While attending an International Myeloma Foundation (IMF) Patient and Family Seminar last fall in Minneapolis, I met an impressive, young myeloma doc and researcher on the rise, Mayo Clinic’s Dr. Kieth Stewart. I felt he had a very reasonable and balanced approach to myeloma therapy. Here is a research paper the prestigious hematological publication, Blood, just published by Dr. Stewart, about the new therapy approach of combining Velcad with Revlimid in newly diagnosed patients:
Union of forces advances myeloma care
In this issue of Blood, Richardson et al report on a landmark treatment regimen for newly diagnosed myeloma patients that for the first time combines lenalidomide and bortezomib. This effort required a team approach comprising 2 competing pharmaceutical companies (joining forces to study this promising regimen) and multiple academic medical centers.1
Together, this team conceived of a winning combination chemotherapy regimen using lenalidomide, bortezomib, and dexamethasone (RVD) in newly diagnosed myeloma patients. An unprecedented 100% of patients treated at the defined phase 2 dose level responded to treatment: 74% of patients experienced a 90% reduction in tumor burden and 57% entered a complete remission (CR) within a few months of starting treatment. Comparable results have previously been reported only after comparatively toxic regimens involving intensive rounds of combination chemotherapy and repeated doses of high-dose melphalan supported by autologous stem cell transplantation.2,3 It is noteworthy that the RVD regimen often took more than 4 cycles of therapy to achieve maximal response, with an upgrade in response occurring in 75% of patients who continued therapy up to 8 cycles and in half of the patients treated for more than 8 cycles.
There is little doubt that this regimen represents a leap forward in myeloma care and serves as an important platform on which to build. Nevertheless, there were still significant issues. The combination is complicated by painful sensory neuropathy in 32% of patients; 40% of patients required dose reductions, missed doses, or had to discontinue therapy due to toxicity. Furthermore, despite such high initial response rates, 25% of patients relapsed within 18 months of beginning therapy, particularly those with advanced stage II/III disease (using the international staging system)4 at baseline. These drawbacks highlight the need for further refinements of dosing schedules, consideration of longer treatment periods, addition of active agents targeting new pathways, and adoption of genetic risk stratification to “tease out” very high-risk patients requiring a bolder treatment plan.5
Building on the spirit of collaboration and excitement over the encouraging results fostered by the RVD trial, studies addressing these issues are already under way, for example, through the Multiple Myeloma Research Consortium (addition of doxorubicin to RVD),6 in company-sponsored trials (adding cyclophosphamide to RVD),7 or by examining longer-term use of the RVD cocktail (P. G. Richardson, personal communication, June 2010). As these and larger phase 3 trials expand and build on the RVD regimen, the impact of this drug combination on stem cell collection success, need for thrombosis prophylaxis, effects on cardiac function, and its use and safety in the face of renal failure will all need ongoing monitoring.
For some, the glass will still be half empty, highlighting the need to also prove survival advantages given the potential economic impact of the use of 2 very expensive drugs in combination. Funding agencies and insurance providers will no doubt ask for a higher burden of proof before paying for this expensive regimen. Phase 3 trials which will address survival benefit are under way through US cooperative groups examining the use of RVD versus lenalidomide and dexamethasone alone in newly diagnosed patients (http://clinicaltrials.gov/ct2/show/NCT00644228). Until the results of such trials are mature, one can point to an increasing volume of studies in myeloma that highlight the value of obtaining a CR in this disease8–10; thus, as a surrogate for survival, the high CR rate reported with RVD treatment bodes well. Economic considerations aside, this pilot study, and other small combination studies recently reported with similar high CR rates,6,7,11–14 should be especially encouraging for patients worldwide.
