Introduction 

There has been much progress in the development of new drugs and treatment strategies for patients with multiple myeloma (MM) over the past decade that has led to improved survivals. Many recent studies of new treatments for MM were presented at the December 2006 meeting of the American Society of Hematology (ASH) in Orlando, Florida.

Initial Treatment of Multiple Myeloma

At the recent ASH meeting, data was presented which confirms the activity of the new drugs available for the treatment of MM and helps to place their relative value in treating new and relapsed patients. The IFM group presented very preliminary data on response rates to Velcade® (bortezomib) + dexamethasone (Dex) compared to Oncovin® (vincristine), Adriamycin® (doxorubicin) and dex (VAD) for newly diagnosed patients with MM who were scheduled to undergo autologous stem cell transplantation.[1] Reporting on 165 of a planned 480 patients, they observed a 29% CR/near CR rate with the Velcade + dex combination versus 13% with VAD. Furthermore, after first autologous transplant, only 22% of patients in the Velcade group had less than a very good partial response (VGPR, >90% reduction in monoclonal protein) compared with 45% of patients in the VAD group.  Thus in preliminary studies Velcade + Dex as induction may allow more patients to achieve a major response to induction therapy. 

The MAG group compared Thalomid® (thalidomide) + Dex induction to VAD prior to autologous transplant.[2] The Thalomid + Dex group achieved a VGPR or better of 25% compared to 7% with VAD. The Greek Myeloma study group compared VAD-Doxil® (pegylated liposomal doxorubicin) to VAD-Doxil +Thalomid as primary induction therapy.[3] The overall response rate after 4-6 cycles was better with the addition of Thalomid; 81% versus 66%. There were more toxicities, constipation, neuropathy and skin rash with the addition of Thalomid. An intergroup trial of Thalomid + Dex versus Dex alone as primary therapy for older patients (median age 65) was presented.[4] The CR + PR rate was higher with Thalomid +Dex, 59% versus 42%, with a median time to progression not reached in the Thalomid + Dex group versus 8.1 months for the Dex alone group. Grade 4 toxicities were 30% with Thalomid + Dex versus 23% for Dex alone and more thromboembolic events 18% versus 4%. A phase 2 CALGB trial of Velcade + Doxil induction was reported.[5] Of 63 patients, 29 had completed therapy and were evaluable with a 28% CR/near CR and 51% PR. There were tolerable toxicities including gastrointestinal, hematologic and hand-foot syndrome. The ECOG trial of Revlimid® (lenalidomide) + high (12 days) or low (4 days) dose Dex was reported only for toxicities.[6] There were clearly more side effects of thromboses, hyperglycemia, pneumonitis and cardiac ischemia with high Dex, but it remains to be seen if response rates were different. Revlimid added to Alkeran® (melphalan) + prednisone was reported in a phase 1 study in older patients (median age 71).[7] The maximum tolerated dose (MTD) of Revlimid was 10 mg on days 1-21, with Alkeran 0.18 mg/kg and prednisone 2 mg/kg daily x4. At the higher dose, a 48% CR + VGPR and 33% PR rates were observed in approximately 40 patients.

Relapsed Refractory Patients

A large trial of over 600 patients with relapsed or refractory MM compared Velcade alone to Velcade plus Doxil after up to 8 cycles.[8] The overall response rate was not significantly different, 43% versus 48%, but the median time to progression was significantly longer with Velcade + Doxil: 9.3 months versus 6.5 months. Overall survival was not different at the time of analysis. A novel four drug combination of Velcade, Thalomid, Alkeran and prednisone for relapsed MM patients (n=30) was reported by the GIMEMA group.[9] Low dose Thalomid, 50 mg continuous, and Velcade 1.0 to 1.3 mg/m2 x 4 doses were given every 35 days for up to 6 cycles. The MTD of Velcade was 1.3 mg with response rates of 17% CR, 26% VGPR and 23% PR.  The 1 year progression free and overall survivals were 61% and 84%. Neutropenia and thrombocytopenia were dose limiting.

A phase 1 study combined Velcade with Revlimid in 38 patients with recurrent disease.[10] The MTD were 15 mg Revlimid with 1.0 mg Velcade. Neutropenia and thrombocytopenia were dose limiting. Responses were 1CR, 1nCR, and 12PR. The heat shock protein inhibitor tanespimycin (17AAG) was studied with Velcade in a phase 1 trial of relapsed, heavily pre-treated MM patients.[11] The MTD was found to be tanespimycin 275 mg/m2 and Velcade 1.3 mg/m2 with thrombocytopenia, metabolic acidosis and pancreatitis as dose limiting toxicities. A 35% CR + PR rate was observed. Other small phase 1 trials of histone deacetylace inhibitor[12], antiCD40 monoclonal antibodies[13],[14], and antibody cyotoxic drug conjugate[15] were reported. 

