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Up-Front Management of Multiple Myeloma

Up-Front Management of Multiple Myeloma

ABSTRACT: The management of multiple myeloma (MM) has undergone rapid change with the recent emergence of several effective novel agents that have added complexity to individualized treatment decision-making. This paper reviews the initial management of 276 patients with MM diagnosed and treated by 43 US-based community oncologists since January 1, 2008. The case survey data obtained are evaluated within the broad context of published findings from major phase III randomized trials and as such reveal potential education gaps and implications for oncology CME. Overall, the results reveal that most patients were symptomatic at diagnosis and were risk-stratified by fluorescene in situ hybridization (FISH) and/or cytogenetics. When analyzed by age, the overall symptomatology and biomarker-defined risk profiles appeared similar in the three age groups studied (<65, 65-74, ≥75 years). Moreover, the short-term clinical benefits and toxicity associated with the induction regimens described did not vary by age group, and the physician-reported response rates broadly corresponded to those documented in the literature for the respective treatments employed. The findings also illustrate that both proteasome inhibitors and immunomomodulataory agents are widely utilized for patients who are and are not eligible for transplant, suggesting that the rapid development of newer management strategies in MM is being effectively translated into community-based patient care.

As described in the introduction to this supplement to ONCOLOGY, this article highlights findings obtained from a cross-sectional case survey (CCS) consisting of 276 patients newly diagnosed and treated for multiple myeloma (MM) since January 1, 2008, from the practices of 43 community-based medical oncologists. The results are discussed in the context of broadly accepted MM management guidelines and recent findings from major clinical trials.

Multiple Myeloma: Top-Line Findings from the CCS

TABLE 1
Cross-Sectional Case Survey: How Symptomatic (Disease-Related) Was This Patient at the Time Treatment Was Initiated?

Most patients with MM are symptomatic at diagnosis, with the goals of therapy including reduction in tumor burden, improved quality of life, and improved overall survival (OS). In this survey most patients were moderately or very symptomatic at the time of receiving first treatment, and the fraction of patients with different levels of symptomatology was similar in patients younger than age 65, patients aged 65 to 74, and those ≥ 75 (Table 1).

In the management of MM, a number of factors must be considered when planning initial therapy, including staging of disease, comorbid conditions, performance status, renal function, transplant eligibility, and assessment of cytogenetic and fluorescence in situ hybridization (FISH) abnormalities. The simplified International Staging System, which uses two variables—serum albumin and beta-2 microglobulin—has largely replaced the more complicated Durie-Salmon system. Cytogenetic abnormalities are common and often prognostic.[1] Clinical research is attempting to further define the treatment implications of these unique disease features. Approximately 25% of patients were considered to have poor risk profiles based on metaphase cytogenetics and FISH, with no significant differences seen between younger and older patients (Table 2).

TABLE 2
Cross-Sectional Case Survey: What Was the Patient’s Risk Profile Based on Metaphase Cytogenetics and FISH Analysis?

In the CCS, the age distribution of patients with newly diagnosed MM was similar to that seen in prior reports,[2] and the median age was 68. One key determinant in initial disease management is primary assessment of eligibility for high-dose chemotherapy with autologous stem-cell transplant (SCT).

Short-Term Outcomes in the CCS

FIGURE
Results of Cross-Sectional Case Survey Question, “Did You Initially Consider This Patient to Be a Candidate for Stem-Cell Transplant?” (N = 264 Assessed)

In the CCS, approximately half of the patients were considered eligible for SCT. Most of the patients determined to be transplant-eligible were younger than age 70, with the oldest being 78. The youngest patient deemed unsuitable for SCT was 50, and considerable variability in clinician perception of eligibility was evident among patients in their 60s (Figure). In addition to age, many clinical factors are considered in this decision, including performance status, comorbidities, and psychosocial variables, as well as the patient’s attitude toward this treatment approach.

