Supplement No. 3
Best Practices in the Management of Newly Diagnosed Multiple Myeloma Patients Who Will Not Undergo Transplant
By Ruben Niesvizky, MD1, Morton Coleman, MD2, Tomer Mark, MD3 |
March 8, 2010
1Associate Professor of Medicine, Weill Cornell Medical College
2Clinical Professor of Medicine, Weill Cornell Medical College
3Assistant Professor of Medicine, Weill Cornell Medical College, New York, New York
In a phase I/II trial by GIMEMA that involved newly diagnosed patients ≥ 65 years, MP + lenalidomide (MPR) resulted in a CR rate of 24% and an ORR of 81%. On exploratory analyses, VGPR or better was linked to significantly better 1-year event-free survival (EFS), and MPR overcame the adverse prognostic effects of del(13) or t(4;14). Myelosuppression with MPR was greater than the rates in most of the phase III studies of MPT. At the maximum tolerated dose of MPR, grade 3/4 neutropenia was detected in 52% of patients, thrombocytopenia in 24%, and anemia in 5%. Peripheral neuropathy did not occur, and the investigators suggest that a lenalidomide-containing regimen may be indicated for patients with preexisting PN.
Based on a subsequent analysis of cytopenia data, the investigators suspect that cytotoxic bone marrow injury with MPR is related to melphalan(Drug information on melphalan). They recommend a lower number of MPR cycles or a lower dose of melphalan for patients who experience neutropenia or thrombocytopenia, especially those aged ≥ 75 years and those with previous prolonged exposure to cytotoxic agents.
In another phase I/II trial of MPR as initial myeloma therapy, adults of any age were eligible if they were not candidates for ASCT or declined it; the median age was 74 years. The MPR regimen showed substantial activity (CR 12%, ORR 69%) and had a manageable toxicity profile. The most common grade 3/4 toxicities were neutropenia (58% of patients) and thrombocytopenia (27%). No patient developed PN or thromboembolic complications.
A phase III trial has been evaluating 459 patients, ≥ 65 years of age, with newly diagnosed myeloma who were randomly assigned to MPR followed by lenalidomide maintenance, MPR followed by placebo maintenance, or MP followed by placebo maintenance. At a preplanned interim analysis with 50% of information available, the data monitoring committee detected a highly statistically significant improvement in PFS, the primary endpoint, for patients treated with MPR + lenalidomide maintenance compared with those who received MP. There was no significant different in PFS between the group that received MPR + placebo maintenance and the group that received MP.
Our group is investigating the combination of clarithromycin(Drug information on clarithromycin) (Biaxin, 500 mg twice daily), lenalidomide, and low-dose dexamethasone(Drug information on dexamethasone) (BiRD) for front-line treatment of myeloma. Clarithromycin has immunomodulatory properties and it may also have a direct antineoplastic effect,[51,52] which suggested to us that BiRD would have excellent efficacy despite the lower corticosteroid dose.
A phase II trial of BiRD involved 72 patients (median 63 years). After a mean time on treatment of 368 days, 31% had achieved stringent CR. An additional 8% achieved CR, and the ORR was 90%. A subset of patients developed atypical serum immunofixation patterns that were correlated with a remarkable 100% ORR and a 71% CR rate. The major grade 3 or higher toxicities were cytopenias, thromboembolic events, myopathy, rash, and diverticular abscess. More than 70% of patients on BiRD who did not undergo ASCT achieved greater than VGPR. Their baseline characteristics did not differ from the overall study population; however, their older age and comorbidities led them to decline high-dose chemotherapy.
The responses with BiRD were durable after 48 months of follow-up, with 46% of patients alive and in CR. The 4-year OS rate was 93%. Median PFS and OS were not reached. The median EFS was 40.5 months and the 3-year EFS rate was 59%. Intriguingly, no survival advantage was found for patients who chose to go on to consolidative ASCT compared with those who stayed on BiRD therapy. Like some of the other newest combinations, BiRD is charting new territory in terms of depth and quality of response.
