Continuing the trend set in the first decade of this century, in 2011 we continued to see major advances both in the basic science arena and in the clinical care of patients with multiple myeloma. This article seeks to summarize some of these key developments.
In 2011, we saw the first report of using next-generation sequencing tech-nology to sequence the genome of patients with multiple myeloma. Chapman et al (Nature 2011;471:467-472) reported on massive parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected somatic mutations were reported in genes involved in protein translation, histone methylation, coagulation, and in 11 members of the NF-kappa-B pathway. Mutations of the B-Raf kinase were observed in 4% of patients, suggesting potential for evaluation of B-Raf inhibitors in clinical trials.
Hopefully, as additional myeloma genomes are sequenced, and other technologies, including RNA sequencing and the study of methylation patterns unfold, one will be able to unravel the key genetic changes that underlie this disease and identify additional targets for drug development, truly leading us into an era of personalized medicine for treatment.
Another key development was a report by Zhu et al (Blood, 2011;118:4771-4779), suggesting that cereblon (CRBN) is an essential requirement for the antimyeloma activity of lenalidomide and pomalidomide. CRBN had previously been identified as a primary target of thalidomide teratogenicity. The authors showed that CRBN depletion is initially cytotoxic to human myeloma cells, but that surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to bortezomib, dexamethasone, and melphalan. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion.
Workup of Patients
A series of back-to-back publications reported on consensus recommendations for standard investigative workup and for risk stratification in multiple myeloma from the 2009 International Myeloma Workshop (Blood 2011;117:4691-4695 and Blood 2011;117:4696-4700). The manuscripts provided detailed guidelines on the role of various investigative modalities, including blood tests and bone marrow biopsy with cytogenetics/FISH testing, as well as guidelines on how to integrate MRI testing and PET scanning in the workup of patients. High-risk features at diagnosis and progression were reviewed.
The literature on the utility of PET scanning in multiple myeloma continued to grow, with Zamagni et al (Blood 2011;118:5989-5995) reporting on the prognostic relevance of PET/CT scanning at diagnosis after thalidomide and dexamethasone induction therapy and double autotransplantation in 192 newly diagnosed multiple myeloma patients. PET/CT involvement at diagnosis, after novel agent based induction and subsequent transplantation, was found to be a reliable predictor of prognosis in multiple myeloma patients.
The year saw the continued development of a number of novel drugs that will hopefully provide for additional therapeutic options for our patients in the not-too-distant future.
Novel Immunomodulatory Drugs and Proteosome Inhibitors
Lacy et al (Blood 2011;118:2970-2975) reported on the combination of the novel immunomodulatory drug pomalidomide in combination with low-dose dexamethasone in myeloma patients refractory to both bortezomib and lenalidomide. Responses were seen with pomalidomide given orally at 2 and 4 mg doses, with documented responses or better in 49% and 43% of patients, respectively.
Several additional reports, including those by Paul Richardson from Dana-Farber Cancer Institute and Leleu et al, from the IFM Group, presented results that confirmed similar response rates in other trials with the drug (Abstracts 632 and 812, respectively). Preliminary data presented by Antonio Palumbo (Abstracts 632) and Tomer Mark (Abstract 635) from Weill Cornell Medical College, also presented at the ASH meeting, looking at three-drug combinations, including pomalidomide, showed very impressive results, with close to two thirds of patients having responses to therapy. FDA filing seeking accelerated approval for pomalidomide is expected later this year.
A fair amount of excitement also exists with carfilzomib, a next-generation proteosome inhibitor, which is currently before the FDA seeking accelerated approval based on the PX-171-003 A1 trial, which demonstrated activity of the drug in a patient population that had been exposed to bortezomib and an immunomodulatory drug in patients who had relapsed and were refractory to their last line of therapy.
Several additional trials with carfilzomib in less heavily pretreated patients, and as combination therapy in both previously treated and untreated patients reported at the ASH meeting showed impressive response rates. The drug is associated with minimal peripheral neuropathy and is amenable to long-term administration. A phase III trial (ASPIRE) comparing the three-drug combination of carfilzomib, lenalidomide, and dexamethasone, with use of lenalidomide and dexamethasone alone is currently recruiting patients (clinicaltrials.gov/ct2/show/NCT01080391).
At ASH 2011 we also saw several oral presentations on an oral proteosome inhibitor (MLN9708), both as a single agent and as combination therapy. In addition data on the pan-proteosome inhibitor marizomib (NPI-0052) were presented.
The year saw the emergence of several monoclonal antibodies targeted to the therapy of patients with multiple myeloma. Elotuzumab, a humanized IgG-1 monoclonal antibody targeting CS1, a cell surface glycoprotein, highly expressed in over 95% of myeloma cells in reports presented at several international meetings in 2011, showed robust activity when combined with lenalidomide and dexamethasone in phase I/phase II studies. Impressive rates of progression-free survival seem to be emerging.
Other monoclonal antibodies to a variety of targets including lorvotuzumab mertansine (neural cell adhesion molecule CD56), BT062 (syndecan-1, CD138), daratumumab, MOR03087, SAR650984 (CD38) siltuximab (IL6), and LY2127499 (BAFF) also continue to move forward in clinical trials.
