What's new for the treatment of multiple myeloma and related disorders in 2010? Angela Dispenzieri, M.D.

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1 What's new for the treatment of multiple myeloma and related disorders in 2010? Angela Dispenzieri, M.D. The progress being made for the treatment of multiple myeloma has resulted in a significant prolongation of survival for patients. 1,2 The influx of new drugs, however, has presented the challenge of determining how they can best be used. Finding the best risk-benefit balance between side-effects and surrogate endpoints like complete response is controversial in the absence of definitive data. Since the overall strategy of therapy is so different for patients who are elderly (and not transplant eligible) from those younger patients who are younger (and transplant eligible), the discussion will be divided along these lines. INDUCTION FOR TRANSPLANT INELIGIBLE PATIENTS For patients who are not candidates for transplant, there have been many interesting phase 2 trials, but given the limitations of phase 2 trials, phase 3 trials will be our focus. Using novel agents, there have been 6 randomized controlled trials comparing melphalan and prednisone (MP) to MP and a novel agent. 3-9 In terms of the 5 MP plus thalidomide (MPT) studies, all have been positive favoring MPT with regards to higher CR rates (~15%). Three of five have been positive with regards to PFS (median months), again in favor of 3 drugs over 2 drugs, but only 2 of 5 have been positive with regards to OS (median months). A recent meta-analysis suggests that the 3 drug regimen results in significantly improved PFS (p<0.05) with a trend to better OS (p=0.09). The combination of MP plus lenalidomide (MPR) has been studies as part of a phase 3 trial (MP versus MPR versus MPR plus R maintenance). Once again, very good partial response rates are higher with the 3 drug combination (32% versus 11%), but with a median follow-up of 9.4 months, there is no difference in PFS except in the maintenance arm. 10 The one MP plus bortezomib (VMP) trial was positive, favoring VMP with regards to CR rates (30%), PFS (median 24months), and OS (87% alive at 16 months). 9 An interesting phase 3 trial for the elderly that compares VMP to bortezomib, thalidomide, prednisone (VTP) has been presented preliminarily. 11 Both time to response and response rates appeared similar between the two arms, there was more myelosuppression with VMP than VTP, but more non-hematologic toxicity with VTP. Twice as many patients randomized to VTP as compared to VMP discontinued therapy due to AEs., With 24 months follow-up, the estimated 3 yr OS is 80% with VMP as compared to 64% for VTP, making the preferred regimen is felt to be VMP, i.e. combining 1 novel agent (bortezomib) with 2 old agents (MP) rather than 2 novel agents and prednisone. The point was again made that with these bortezomib 1

2 containing regimens, the effect of high risk cytogenetics (t(4;14), t(4:16), or del 17p) is abrogated by inclusion of bortezomib. Yet another combination being studied is VMP versus the four drug regimen of VMP and thalidomide (VMPT). 12 Follow-up is short, and although there is a difference in PFS with maintenance, there is no OS difference to date. A major challenges in interpreting these studies relates to whether or not all patients received the novel agent as salvage, i.e. are these studies testing: ABC vs AB followed by C; or ABC versus AB. In the former case, the conclusion would be that there is indeed synergy amongst the 3 drugs, which then translates to better overall survival. Unfortunately, information on salvage therapy is sketchy in many of these trials. For the majority of the trials, only about 50% of relapsing patients actually get the novel agent to treat their relapse. With further follow-up, it should become more clear whether the observed benefits are a function of synergy or drug access. Outside of a clinical trial, most would agree that the new standard for elderly with newly diagnosed MM is either VMP or MPT. Beyond that and the recognition of the importance that patients be enrolled onto clinical trials, the consensus breaks down, and investigators have their personal favorites. Those who are advocates of attaining the highest complete response (CR) rates tend to be proponents for VMP, since CR rates for this regimen appear to be higher (30%) than those for MPT (~15%). Investigators, who are less influenced by CR rates, but more by overall survival and quality of life (QOL), tend to favor the MPT. They argue that the convenience of oral therapy and lower neuropathy rates (6 versus 13%) outweigh the cosmetically appealing CR even though MPT has higher potential for thromboembolic events (~12%), which can be managed by prophylaxis. INDUCTION FOR TRANSPLANT ELIGIBLE PATIENTS The discussion for those patients who are transplant candidates is even more complex since there are dozens of phase 2 trials and more than a half a dozen phase 3 trials, whose results are difficult to interpret due to very limited follow-up In the absence of long term follow-up, recommendations will be dependent on whether they are proffered by a CR proponent or a QOL enthusiast. CR enthusiasts will cite that much of the time CR translates into better PFS and OS, 21 and QOL proponents will counter that in randomized trials the group achieving higher CR (or VGPR) rate does not always enjoy better overall survival. 3,14,15,22-28 It has been suggested that it is among the most elderly and frail patients that the use of more effective but more aggressive treatments may induce more frequent and more severe toxicities, which may overcome the potential benefit of CR achievement. 21 2