Stem Cell Transplantation 

In a registry analysis, 43 patients with MM undergoing syngeneic transplant were matched to 170 patients undergoing autologous transplant between 1988 and 2003.[16] The authors found lowered risk of relapsed with syngeneic transplant, 47% versus 79%, and superior overall survival 59% versus 40%. These results might suggest the difference was due to a “tumor free” graft, but considering this is registry data, the results must be interpreted cautiously. 

Another international trial examined the maintenance effects of Thalomid and alternate day prednisolone compared to prednisolone alone after single autologous transplant.[17] At 12 months of maintenance, the combination group had a CR rate of 24% compared to 15% with prednisolone alone. There was a 15% improvement in time to progression and 10% improvement in overall survival with the combination maintenance. 

A group from Tunisia compared single autologous transplant followed by 6 months of Thalomid to tandem autologous transplant with no maintenance.[18] The CR + VGPR rates were 51% for tandem transplants versus 67% for a single transplant and Thalomid maintenance, p=ns. There were no differences in OS or PFS although there was a trend for improved PFS with Thalomid: 77% versus 59% (p = 0.08). 

The GIMEMA group reported results of tandem autologous transplant with melphalan 200 or melphalan 100 per cycle.[19] As expected, the higher melphalan doses were associated with more mucositis and GI toxicity. The CR and near CR rates were higher with melphalan 200, 35% versus 20%, but overall response rates were no different at 80% versus 71%. The overall survival and event free survivals were not statistically different, but follow-up is relatively short and the event free survival cures appear to separate beyond 24 months. 

A cooperative German-Austrian group compared tandem autologous transplant and melphalan 200 mg/m2 with triple autologous transplant using melphalan 100 mg/m2 in responding patients.[20] The CR and overall response rates were similar at 42% versus 40% and 93% versus 91%, respectively. Overall and PFS were also similar.  The triple transplant regimen may have been less toxic, especially for mucositis

An Italian single arm study examined the impact of Thalomid + Dex induction followed by tandem autologous transplant with melphalan 200 mg/m2.[21] Results were compared to previous results of tandem transplants without Thalomid in the induction regimen. The results of this retrospective trial suggest that Thalomid may overcome the adverse outcome of patients with adverse chromosomal abnormalities. Their analysis showed that deletion 13 and 4(4:14) were not predictive of outcome in patients receiving Thalomid in the induction regimen.

The impact of achieving a VGPR or better was confirmed in a multivariate analysis of the IFM’s 99 series of trials in 849 patients who had VAD induction, tandem autologous transplant or a reduced intensity allogeneic transplant.[22] Following completion of all therapy, a VGPR or better was associated with median PFS and OS of 40 months and 72 months, respectively. Patients who achieved less than a VGPR had median PFS and OS of 28 months and 52 months. The p-value was highly significant. Other risk factors, such as an elevated B2M, deletion of 17p and the 4;14 chromosomal abnormalities, were independently associated with PFS and OS but did not correlate with response. 

The M.D. Anderson group reviewed their total experience with autologous transplants for myeloma.[23] In 748 patients, they confirmed that CR was associated with a significantly increased OS, median 9.9 years, compared to 5.9 years for patients who attained only a PR. Interestingly, patients who were in CR prior to transplant had the same survival as patients who only achieved CR after transplant. 

Summary

The above is an incomplete summary of the large number of abstracts presented at ASH 2006. It would appear that Velcade, Revlimid, Doxil and possibly Thalomid are important drugs for the current treatment of patients with multiple myeloma. The role of stem cell transplantation is still evolving but for younger patients this is an important treatment modality, which may be improved by the addition of new drugs. What is needed in this field is a monoclonal antibody with activity similar to Rituxan® (rituximab) in NHL. Fortunately, there appears to be some progress in this area.

References

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[1] Harousseau H-L, Marit G, Caillot D, et al. Velcade/dexamethasone (Vel/Dex) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): An interim analysis of the IFM 2005-01 randomized multicenter phase II trial. Blood 2006:108;21a, abstract 56.