting DNA. The sequencing libraries generated by this minimal starting amount (MSA-Cap) method generate datasets that are comparable to standard amount (SA) whole exome libraries that use three micrograms of starting DNA. This method, which can be performed in most laboratories using commonly available reagents, has the potential to enhance large scale profiling efforts such as the resequencing of tumour exomes.

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.

The Medical Research Council Myeloma IX Trial (ISRCTNG8454111) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid (ZOL) and oral clodronate (CLO) in 1960 patients with newly diagnosed multiple myeloma. Overall survival (OS) and skeletal-related event (SRE) data have been reported for the overall trial population. The present analysis investigated optimal therapy regimens for different patient populations in Myeloma IX. Patients were assigned to intensive or nonintensive treatment pathways and randomized to induction cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive). Patients were also randomized to ZOL or CLO. In the nonintensive pathway, CTDa produced better responses and lower SRE rates than melphalan and prednisolone. ZOL improved OS compared with CLO independently of sex, stage, or myeloma subtype, most profoundly in patients with baseline bone disease or other SREs. In patients treated for ≥ 2 years, ZOL improved OS compared with CLO from randomization (median not reached for either; P = .02) and also from first on-study disease progression (median, 34 months for ZOL vs 27 months for CLO; P = .03). Thalidomide-containing regimens had better efficacy than traditional regimens, and ZOL demonstrated greater benefits than CLO.

We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

Myeloma develops due to the accumulation of multiple pathological genetic events, many of which have been defined. Hyperdiploidy and reciprocal translocations centered on the immunoglobulin heavy chain variable region constitute primary genetic lesions. These primary lesions co-operate with secondary genetic events including chromosomal deletions and gains, gene mutations and epigenetic modifiers such as DNA methylation to produce the malignant phenotype of myeloma. Some of these events have been linked with distinct clinical outcome and can be used to define patient groups. This review explores the molecular biology of myeloma and identifies how genetic lesions can be used to define high- and low-risk patient groups, and also defines potential targets for therapy. The authors also explore how this information can be used to guide therapeutic decision-making and the design and interpretation of clinical trials, both now and in the future.

Recent advances in multiple myeloma (MM) therapy have led to significantly longer median survival rates and some patients being cured. At the same time, our understanding of MM biology and the molecular mechanisms driving the disease is constantly improving. Next-generation sequencing technologies now allow insights into the genetic aberrations in MM at a genome-wide scale and across different developmental stages in the course of an individual tumor. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed. The potential of targeted next-generation diagnostic tests to rapidly identify clinically relevant molecular subgroups is being evaluated. The technical tools to detect and define tumor subclones may potentially become clinically relevant because intraclonal tumor heterogeneity has become apparent in many cancers. The emergence of different MM subclones under the selective pressure of treatment is important in MM, especially in the context of maintenance therapy and treatment for asymptomatic stages of the disease. Finally, novel diagnostic and therapeutic achievements have to be implemented into innovative clinical trial strategies with smaller trials for molecularly defined high-risk patients and large trials with a long follow-up for the patients most profiting from the current treatment protocols. These combined approaches will hopefully transform the current one-for-all care into a more tailored, individual therapeutic strategy for MM patients.

A 55-year-old man without prior medical problems presented to the emergency room with a 2-month history of progressive fatigue. Initial workup showed a hemoglobin level of 9.0 g/dL and an increased total protein level of 12.6 g/dL. Further testing revealed a normal serum calcium and creatinine, an IgG kappa paraprotein of 5.4 g/dL, and a Bence Jones proteinuria of 450 mg of kappa light chain in 24 hours. The bone marrow showed 60% plasma cells with normal cytogenetics and t(4;14), but no other associated genetic abnormalities by FISH. Skeletal survey and MRI of the spine were negative for myeloma bone disease. The patient's oncologist recently began therapy with lenalidomide, bortezomib, and dexamethasone and recommended the initiation of zoledronic acid monthly. The patient questions the benefit of this drug because he has no bone disease.