Treatment of Multiple Myeloma: Whence Truth Over Belief?

New treatments and an improved biologic understanding of why malignant plasma cells are able to survive have dramatically changed the natural history of multiple myeloma. Along with these new treatments, therapeutic options for patients at each stage of their disease have become a collection of confusing consonants. Combinations such as Rd,[1] CRd,[2] VD,[3] VTD,[4] VRD,[5] CyBorD,[6] PAD,[7] and BiRD[8] all produce impressive response rates in the induction therapy setting, and can be used for patients with relapsed disease as well.

While more choices and new drugs have resulted in improved overall survival for patients,[9] the growing number of therapeutic options has led to considerable confusion for clinicians regarding how to sift through all these data and make the “right” decision. In an era of more choice, several questions remain. First, what does current risk stratification tell us about response to these combinations? Second, do we have enough data to tailor therapy as the authors suggest in their comprehensive review? Finally, how do we best answer these questions to continue the forward momentum we have gained over the past 6 years?

Risk Stratification
For years, several different prognostic tests-C-reactive protein (CRP), lactate dehydrogenase (LDH), plasma cell labeling index (PCLI), and others-have been used to try and identify subsets of patients with “high-risk” disease.[10] What have we learned in the modern era that helps us to identify risk? The International Staging System (ISS) is based on the measurement of beta-2-microglobulin (β2M) as a method for risk stratification.[11] Barlogie and colleagues reported on the use of cytogenetic abnormalities such as deletion of chromosome 13 as another high-risk feature,[12] and more recently the Intergroupe Francophone du Myelome (IFM) presented data on the presence of t(4:14) and deletion of 17p as high-risk features.[13]

All of these data were initially defined in a group of patients who received conventional therapy. Emerging data from the relapsed and induction therapy settings suggest that perhaps the use of bortezomib (Velcade) and lenalidomide (Revlimid) can overcome these high-risk features, but data on the duration of response and overall survival are limited.

What about additional benefit for patients with “standard-risk” disease? Should we be content with “standard” responses and durations for these patients, or should we push ahead to improve their outcomes as well? We often find that if therapy benefits high-risk patients, it may be of more benefit for low-risk patients. Data from Barlogie and colleagues suggest that in the Total Therapy 3 setting, low-risk patients actually seem to have gained the greatest benefit in terms of improvement in overall survival.[14] Indeed, while the introduction of bortezomib and lenalidomide have improved outcomes for high-risk patients, low-risk patients seem to gain more. In the context of high-dose therapy as well, low-risk patients gain more benefit than patients with high-risk disease. Thus, regardless of risk, the benefit from combination therapy appears to hold up, and in fact is likely superior for patients whose disease is more indolent.

Tailored Therapy
What data do we have that addresses a tailored approach, either prospectively or retrospectively, and supports a risk-adapted treatment algorithm? To date, no such trials have been conducted, but data should be available in the not-too-distant future.

Three major randomized phase III trials have evaluated the benefit of newer regimens as induction therapy. In the Eastern Cooperative Oncology Group (ECOG) trial,[1] patients were randomized to receive lenalidomide with either low-dose or high-dose dexamethasone. This trial suggests that for all patients, but more specifically older patients, high-dose dexamethasone in conjunction with lenalidomide is inferior with regard to survival, and equivalent with regard to duration of remission. However, we do not know how response and response duration breaks out with regard to risk, nor do we know the duration of response, with or without a transplant, based on the specified risk criteria. Thus, while we may have strong suggestions that lenalidomide with low-dose dexamethasone is a good treatment for standard-risk disease, this statement is made without the benefit of risk-based data. Both the Italian trial (VTD [bortezomib/thalidomide (Thalomid)/dexamethasone] vs TD [thalidomide/dexamethasone])[4] and the IFM trial (VD [bortezomib/dexamethasone] vs VAD [vincristine/doxorubicin (Adriamycin)/dexamethasone])[3] provide information regarding the effect of the combination on response rate for high- and standard-risk patients, but duration of response and overall survival data for these specific risk groups are currently lacking.