TABLE 3
Clinician-Reported Responses to and Tolerability of Initial Induction Regimens Overall

One of the most important goals of the CCS was to assess the choice of initial induction therapy and the resultant outcomes as measured by the treating physician. It is widely acknowledged that the therapeutic options for patients with newly diagnosed active MM and the associated disease outcomes have markedly improved in the past few years, mainly due to the evolution of clinical research with two classes of novel agents: (1) proteasome inhibitors, including bortezomib (Velcade), and (2) immunomodulatory agents (IMiDs), particularly thalidomide (Thalomid) and lenalidomide (Revlimid).

It is important to note that in the CCS, overall response to treatment and treatment tolerance were similar across the three age groups studied: < 65, 65–74, and ≥ 75 (Table 3). Overall, more than 60% of patients were reported to have achieved at least a partial response (PR); less than 25% had significant or major toxicities. These findings suggest that the CCS physician participants were able to modify the selection of treatment, dose, and schedule to allow both older and younger patients to realize similar short-term benefits without compromising quality of life.

TABLE 4
Cross-Sectional Case Survey: Choice of Induction Regimens

A review of the CCS demonstrates that the use of both proteasome inhibitors and IMiDs is firmly established in community-based practice. Patients eligible for transplant most frequently received lenalidomide- or bortezomib-based doublet regimens or the triplet regimen lenalidomide/bortezomib/dexamethasone (RVD) (Table 4). Similarly, bortezomib/dexamethasone (VD) and lenalidomide/dexamethasone (RD/Rd) were the most commonly used treatments for patients not considered transplant-eligible, followed by the melphalan-based regimens melphalan/prednisone/thalidomide (MPT) and melphalan/prednisone/bortezomib (MPV) (Table 4). These findings are not unexpected, as they are consistent with the systemic treatment recommendations currently endorsed by a variety of contemporary MM practice guidelines and the recently published level 1 clinical evidence (Tables 5 and 6).

TABLE 5
Select Key Trials Evaluating Induction Regimens: Transplant Eligible

There was little difference in physician-reported short-term response rates across the five most frequently used induction regimens (Table 7), although the fraction of complete responses (CRs) was greater among the patients receiving RVD. Similarly, these physicians perceived that the majority of their patients experienced only mild to moderate treatment-related toxicity (Table 7). When examining the incidence of specific treatment-related side effects, findings from the CCS are comparable to those documented in published clinical trials. In the CCS, physicians reported significant rates of treatment-related fatigue, peripheral neuropathy (PN), and neutropenia (Table 8).

Patients Eligible for Transplant: Comparing the Evidence to Strategies Employed in the CCS

Another major objective of this CME needs assessment project was to globally compare the physician-reported outcomes of treatments utilized in the CCS to those demonstrated in prior major clinical trials. Here we review select key clinical research data sets of evidence-based standard induction regimens that have influenced current standard treatments and that correspond to the regimens most often used by clinicians in the CCS (Table 4).

Higher- and Lower-Dose Dexamethasone Plus Lenalidomide

TABLE 6
Italian Phase III Study of VMPT vs VMP for Newly Diagnosed MM: Efficacy and Sensory Peripheral Neuropathy (PN) According to Bortezomib (V) Infusion Schedule

This all-oral regimen was utilized in 59 patients (21%) in the CCS. The outcomes were generally similar to what has been reported in major clinical trials, including the recently published Eastern Cooperative Oncology Group E4A03 study[3] that evaluated higher- and lower-dose dexamethasone with lenalidomide (RD and Rd, respectively) and that demonstrated greater response rates with higher doses but also greater toxicity and inferior survival. In the CCS, 52 of 59 patients (88%) who received lenalidomide/dexamethasone had at least a PR, and only six patients (9%) had significant or major problems with this treatment (Table 7).