Data from a case-matched study confirm that adding clarithromycin to Rd has significant benefit. We matched the 72 patients, based on age, gender, and transplant status, with Mayo Clinic patients who had received Rd. Rates of CR were 46% with BiRD vs 14% with Rd (P < .001), and at least VGPR occurred in 74% vs 33% of patients (P < .001). BiRD was also significantly superior with regard to PFS and time to next treatment. The principal grade 3/4 toxicities of BiRD were hematologic, especially thrombocytopenia (24% vs 8% with Rd, P = .0012). Rates of neutropenia, infection, dermatologic toxicity, and venous thromboembolism were similar in the two groups. These differences are compelling but are yet to be confirmed by a randomized study.
Another alkylator-free regimen showing promise for newly diagnosed myeloma is lenalidomide/bortezomib/dexamethasone (RVD). Thirty-five patients (median age 59 years; range 22–86 years) were evaluable for both efficacy and safety in the phase II portion of a phase I/II study. After four cycles of therapy (n = 31), the ORR was 78%, with 12% of patients achieving CR/near-CR (nCR) and 12% achieving at least VGPR. Among the 24 patients without CR at cycle 4, response improved between cycles 4 and 8 in 16 (67%) patients and the ORR was 100%, with 33% and 67% achieving CR/nCR or at least VGPR, respectively. After median follow-up of 19.3 months, median TTP, PFS, and OS were not reached; estimated 1-year TTP and PFS were 76%, and estimated 1-year OS was 100%. Deep-vein thrombosis/pulmonary embolism occurred in 6%; there was no PN of at least grade 3 or treatment-related mortality.\
As reported above, phase III data suggest that MPR is superior to MP only when followed by lenalidomide maintenance. In another phase III study, 511 patients > 65 years were randomly assigned to receive bortezomib(Drug information on bortezomib)/melphalan/prednisone/thalidomide (VMPT) followed by maintenance with bortezomib and thalidomide(Drug information on thalidomide), or to VMP without maintenance. Initially, patients received nine 6-week cycles of either regimen; the protocol was later changed to nine 5-week cycles with weekly bortezomib in all cycles. VMPT plus maintenance was superior with regard to response rates (CR, 34% vs 21%, P < .001; at least VGPR, 55% vs 47%, P = .07) and the primary endpoint, PFS (at 2 years, 70% vs 58%, P = .008). The change from twice-weekly to weekly bortezomib significantly decreased the incidence of grade 3/4 PN in both treatment arms without affecting CR rates or 2-year PFS, and of course, weekly bortezomib will give better dose intensity. This is the first report showing the superiority of a four-drug combination followed by maintenance compared with the most recent standard therapy, VMP.
For myeloma patients who are elderly or have significant comorbidities, the traditional purpose of treatment was palliation. But it is now reasonable to set a goal of achieving CR or nCR. Three highly active, newer combinations—MPT, VMP, and Rd—are recommended by the NCCN and the IMWG: Melphalan/prednisone should no longer be considered the reference treatment, although it may be appropriate for a small number of patients with serious comorbidity and/or poor performance status.
Both MPT and VMP have been demonstrated to have superior efficacy compared with MP. Advantages of VMP over MPT include more rapid response and higher rates of CR, which is associated with improved survival in the nontransplant setting.[59,60] Results of VISTA also support use of VMP in patients with high-risk cytogenetics and/or impaired renal function. The IMWG guidelines suggest considering Rd for patients who wish to postpone ASCT.
Data from phase II trials suggest high efficacy rates for MPR, BiRD, and RVD, among other emerging regimens. Toxicity profiles differ among the newly established and emerging regimens, and oncology teams must take care to apply the appropriate risk management measures, including dose reduction where necessary. Additional prospective studies are needed to assess the optimal dosages and combinations in transplant-ineligible patients with multiple myeloma.
Acknowledgements: The authors thank medical writer Faith Reidenbach for assistance with drafting the manuscript.
Address all correspondence to: Ruben Niesvizky, MD Weill Cornell Medical College 520 East 70th St Starr 341 New York, NY 10021 e-mail: email@example.com
Multiple Myeloma Therapy Supplement
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