The year saw several reports on inhibitors of histone deacetylase (HDAC) in combination therapy regimens. ASH 2011 included the presentation of data from the Vantage 088 and 095 studies.
The Vantage 088 trial assessed vorinostat, an oral inhibitor HDAC class I and class II proteins in combination with bortezomib in patients with relapsed and refractory myeloma. Patients with pretreated disease were randomized to bortezomib plus oral vorinostat or bortezomib plus placebo (Abstract 811). Although the overall response rate of 56% on the vorinostat arm was statistically superior to the 41% seen on the placebo arm, the magnitude of the benefit in terms of progression-free survival was relatively modest, at 7.83 months versus 7.63 months, respectively.
The Vantage 095 trial was a global phase IIB trial combining vorinostat with bortezomib in bortezomib-refractory patients (Abstract 480). A response rate of 17% was observed.
Harrison et al reported on the activity of the combination of the HDAC inhibitor romidepsin together with bor-tezomib and dexamethasone in patients with relapsed and refractory myeloma (Blood 2011;118:6274-6283). A large international randomized phase III trial of bortezomib plus panobinostat called PANORAMA 1 in relapsed multiple myeloma is ongoing.
Combinations of the mTOR inhibitor CCI779, both with bortezomib (Ghobrial et al: Lancet Oncology 2011;12: 263-272), and lenalidomide (Hofmeister et al: JCO 2011;29:3427-3434) were reported. The combination of perifosine with bor-tezomib and dexamethasone in patients with relapsed and refractory multiple myeloma previously treated with bortezomib was reported to show an overall response rate of 41%, including 32% in bortezomib refractory patients (Richardson et al: JCO 2011;29:4243-4249). In addition, encouraging preliminary data from the MEK1/2 inhibitors AZD 6244 were presented at the ASH 2011 meeting.
Autologous Stem Cell Transplantation
In 2011, data presented at the International Myeloma Workshop Meeting in Paris in May, from the CALGB 100104 study, showed a survival advantage for patients receiving maintenance therapy with lenalidomide post autologous transplant. This has led to most physicians adopting this as a standard of care.
However, a French study (IFM-2005-02) looking at lenalidomide maintenance post autologous transplant has yet to show a survival advantage, although progression-free survival has been demonstrated to be superior in those patients who receive lenalidomide maintenance as compared with no maintenance.
A provocative publication by Martinez-Lopez et al (Blood 2011;118:529-534), brought up the possibility of autologous transplantation being potentially curative for a small percentage of patients with multiple myeloma. After a long-term follow-up of 153 months of 344 patients who underwent transplantation between 1989 and 1998, overall survival at 12 years was reported to be 35% for patients in complete remission.
A landmark analysis found a plateau in overall survival after 11 years with 35% of patients in the CR group and 11% in the greater than or equal to partial response group being alive at 17 years. This follows on earlier data by the group in Arkansas, suggesting that a proportion of patients with multiple myeloma can indeed be cured with autologous stem cell transplantation.
Allogeneic Stem Cell Transplantation
Results of the BMT CTN 10102 phase III study of autologous stem cell transplantation, followed by allogeneic or autologous stem cell transplantation, in patients with multiple myeloma (Krishnan et al: Lancet Oncology 2011;12:1195-1203) showed that non-myeloblative allogeneic stem cell transplantation after autologous stem cell transplantation was not more effective than tandem autologous transplantation for patients with standard risk multiple myeloma.
However, another trial with more long-term follow-up (Björkstrand et al: JCO 2011;29:3016-3022) showed that both progression-free survival and overall survival were superior after auto-allo as compared with auto only. Giaccone et al (Blood 2011;117:6721-6727) also reported long-term clinical outcomes after a median of seven years of follow-up showing superior overall survival and event-free survival for patients who received a cytoreductive autograft followed by a non-myeloblative allograft over those receiving a second melphalan-based autograft.
Diehard proponents of allografting are optimistic that perhaps trials that still fail to show a survival advantage for allogeneic transplantation may also show a survival advantage with longer-term follow-up. However, in 2011 few people would consider allografting patients with myeloma outside of the context of a clinical trial, except perhaps in a few very young patients.
Outcomes of Therapy
A report from the 2009 International Myeloma Workshop also updated recommendations for the uniform reporting of clinical trials. 2011, however, provided no resolution on the fundamental clash of philosophies of cure versus control in multiple myeloma (Rajkumar et al: Blood 2011;118:3205-3211), although additional data continue to emerge on the correlation of complete responses with long-term progression-free and overall survival (Gay et al: Blood 2011:117:3025-3031).
Despite all of the advances in the treatment of this disease, we still have a lot of work ahead of us, as demonstrated by Kumar et al (Leukemia 2012;26:149-157; published online 7/29/11), demonstrating that in patients with relapsed myeloma who are refractory to bortezomib and were relapsed, refractory to, or ineligible to receive an immunomodulatory drug, the median overall survival and event-free survival times were a sobering nine and five months, respectively. This will certainly keep us busy in 2012 and beyond.