Bortezomib and Dexamethasone

Bortezomib/dexamethasone was administered as induction therapy to 53 patients (19%) in the CCS. Physician-reported risks and benefits were generally similar to what has been demonstrated in clinical trials, including the Intergroupe Francophone du Mylome study of 482 patients that compared VD to vincristine/doxorubicin/dexamethasone (VAD) in patients ≤ 65 years old with previously untreated disease.[4] The primary end point of postinduction CR or near CR (nCR) was superior for VD, with a 14.8% CR/nCR rate, and at least a very good partial response rate of 37.7% and an overall response rate of 78.5%. The response rates did not vary according to cytogenetic status. With a median follow-up of only 32.2 months, this early benefit in response has yet to translate into a statistically significant difference in progression-free survival (PFS) or OS. Treatment with VD was considered tolerable, with no deaths during induction therapy, but 9.2% of patients experienced grade 3/4 neuropathy with the twice-weekly scheduling. In the CCS, 45 of 53 patients (85%) receiving this regimen had at least a PR, but 15 patients (24%) experienced significant or major toxicity with this treatment (Table 7).

Lenalidomide, Bortezomib, and Dexamethasone

TABLE 7
Cross-Sectional Case Survey: Clinician-Reported Responses to and Tolerability of Top Five Selected Initial Induction Regimens

In the 2 years since the data from the original phase I/II study of RVD were first reported, there has been a rapid increase in use of this regimen in clinical practice.[5] In the CCS, 30 patients (11%) received this regimen, with 27 (90%) achieving at least a PR (Table 7). This antitumor effect is similar to the unprecedented data set on RVD recently published[6] and updated at this year’s annual meeting of the American Society of Clinical Oncology[7] reporting a ≥ PR rate of 100% and a nCR/CR rate of 57% without autologous SCT. The trial report estimated 24-month PFS and OS rates of 68% and 95%, respectively. Adverse cytogenetics did not appear to affect response or PFS.

As in the clinical trial data set, RVD was reported to be generally well tolerated among the patients in the CCS, with only four patients (14%) experiencing significant or major toxicity. Richardson et al reported sensory peripheral neuropathy (SPN) to be the most common adverse event, and it was primarily of grade 1 (52%) or grade 2 (27%) severity, with only 2% of patients experiencing grade 3 SPN.[6]

Patients Not Eligible for Transplant: Comparing the Evidence to Strategies Employed in the CCS

TABLE 8
Cross-Sectional Case Survey: Clinically Relevant Side Effects of Most Commonly Utilized Induction Regimens

Melphalan/prednisone (MP) has been a mainstay in the treatment of MM for more than half a century, with response rates of 33% to 83%[8,9] and a median OS ranging from 19 to 50 months.[9] In the past 5 years, several large phase III studies have reported improved outcomes by adding thalidomide to MP,[10-13] and recently a large trial evaluated the addition of bortezomib to MP, again yielding superior results with the melphalan-based triplet[14] (Table 9). Quadruplet regimens, such as bortezomib/dexamethasone/cyclophosphamide/lenalidomide, that incorporate proteasome inhibitors, IMiDs, and cytotoxics are also being evaluated.

Melphalan, Prednisone, and Thalidomide

Melphalan/prednisone/thalidomide was received by 22 patients (8%) in the CCS, with 18 patients (82%) reported to have at least a PR and 7 (27%) experiencing significant or major toxicity (Table 7). A related clinical research data set is the Dutch-Belgian Hemato-Oncology Cooperative Group phase III study comparing MP to MPT in 333 patients with newly diagnosed MM. This regimen was associated with a 50% rate of grade 3/4 toxicity, primarily polyneuropathy, with 23% of patients experiencing grade 3/4 SPN.[13] Studies evaluating the addition of thalidomide to MP have consistently demonstrated significantly higher overall response rates; however, only two of the five well-controlled randomized trials demonstrated improvement in survival relative to MP.

