Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone

Abstract

The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.

Introduction

Multiple myeloma (MM) is a heterogeneous disease with divergent outcomes driven by the biologic characteristics, with survival ranging from a few months to several years. The primary aim of risk stratification in newly diagnosed myeloma is to determine prognosis, but more data are needed to assess the impact of known high-risk features after the introduction of novel agents, such as lenalidomide. The cardinal independent high-risk factors for prognostication in myeloma include specific genetic abnormalities and a high proliferative rate of plasma cells.^1–3 Randomized trials have demonstrated the superiority of stem cell transplantation (SCT) over conventional chemotherapy.^4,5 However, early relapse after transplantation in a majority of patients with high-risk features questions the strategy of SCT alone.^6–9 High-risk patients have therefore been considered appropriate candidates for alternative approaches, including early incorporation of novel agents. The objective of our study was to determine the relevance of risk stratification among patients with newly diagnosed MM, receiving initial therapy with lenalidomide-dexamethasone (Len-Dex).

Methods

After approval of the Institutional Review Board of the Mayo Clinic, we reviewed the outcome of 100 consecutive patients who received Len-Dex as initial therapy for symptomatic MM, between March 2004 and November 2007. Patients received lenalidomide (25 mg/day orally) on days 1 to 21 of a 4-week cycle in combination with either low-dose (40 mg weekly; n = 43) or high-dose (40 mg, days 1-4, 9-12, and 17-20 of each 28-day cycle; n = 57) oral dexamethasone.

The patients were risk-stratified into 2 groups. The high-risk group was defined by the presence of at least one of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm by metaphase cytogenetics only, deletion of p53 (locus 17p13), immunoglobulin heavy chain (IgH) translocations [t(4;14) or t(14;16)] by fluorescence in situ hybridization (FISH) or cytogenetics, or plasma cell labeling index (PCLI) more than or equal to 3%. PCLI was performed as previously described.¹⁰ Patients without any of these features were considered standard risk. Responses were assessed by the IMWG uniform response criteria.¹¹ Progression-free survival (PFS), time to progression (TTP), and overall survival (OS)¹¹ were estimated by Kaplan-Meier method and compared by log-rank tests.

Results and discussion

The median follow-up of the entire cohort (N = 100) was 36 months (range, 2.3-53.1 months). The baseline characteristics and laboratory findings are presented in Table 1. Sixteen (16%) patients had at least one high-risk feature identified by metaphase cytogenetics, FISH, or PCLI. Overall, 95 patients had at least one of the aforementioned test results available for risk stratification (cytogenetics, n = 95; PCLI, n = 89; FISH, n = 57), and those without any test results were considered standard risk. The response to therapy was similar in the 2 groups as indicated in Table 1. The median PFS for the entire cohort was 31 months; the median OS was not reached, and the 2- and 3-year OS estimates were 93% and 83%, respectively. The median PFS was 18.5 months for the high-risk group compared with 36.5 months for the standard-risk group (n = 84, P < .001; Figure 1A). The corresponding values of the TTP were similar to the PFS, 18.5 months and 37 months, respectively (P = < .001). The OS was comparable between the groups (P = .4), with median OS not reached for either group (Figure 1B). Both groups had a 2-year OS of 92%, whereas the 3-year OS was 77% and 86% for the high-risk and standard-risk groups, respectively. The PFS (or OS) of patients receiving high-dose and low-dose dexamethasone was comparable.

Table 1.

Baseline characteristics of newly diagnosed patients with multiple myeloma

	High risk (N = 16)	Standard risk (N = 84)
Age, y (range)	67 (48-78)	63 (32-78)
Sex, male:female	1.3:1	2:1
ISS, N = 95
Stage I	12%	43%
Stage 2	44%	47%
Stage 3	44%	10%
Parameter	Median (range)	Median (range)
Hemoglobin, g/dL	10.8 (7.9-15.6)	11.1 (6.4-15.6)
White blood cells, ×109/L	5.7 (3.3-8.1)	5.5 (2.2-56)
Platelets, ×109/L	214 (141-350)	258 (117-471)
Calcium, mg/dL	9.5 (8-11)	9.3 (7.3-18.8)
Creatinine, mg/dL	1.3 (0.3-1.7)	1.1 (0.7-2.4)
Lactate dehydrogenase, units/L	142 (118-286)	156 (90-317)
C-reactive protein, mg/dL	0.59 (.07-1.8)	0.3 (.02-74)
Monoclonal (M)–Spike, g/dL	3.5 (0-6.1)	2.9 (0-6.7)
Response rates to lenalidomide-dexamethasone therapy
CR + VGPR (P = .36)	38%	45%
≥ PR (P = .56)	81%	89%

ISS indicates international staging system; CR, complete remission; VGPR, very good partial remission; and PR, partial remission.

Figure 1.

Survival analysis of patients with newly diagnosed MM who received Len-Dex as initial therapy. (A) PFS by risk stratification; median PFS is 18.5 months for high-risk versus 36.5 months for standard-risk patients (P < .001). (B) OS by risk stratification (high-risk vs standard-risk patient); median OS not reached (P = not significant). (C) PFS of strictly categorized patients (N = 55) who either had all the 3 tests (metaphase cytogenetics, fluorescence in situ hybridization [FISH], and PCLI) or at least 1 test that led to their inclusion in the high-risk group; median PFS = 18.5 months for the high-risk group and 36.5 months for the standard-risk group (P < .001). (D) OS of strictly categorized patients (N = 55) who either had all the 3 tests (cytogenetics, FISH, and PCLI) or at least 1 test that led to their inclusion in the high-risk group; median OS not reached for either high-risk or standard-risk group.

