Rapid Review

Multiple Myeloma

Guest Discussant: Robert Fenton, MD, PhD

Myeloma patients with symptoms caused by the disease (i.e., anemia, lytic bone lesions, hypercalcemia, renal insufficiency, extramedullary plasmacytoma) require treatment with chemotherapy. Autologous stem cell transplant (ASCT) is still considered a standard of care for non-high-risk MM patients below the age of 70, as it prolongs event-free survival and overall survival compared with standard chemotherapy.1,2 This concept is under scrutiny, as "standard chemotherapy" now includes new agents such as thalidomide, lenalidomide, and bortezomib, which have potent myeloma activity when used alone or when combined with chemotherapeutic agents with known activity against MM (e.g., melphalan, cyclophosphamide, doxorubicin, steroids). Important decisions concerning the use of ASCT in MM include:

1. Who to transplant? Patients with poor risk features, such as those with deletion of chromosome 13 or hypodiploidy on routine cytogenetic analysis; those with t(4;14), t(14;16), or 17p- by FISH; or a plasma cell labeling index 3 define a subgroup of 25% of MM patients with a median survival of less than two years following ASCT.3 These patients should receive treatment with a regimen that includes bortezomib (which appears to overcome many poor-risk cytogenetic features), preferably on a clinical trial, and possibly followed by an allogeneic stem cell transplant for appropriate candidates. ASCT for standard-risk patients is generally excluded for those older than 75 years (depending on physiologic age), BR > 2 mg/dL, creatinine > 2.5 mg/ dL, ECOG PS >2, and NYHA CHF level 3 or 4 due to the increased likelihood of severe toxicity.

2. What induction chemotherapy to use? Lenalidomide (25 mg/m2 PO d1-21 of a 28-day cycle) plus low-dose dexamethasone (40 mg PO at the start of each week) is the preferred induction therapy for standard-risk patients (those with no high-risk features). This regimen has a high overall response rate, and the one-year overall survival is higher with the low-dose dexamethasone regimen.4,5 An alternative is 20 Clinical Oncology Alert the combination of thalidomide with dexamethasone, which is associated with an increased risk of thromboembolic complications (even after prophylaxis) and a lower response rate in untreated patients. For patients with poor-risk myeloma, who have rapid progression after ASCT, there are accumulating data that bortezomib can overcome poor cytogenetic features when used in combination with standard chemotherapy or in more elaborate transplant regimens.6,7 It is likely that new regimens containing bortezomib and other highly active myeloma therapeutics such as lenalidomide, thalidomide, liposomal doxorubicin, melphalan, and dexamethasone or prednisone will yield higher rates of CR than currently attainable. Such combinations, initially investigated in poor-risk patients, may be moved up-front for use in standard-risk patients, with ASCT being used as consolidation therapy. Furthermore, it will be important to determine if upfront combinations of active agents will prolong survival compared to withholding their use until relapse after ASCT.

3. When to transplant? Stem cells are usually collected after 2-4 cycles of induction therapy. This treatment should reduce the MM burden of the BM and peripheral blood without damaging hematopoietic stem cells and preventing adequate collection of sufficient stem cells for two transplants (e.g. > 6 x 106 CD34+ cells, to be used for tandem transplant).8 Mobilization with cytoxan and G-CSF may be required after lenalidomide-based induction, although the role of plerixafor (AMD3100, an inhibitor or chemokine receptor 4) is being studied.9 SCT is usually performed 2-4 weeks after stem cell harvest, although data indicate that delaying ASCT until resistance develops to standard chemotherapy does not significantly affect OS, although early SCT is associated with a better QOL and event-free survival.10

4. Which patients should receive a tandem transplant? Meta-analysis of six randomized, controlled trials of single vs. double HSCT did not demonstrate a survival benefit for tandem transplant; however, data indicated an increase in OS for the subgroup of patients that do not achieve either a CR or very-good partial response (VGPR) from the first transplant.11 Until data from new studies indicate otherwise, tandem transplant is a reasonable choice for patients with less then a VGPR after the initial transplant, with the second transplant given within six months of the first.12 For patients with CR or VGPR after one ASCT, stem cells can be stored and used at the time of relapse.13

References

1. Attal M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Eng J Med. 1996 335:91-97.

2. Child JA, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883.

3. Stewart AK, t al. A practical guide to defi ning high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia. 2007;21:529-534.

4. Rajkumar SV, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106:4050-4053.

5. Rajumar SV, et al. Phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group (abstract). J Clin Oncol. 2007;25:968s.

6. San Miguel SF, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Eng J Med. 2008;359:906-917.

7. Barlogie B, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185.

8. Kumar S, et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood. 2009;114: 1729-1735.

9. DiPersio JF, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;13:5720-5726.

10. Fermand JP, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: upfront or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-3136.