Melphalan, Prednisone, and Bortezomib

TABLE 9
Select Phase III Trials of Commonly Used Induction Regimens: Transplant Ineligible

Melphalan/prednisone/bortezomib was used in 21 patients (8%) in the CCS and resulted in at least a PR in all but 1 patient (95%). Four of the patients experienced significant toxicity (18%). One recent large phase III study, the VISTA trial, evaluated MP vs MPV in 682 patients with previously untreated MM.[14] Use of the MPV regimen resulted in a PR rate of ≥ 71% and a significant improvement in PFS and OS.[14] Adverse cytogenetics and impaired renal function appeared to have no effect on the efficacy of this melphalan- and bortezomib-based regimen. The MPV regimen was generally well tolerated, but 15% of patients required treatment discontinuation because of toxicity. Grade 1/2 SPN was reported in 31%, and grade 3/4 SPN was reported in 13%.

In a subanalysis of VISTA, the SPN rate was dose-related. The median time to PN was 2.3 months, and the bortezomib-related SPN was reversible in that 79% of SPN cases improved within less than 2 months and 60% completely resolved within 6 months.[15] Two recent reports of the use of once-weekly dosing of bortezomib in the MPV regimen demonstrated a marked reduction in the rate of SPN; use of the once-weekly dosing approach is gaining rapid acceptance in clinical trials (Table 6). In the CCS, data were not gathered on the scheduling of bortezomib, but this would be an important consideration for future study.

Discussion

The treatment of MM is complex and requires consideration of a number of diverse factors. This educational exercise examining the clinical management of patients with MM in community-based practice uncovers several important, thought-provoking, and hypothesis-generating findings. First, and quite significantly, this work reveals that the overall short-term clinical benefits and risk of toxicity with induction treatment did not vary significantly in the three age groups studied, including the cohort of patients over age 75. This suggests that the physicians participating in this project, and likely other oncologists in practice, are able to provide safe and effective therapy irrespective of a patient’s advanced age and/or the presence of comorbidities. The availability of relatively nontoxic treatment options means that patients of any age—many of whom have significant disease symptomatology—might benefit from treatment.

Secondly, as observed in the CCS, the most commonly used up-front induction regimens were RD/Rd, VD, and RVD in patients eligible for SCT, and RD/Rd, MPV, and MPT in patients who were deemed transplant-ineligible. These selections match closely those endorsed by current published guidelines and indicate that the clinician participants in this activity are widely practicing within the confines of evidence-based decision-making. More importantly, the physician-reported outcomes with these specific regimens—specifically, clinical response rates and side effects—closely resemble the findings from major clinical trials formally investigating these agents.

While the CCS evaluated selection of induction treatment and the resultant short-term efficacy and tolerability of these choices, there are many additional questions that might be addressed in future similar studies: the dose and schedule of specific agents such as dexamethasone and bortezomib, the incidence of specific side effects, and the use of maintenance treatment, particularly with lenalidomide, in both the transplant and nontransplant settings.

Finally, the findings reported here suggest that the rapid developments in clinical research in MM over the past few years are being effectively translated into patient care in the community-based setting. Further research is essential to document whether these findings are reproducible across a larger and perhaps more diverse cohort of community oncologists/hematologists. However, it is encouraging to observe that in many instances pivotal research advances are quickly being applied at a public health level, and further research may define the most effective and widely used methods of access to research findings and continuing education.

References

References

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2. Surveillance, Epidemiology and End Results: SEER Stat Fact Sheet: Myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html

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4. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: Results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;Sept 7 [Epub ahead of print].

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8. Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: An overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998;16(12):3832-42.

9. Gregory WM, Richards MA, Malpas JS. Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: An overview of published trials. J Clin Oncol. 1992;10(2):334-42.

10. Palumbo A, Bringhen S, Caravita T, et al. Italian Multiple Myeloma Network, GIMEMA. 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(9513):825-31.

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15. Dimopoulos MA, Mateos MV, Richardson PG, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed multiple myeloma patients: Subanalysis of the phase 3 VISTA study. Eur J Haematol. 2010;Sept 28 [Epub ahead of print].

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19. Cavo M, Tacchetti P, Patriarca F, et al. A phase III study of double autotransplantation incorporating bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) for multiple myeloma: Superior clinical outcomes with VTD compared to TD. Proc ASH. 2009:Abstract 351.

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