We repeated the analysis using a more stringent criterion by excluding the patients with insufficient pertinent information for adequate risk stratification. Fifty-five patients either had all 3 tests (metaphase cytogenetics, FISH, and PCLI) or at least one test that led to their inclusion in the high-risk category. A subgroup analysis restricted to these 55 patients demonstrated similar results (Figure 1C-D). Fifty patients underwent SCT after Len-Dex induction therapy. Because the SCT could have affected the outcome, given its lesser impact on high-risk disease, we performed a separate analysis with patients who underwent SCT before MM progression being censored on the date of SCT. The median PFS of the high-risk group was 18.5 months compared with 36.9 months for standard-risk patients (P = .002).

Because of the paucity of long-term outcome data in the high-risk population, induction regimens involving bortezomib or lenalidomide plus dexamethasone with very low early death rates^12–14 have been preferentially used in patients with high-risk features. Bortezomib-based regimens may overcome the poor prognostic effect of many cytogenetic abnormalities,^15–17 including metaphase del(13q) and t(4;14). Outcome data on the efficacy of Len-Dex regimen in high-risk patient population are scant.^18–20

A Canadian study involving 159 relapsed/refractory MM patients demonstrated the efficacy of Len-Dex in surmounting poor prognosis conferred by t(4;14) and del(13) by FISH.²⁰ However, besides dissimilar patient cohorts (relapsed/refractory vs newly diagnosed in our study), differences exist in risk stratification of patients as del(13q) by FISH only is considered a standard-risk feature by our prognostic model but a high-risk feature in the Canadian trial. Furthermore, the possibility of selection in the high-risk relapsed/refractory t(4;14) cases surviving long enough to be enrolled in the Len-Dex expanded access program cannot be ruled out, perhaps accounting for improved PFS in the Canadian study. A subset of t(4;14) patients with β2-microglobulin less than 4 mg/L is known to have a distinct survival advantage.²¹ Possibly, a greater proportion of patients with t(4;14) in the Canadian study had β2-microglobulin of less than 4 mg/L as reflected by the low median β2-microglobulin (3.05 mg/L). In our study, the subgroup analysis of specific chromosomal abnormalities was limited by the small sample size for individual groups. Interestingly, the Canadian study is in disagreement with a recently reported French study of Len-Dex demonstrating shorter PFS and reduced OS in relapsed/refractory MM patients with FISH-detected del(13) and/or t(4;14).¹⁹

Not surprisingly, in line with results of other studies,²² the overall response rates of high-risk patients and standard-risk patients were similar. Although the TTP and PFS of high-risk group were shorter, the absolute values are similar to those reported in recent studies⁶ involving other therapies, for example, 18.5 months in our study and 19.8 months in a recent trial using bortezomib, melphalan, and prednisone.¹⁶ In contrast, the TTP and PFS of low-risk patients are particularly impressive. Although no adverse effect of high-risk MM on OS was seen with Len/Dex, we cannot account for the individual contribution of various salvage therapies on the OS rate. Notably, bortezomib-based rescue was attempted in 50% of the relapsed high-risk patients on disease progression/relapse.

We recognize that our study lacks uniform risk stratification of the entire cohort because of unavailability of all 3 tests for each patient. However, our overall findings are validated by similar outcome data emerging from subgroup analysis of 55 stringently classified patients, risk-stratified either on the basis of all the 3 tests, or the single test that placed them in the high-risk category. Furthermore, our attempt to negate the impact of SCT yielded similar results.

These preliminary results highlight the poor outcome among high-risk MM patients (a median TTP/PFS of 18-20 months in most recent studies) despite significant advances in recent years in the treatment of MM and improvement in OS.^23,24 Future strategies need to target high-risk myeloma, both in terms of understanding the disease biology as well as developing targeted therapies. Only larger, prospectively designed studies with extended follow-up can more definitively assess the impact of Len-Dex therapy on patients with high-risk MM.

Authorship

Contribution: S.K. and S.V.R. designed the study; P.K. and S.K. collected the data; P.K., S.K., and S.V.R. wrote the manuscript; S.K. performed statistical analysis; P.K., S.K., R.F., M.Q.L., T.E.W., S.R.H., A.D., F.B., P.L.B., M.A.G., R.J.D., J.R.M., D.D., C.B.R., J.A.L, S.J.R., V.R., S.R.Z., A.K.S., R.A.K., P.R.G., and S.V.R. analyzed and interpreted the data; S.K., R.F., M.Q.L., T.E.W., S.R.H., A.D., F.B., P.L.B., M.A.G., R.J.D., J.R.M., D.D., C.B.R., J.A.L, S.J.R., V.R., S.R.Z., A.K.S., P.R.G., and S.V.R provided study patients; T.E.W., P.R.G., and S.V.R. read slides of PCLI; and M.A.G., P.R.G., and R.A.K. edited the paper.

Conflict-of-interest disclosure: S.K., R.F., T.E.W., A.D., A.K.S., and S.V.R. receive research funding from Celgene Corporation; T.E.W. has been on the advisory board of Celgene Corporation but has deferred the honorarium to Mayo Clinic (Rochester, MN); P.L.B. and M.A.G. have received honoraria from Celgene Corporation. R.A.K. has been on independent data monitoring committees of celgene-sponsored studies. The remaining authors declare no competing financial interests.

Correspondence: S. Vincent Rajkumar, Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: rajks@mayo.edu.