11. Cavo M, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007;25:2434-2441.

12. Barlogie B, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93:55-65.

13. Elice F, et al. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. Am J Hematol. 2006;81:426-431.

Rate and Significance of Persistent Cytopenia after Fludarabine-Combination Chemotherapy

By William B. Ershler, MD

ABSTRACT & COMMENTARY

SYNOPSIS: In a cohort of 61 patients treated with frontline fludarabine combination chemotherapy for CLL or low-grade lymphoma, 43% experienced cytopenias for three or more months after completion of therapy. The median time to recovery for this group was between 7-10 months, and complications (e.g., infection, transfusions) were more common. Explanation for the persistent cytopenias remain unclear, but it does not appear to be the result of a greater propensity for residual or aggressive disease as features of such were seen equally in those with and without persistent cytopenias.

Source: Gill S, et al. The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy. Ann Oncology. 2010;21:331-334.

Fludarabine-based combination chemotherapy, with or without added rituximab, has become established treatment for patients with low-grade lymphomas and chronic lymphocytic leukemia. Although, generally, combinations that include cyclophosphamide and/or mitoxantrone have been well tolerated, hematological toxicity is frequently observed, including protracted cytopenias, impaired mobilization of peripheral blood progenitor cells, and the development of myelodysplasia.1-3 Despite the common use of fludarabine combinations, the rate of development and clinical consequences of treatment-related prolonged cytopenias has not been clearly established.

To address this, Gill et al at the Peter MacCallum Cancer Centre in Victoria, Australia, performed a retrospective analysis of patients with lymphoma or CLL treated at their institution with a fludarabine combination as their first cytotoxic therapy over a 12-year period (1996-2007). Typically, patients were treated with fludarabine (25 mg/ m2) and cyclophosphaminde (250 mg/m2) intravenously for three days, every 28 days.

The primary endpoint of the analysis was the rate of cytopenias present at three months and beyond after the fi nal cycle of chemotherapy. This was defined as at least two measurements below the lower limit of the reference range at their laboratory for hemoglobin (Hb, <13 g/ dL for men < 65 years or 12.5 g/dL for men > 65 years, < 11.5 for women < 65 years or < 11 g/dL for women > 65 years), absolute neutrophil count (ANC = 2000/ uL) and platelet count = 140K/uL. Alternative causes of cytopenias (i.e., other than chemotherapy) were excluded by bone marrow assessment and by examination of patient records for the presence of possible causative medicines, nutritional deficiencies, or the presence of persisting splenomegaly.

Sixty-one patients receiving initial therapy with fludarabine-based regimens were categorized according to the presence of post-treatment cytopenias based upon the data available. Cytopenias, unrelated to residual disease, persisting three months after completion of chemotherapy, were found in 43% of patients. Cytopenias were associated with clinically important rates of infection and transfusion requirement (p = 0.03), and predicted for worse overall survival (61% vs. 96% at 60 months, p = 0.05). Increasing age predicted for persistent cytopenias (p = 0.02), but the presence of pretreatment cytopenias and delivered-dose intensity were not predictive. The median times to resolution of anemia, neutropenia, and thrombocytopenia were 7, 9, and 10 months, respectively.

During the first six months after therapy, the overall complication rate (including infection and transfusion requirement) was significantly higher for those who had protracted cytopenias compared with those who did not. Treatment-related myelodysplastic syndrome/ acute myeloid leukemia (AML) developed in three of the patients with (at 12, 40, and 94 months), and one patient without (at 8 months), persistent cytopenias. The overall survival at 60 months was 61% for patients with persistent post-treatment cytopenias and 96% for those patients without. Yet, need to retreat lymphoid malignancy was not different in the two groups (27% for those with persistent cytopenias and 23% for those without).

Commentary

Thus, cytopenias often persist > 3 months after first-line fludarabine-combination therapy and can lead to important clinical sequelae. Although cytopenias generally resolve over time, treating physicians should be aware of these factors when considering fludarabine-combination chemotherapy and when documenting treatment-response status in chronic lymphocytic leukemia. Of the many factors that one might predict would result in persistent cytopenias, only age was found to be significant.

References

1. Morgan SJ, et al. Predictive factors for successful stem cell mobilization in patients with indolent lymphoproliferative disorders previously treated with fl udarabine. Leukemia. 2004;18:1034-1038.

2. Tam CS, et al. Long-term results of the fl udarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-980.

3. Tam CS, et al. Treatment-related myelodysplasia following fudarabine combination chemotherapy. Haematologica. 2006;91:1546-1550.

4. Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-5456.