3 Certainly this principal has held true even amongst young otherwise healthy patients in the case of full myeloablative allogeneic stem cell transplant in which up-front mortality has been 30-40%. 29 Outside of clinical trials, options for induction treatment include 7-drug (VDT-PACE), 4 drug (VDCR), 3 drug (PAD, VTD, CBD, VRD), and 2 drug (Rd and Vd) combinations. 30 In general, the more drugs used, the higher the CR and VGPR rates achieved, but usually at the cost of higher rates of toxicity. There are seven randomized trials for this population that have been reported at least in part. All demonstrate superior CR rates post-induction and prior to autologous hematopoietic stem cell transplant (ASCT) when novel agents are included; all but two show persistently higher CR rates in the novel therapy arm after consolidative ASCT. However, only 3 studies have preliminary PFS and OS data. All 3 demonstrate superior PFS, but none yet shows improved OS by incorporating the novel agent upfront. The Total Therapy (TT) approach championed by the University of Arkansas is the epitome of striving for deepest response Each of these clinical trials builds upon the backbone of its predecessor, which is a major strength. By increasing the number and intensity of agents used, complete response rates have increased from 41% to over 60%. In addition, both EFS and OS survival have increased, but this must be interpreted with caution. In the case of EFS, the duration of planned therapy has increased from 1 year in TT1 to greater than 3 years in TT2 and to 4.2 years in TT3. It is unclear how much of the observed advancement in EFS is due to maintenance with active agents versus true synergy. Similarly, the improvement in overall survival must be considered in the context of the accrual periods and the availabilities of novel agents over the past 20 years. TT1 completed accrual in 1995, long before recognition of thalidomide s activity in myeloma in and long before FDA approval of bortezomib in or lenalidomide in ,37 One would assume that more patients on TT2, which accrued patients between 1998 and 2004, had access to the novel agents than the TT1 patients, but certainly fewer than had access among TT3 patients. This said, however, long term results of TT2 would suggest that early and continuous use of thalidomide in the context of TT is advantageous to the subgroup of patients with high-risk disease (data not shown), but not among those with standard risk disease. More time will be required to discern whether the advances seen with TT3 are regimen-based or period-based. The question remains whether or not to default to the regimen with the highest response rate irrespective of toxicity. What is one to recommend to their transplant eligible patients? The best option is unequivocally a clinical trial. When a trial is not possible, one is forced to make a philosophical decision regarding treatment. Does one 3