In Search of an Optimal Approach
Where does this leave the practicing oncologist with regard to a treatment approach? Unfortunately, when there is little data, “belief” triumphs over “truth,” and as a community we are left with uneasiness as we navigate treatments and choices with our patients.

What should we do? There is one clear answer, as far as we can tell. Of the nearly 20,000 newly diagnosed myeloma patients this year, fewer than 2,000 (10%) will be enrolled on clinical trials. The irony of this paltry sum is that it was clinical trials with rapid accrual that led to the approvals of thalidomide (Thalomid), bortezomib, and lenalidomide. This, in turn, led to the groundswell of interest and clinical investigation in myeloma that has occurred over the past 10 years.

Currently, there are at least four large randomized induction trials that physicians in the United States can participate in, with several dozen smaller trials that are regionally based. Participation in studies by the Southwest Oncology Group (SWOG), ECOG, and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) provides physicians with the opportunity to answer and address some of the very questions that we and our patients are asking: Does combination therapy improve outcomes (SWOG 777, ECOG E1A05), what is an optimal approach for older patients with myeloma (ECOG E1A06), and what is the role of high-dose therapy in the context of newer and more effective inductions (BMT CTN trial), to name a few.

The question that each of us needs to ask when confronted with a newly diagnosed symptomatic myeloma patient is not what drug should I use (or what would my favorite expert recommend), but rather, on which trial should I enroll this patient? Only through collective experience and clinical trials are we able to advance the state of affairs for myeloma patients. Only then will we see the triumph of truth over belief.

References:

1. Rajkumar SV, Jacobus S, Callander N, et al: A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group (abstract 74). ASH Annual Meeting Abstracts. Blood 110, 2007.
2. Kumar S, Hayman SR, Buadi FK, et al: Phase II trial of lenalidomide, cyclophosphamide, and dexamethasone (CRd) for newly diagnosed myeloma (abstract 190). ASH Annual Meeting Abstracts. Blood 110, 2007.
3. Harousseau JL, Mathiot C, Attal M, et al: Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantion (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial (abstract 8505). J Clin Oncol 26(15S):455s, 2008.
4. Cavo M, Tacchetti P, Patriarca F, et al: Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma (abstract 158). ASH Annual Meeting Abstracts. Blood 112, 2008.
5. Richardson P, Jagannath S, Raje N, et al: Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): Preliminary results of a phase 1/2 study (abstract 187). ASH Annual Meeting Abstracts. Blood 110, 2007.
6. Reeder CB, Reece DE, Fonseca R, et al: A phase ii trial of myeloma induction therapy with cyclophosphamide, bortezomib, and dexamethasone (Cybor-D): Improved response over historical lenalidomide-dexamethasone controls (abstract 3601). ASH Annual Meeting Abstracts. Blood 110, 2007.
7. Popat R, Oakervee HE, Hallam S, et al: Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: Updated results after long-term follow-up. Br J Haematol 141:512-516, 2008.
8. Niesvizky R, Jayabalan DS, Christos PJ, et al: BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood 111:1101-1109, 2008.
9. Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516-2520, 2008.
10. Stewart AK, Bergsagel PL, Greipp PR, et al: A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 21:529-534, 2007.
11. Greipp PR, San Miguel J, Durie BG, et al: International staging system for multiple myeloma. J Clin Oncol 23:3412-3420, 2005.
12. Desikan R, Barlogie B, Sawyer J, et al: Results of high-dose therapy for 1000 patients with multiple myeloma: Durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95:4008-4010, 2000.
13. Avet-Loiseau H, Attal M, Moreau P, et al: Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myelome. Blood 109:3489-3495, 2007.
14. Barlogie B, Anaissie EJ, Shaughnessy JD Jr, et al: Ninety percent sustained complete response (CR) rate projected 4 years after onset of CR in gene expression profiling (GEP)-defined low-risk multiple myeloma (MM) treated with total therapy 3 (TT3): Basis for GEP-risk-adapted TT4 and TT5 (abstract 162). ASH Annual Meeting Abstracts. Blood 112, 2008.