Further advances in myeloma should be expected as second-generation proteasome inhibitors (eg, carfilzomib, NPI-052, MLN9074, CEP-18770) and immunomodulatory drugs (pomalidomide) with varying delivery routes and toxicity profiles are now in early clinical testing along with a large series of drugs targeting novel pathways in this disease.15 A critical next step building on RVD will be reducing toxicity (one model might be use of weekly bortezomib)16 and prolonging and maintaining remission through consolidation and maintenance therapy.17,18 Such advances will require an ongoing team effort, with industry, academia, foundations, and government working together. In this era in which increasing oversight, regulation, and negative media attention threaten to suffocate the interaction of the pharmaceutical industry, academic researchers, and hematologist-oncologists19 it is refreshing to point to the example of RVD where the significant benefits to patients that result from such positive interactions are apparent. In this light and with respect to the future of myeloma trials and to the prerequisite for close industry–physician interaction, I will quote President Andrew Jackson who, in a different context, famously opined, “Our Union: it must be preserved.”
Conflict-of-interest disclosure: The author has received research support from Millennium Pharmaceuticals and honoraria from Celgene Corporation and Onyx Pharmaceuticals.
Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679–686.[Abstract/Free Full Text]
Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495–2502.[Abstract/Free Full Text]
Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112(8):3115–3121.[Abstract/Free Full Text]
Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412–3420.[Abstract/Free Full Text]
Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27):5436–5443.[Abstract/Free Full Text]
Jakubowiak AJ, Reece DE, Hofmeister CC, et al. Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: updated results of phase I/II MMRC trial. Blood (ASH Annual Meeting Abstracts). 2009;114(22, Abstract 132.
Kumar S, Flinn IW, Hari PN, et al. Novel three- and four-drug combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for newly diagnosed multiple myeloma: encouraging results from the multi-center, randomized, phase 2 EVOLUTION study. Blood (ASH Annual Meeting Abstracts). 2009;114(22, Abstract 127.
Hoering A, Crowley J, Shaughnessy JD Jr, et al. Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in total therapy protocols. Blood. 2009;114(7):1299–1305.[Abstract/Free Full Text]
Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008;113(2):355–359.[CrossRef][Medline] [Order article via Infotrieve]
Harousseau JL, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 Trials. J Clin Oncol. 2009;27(34):5720–5726.[Abstract/Free Full Text]
Jakubowiak AJ, Kendall T, Al-Zoubi A, et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009;27(30):5015–5022.[Abstract/Free Full Text]
Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23(7):1337–1341.[CrossRef][Medline] [Order article via Infotrieve]
Kim YK, Sohn SK, Lee JH, et al. Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. Ann Hematol. 2010;89(5):475–482.[CrossRef][Medline] [Order article via Infotrieve]
Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology. 2007;12(3):235–239.[CrossRef][Medline] [Order article via Infotrieve]
Stewart AK. Novel therapies for relapsed myeloma. Hematology Am Soc Hematol Educ Program. 2009;578–586.
Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115(16):3416–3417.[Free Full Text]
Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010;28(5):800–807.[Abstract/Free Full Text]
Nair B, van Rhee F, Shaughnessy JD Jr, et al. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with bortezomib, lenalidomide and dexamethasone (VRD) maintenance. Blood. 2010;115(21):4168–4173.[Abstract/Free Full Text]
Fonseca R, Richardson P, Giralt S, et al. Conflicts of interest, authorship, and disclosures in industry-related scientific publications. Mayo Clin Proc. 2010;85(2):197–199; author reply 201–204.[Free Full Text]
I included the reference section of the study so you could look back at marvel at the international “Who’s Who” of the multiple myeloma research and treatment world Dr. Stewart sites. Americans Dr. Barlogie, Dr. Richardson and Dr. Kumar, plus International myeloma docs Dr.Palumbo and San Miguel, to name a few.
You know you have been doing this too long when you recognize the majority of physician names listed in a studies’ footnotes!
I like the way Dr. Stewart gives his opinions in the paper. Refreshing and hopeful!
Feel good and keep smiling! Pat