4 embrace a 27% rate of grade 3-4 peripheral neuropathy to reach for the 60% CR rate seen in TT2? Or does one settle for a VGPR rate of 40% knowing that 2-year overall survival rates are 96%, grade 3-4 peripheral neuropathy and thrombotic event rates are 2 and 12%, respectively? Or does one opt for bortezomib, lenalidomide, and dexamethasone, which boasts an overall response rate of 100% and a ncr/cr rate of 40% with 4% thrombosis rate and 3% peripheral neuropathy rate? 38 Not only is it unclear which induction is best, but in the era of novel therapies there is no firm answer about whether patients should proceed early to transplant or rather to stem cell collection with intention to transplant at relapse. Kumar et al presented retrospective data suggesting that even in the era of novel therapies, timing of transplant does not appear to important. 39 Even the question of maintenance is far from settled. PFS is unequivocally better (and rates of peripheral neuropathy higher) with thalidomide maintenance, but overall survival is only marginally better in a fraction of the trials. 5,8,32,40-42 Several studies at ASH 2009 have also demonstrated better PFS with maintenance, but none so far have demonstrated better OS. Again we are reliant on awaiting the long term results of clinical trials. RELAPSED/REFRACTORY DISEASE There are no optimal therapies for relapsed or refractory disease, but there are numerous choices. Drugs like thalidomide, lenalidomide, and bortezomib have significantly increased options for relapsing patients. At ASH 2009, there were 4 agents that were worthy of note. The first is pomalidomide, which is a next generation immune modulatory drug, is active in 64% of relapsed patients, and in 30% of patients failing lenalidomide. 43 Carfilzomib is a proteosome inhibitor which also results in response rates of approximate 50%. An interesting combination of carfilzomib and lenalidomide yields partial response rates in 59% of patients Finally data on NPI-0052 is another novel proteosome inhibitor was presented demonstrating efficacy in a Phase 1 study. 49,50 Elotuzumab, a humanized monoclonal IgG1 targeting CS1, was combined with lenalidomide and dexamethasone, and 82% of patients had a partial response or better. 51 Follow-up was only 4.5 months, but this appears to be an effective first in class drug for MM patients. SUMMARY POINTS At the Mayo Clinic, the 20 physicians actively engaged in myeloma research and treatment have digested these data and have formulated a consensus algorithm that we use and update twice yearly as new data emerges ( 29,30 Our algorithm takes into account patient fitness, genetic risk categories, ease of drug 4

5 administration, and special circumstances like renal failure at presentation. As shown, our tendency is to start with the most easily tolerated combination for average risk patients, and to save bortezomib-based therapy for patients with renal failure or biologically high-risk disease (t(4;14), t(14;16), deletion 17p, hypodiploidy, deletion 13q on metaphase cytogenetics, or highly proliferative disease) based on preliminary data that bortezomib may neutralize the risk associated with these abnormalities. 9,52 REFERENCES 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111: Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111: Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370: Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367: Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized, controlled trial. Blood. 2008;112: Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27: Wijermans P, Schaafsma R, van Norden Y, et al. Melphalan + Prednison versus Melphalan + Prednison + Thalidomide in induction therapy for multiple myeloma in elderly patients: final analysis. IMWG Waage A, Gimsing P, Juliusson G, Turesson I, Fayers P. Melphalan-Prednisone-Thalidomide to Newly Diagnosed Patients with Multiple Myeloma: A Placebo Controlled Randomised Phase 3 Trial. ASH Annual Meeting Abstracts. 2007;110: San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359: Palumbo A, Dimopoulos MA, Delforge M, et al. A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma. ASH Annual Meeting Abstracts. 2009;114: Mateos M-V, Lopez-Corral L, Hernandez MT, et al. Multicenter, Randomized, Open-Label, Phase III Trial of Lenalidomide-Dexamethasone (Len/dex) Vs Therapeutic Abstention in Smoldering Multiple Myeloma at High Risk of Progression to Symptomatic MM: Results of the First Interim Analysis. ASH Annual Meeting Abstracts. 2009;114: Palumbo A, Bringhen S, Rossi D, et al. Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients. ASH Annual Meeting Abstracts. 2009;114: Macro M, Divine M, Uzunhan Y, et al. Dexamethasone+Thalidomide (Dex/Thal) Compared to VAD as a Pre-Transplant Treatment in Newly Diagnosed Multiple Myeloma (MM): A Randomized Trial. ASH Annual Meeting Abstracts. 2006;108: Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica. 2008;93: Lokhorst H, van der Holt B, Zweegman S, et al. Final Analysis of HOVON-50 Randomized Phase III Study on the Effect of Thalidomide Combined with Adriamycine, Dexamethasone (AD) and High Dose Melphalan (HDM) in Patients with Multiple Myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2008;112:

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