Emerging Therapies for Multiple Myeloma

Abstract In the past decade, the therapeutic landscape for myeloma has changed dramatically with the advent of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib). These agents alone have activity against myeloma with even better responses when combined with additional agents such as steroids and chemotherapy. Initially introduced for relapsed/refractory disease, these agents are being increasingly tested in the upfront setting with improvement in response rates and prolongation of responses. We review the key findings from recently completed and ongoing studies that evaluate the effect of the novel therapies, both in newly diagnosed myeloma and in relapsed disease. The use of these agents in specific settings is also discussed.

Developments in the understanding of multiple myeloma biology have revolutionized our approach to therapy, leading to meaningful improvements in survival.[1] It is becoming increasingly clear that like all tumors, myeloma is a heterogeneous disorder, with different cytogenetic abnormalities, disease kinetics, response to therapy, and prognosis.[2,3] Therefore, a “one size fits all” approach to therapy is no longer tenable for this disease.[4,5] In parallel with this novel understanding of disease biology has been the discovery of novel classes of agents such as the immunomodulatory agents (IMiDs)[6,7] and proteasome inhibitors (eg, bortezomib [Velcade])[8] that alone have significant activity against the disease and more so when used in combination with other agents. With the availability of this expanded therapeutic armamentarium, when faced with a new diagnosis of multiple myeloma, we have to address early on whether the patient is a potential candidate for autologous hematopoietic stem cell transplantation (ASCT). If the answer is in the affirmative, every effort must be made to treat such patients with agents that do not compromise hematopoietic stem/progenitor cell collection. In such a setting, a few cycles of induction therapy followed by early collection of progenitor cells is the current approach.

Diagnostic Evaluation and Prognosis

In our opinion, the diagnostic evaluation of multiple myeloma is incomplete without metaphase cytogenetic studies, interphase fluorescent in situ hybridization (FISH), and an assessment of the proliferative fraction of tumor cells either by flow cytometry or with the plasma cell labeling index (PCLI) (Table 1).[4,5] Many studies now provide incontrovertible evidence that kinetically active myeloma (PCLI > 3%) or the presence of specific cytogenetic abnormalities (del13q, t[4;14], t[14;16], 17p-, hypodiploidy, or a complex karyotype) are associated with high-risk disease.[9,10] In contrast, other cytogenetic abnormalities and a low PCLI imply a good prognosis and considered ”standard-risk” disease.

While patients with “good-risk” disease benefit from stem cell transplantation, patients with high-risk disease do not experience long-term benefit.[11,12] Although high-risk patients respond to transplantation (and even achieve a complete response [CR]), response duration is usually in the region of a few months.[12] These patients (about 25% of all those with newly diagnosed multiple myeloma) should probably not undergo routine front-line transplantation but are best enrolled in clinical trials testing combinations of novel agents with chemotherapy.

Treatment Endpoints

There has been considerable discussion about the importance of a CR or very good partial response (VGPR) in myeloma, and for a long time, achieving higher CR rates was considered an important endpoint of therapy-perhaps even a benchmark by which regimens are compared.[13,14] If there were curative therapy available for multiple myeloma, then achieving a CR would be a necessary but insufficient step in the path to eradication since, all else being equal, the disease would become undetectable before it is cured. However, CR must be sustained, and here lies the problem, since many patients with high-risk disease achieve CR only to relapse rapidly.[12]

The depth of response implied by CR or VGPR inherently also implies that the myeloma cells behave in a homogeneous fashion and neglects the fact that even in the same patient some cells may secrete a great deal of paraprotein while others, little or none at all.[15] The latter cells contribute to the tumor burden (and presumably to morbidity and mortality), yet are undetectable with the technology noted above.

Finally, all of us have seen multiple myeloma patients with stable disease for long periods without therapy even if they achieve less than a CR or VGPR with the best available therapy. Therefore, while a response is essential for improvement in survival and quality of life, it remains unclear that the depth of response by itself is a good guide to improved survival.[16-18]

Initial Therapy for Transplant-Eligible Patients

The best induction regimen for transplant-eligible multiple myeloma patients is not known. Superiority is often determined by the response rate, although as mentioned, the depth of response prior to transplant does not seem to have a major impact on the outcome after ASCT. The combination of vincristine, doxorubicin, and dexamethasone (VAD) had long been the mainstay of induction therapy, but in head-to-head comparisons with TD (thalidomide [Thalomid] and dexamethasone), the latter proved superior. Cavo et al performed a well-matched retrospective analysis involving 100 patients per treatment cohort: TD was associated with superior responses (partial response [PR] or better, 76% vs 52%, P < .001), although the incidence of venous thromboembolism was higher in the TD-treated group.[19] TD had no impact on progenitor cell collection.

These results were confirmed in a large, randomized international phase III trial, which demonstrated improvement in the time to disease progression.[20] In a phase III trial by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and German GMMG-HD3 group, patients with newly diagnosed myeloma were randomized to either three cycles of VAD or TAD (with thalidomide replacing vincristine).[21] Each arm had 201 patients, and both groups were well balanced. Patients treated with TAD had a higher overall response rate before transplantation ( VGPR = 33% vs 15%, P < .001). Posttransplantation, the respective responses improved to 49% and 32% (P < .001).[21] Long-term follow-up from this study is eagerly awaited.

Perhaps the other conclusion from this study is that vincristine does not confer much benefit to myeloma patients. Although it is difficult to compare across studies, dexamethasone alone seems to produce equivalent tumor control compared to VAD,[19,22] with less toxicity, suggesting that the anthracycline has little to offer in combination with dexamethasone (this may change with new combinations), while TD is clearly superior to dexamethasone alone.[22] Moreover, TD is an oral regimen that causes minimal myelosuppression, although it is associated with its own toxicity including a significant risk of deep venous thrombosis and peripheral neuropathy. The current consensus for the prevention of IMiD-induced deep venous thrombosis was recently published.[23]

Lenalidomide/Dexamethasone
Lenalidomide (Revlimid) is a thalidomide derivative that has significant activity in relapsed myeloma. Lenalidomide combined with dexamethasone (Len-Dex, dexamethasone at 40 mg on days 1–4, 9–12, 17–21) is a safe combination and with high levels of activity in newly diagnosed multiple myeloma. In a phase II study with Len-Dex, the VGPR or better response rate was 56%, and overall, 91% of patients had an objective response.[24] Overall survival at 2 years was 91% with an event-free survival of 74%.

In a subsequent phase III trial, Len-Dex was compared to a similar regimen with oral dexamethasone at 40 mg on days 1, 8, 15, and 22 per 4-week cycle (Len-dex). After four cycles of therapy, patients could continue on therapy or proceed to stem cell transplantation if they were eligible. Preliminary results presented in abstract form show that the overall survival at 2 years was 87% for patients on Len-dex compared to 75% with Len-Dex (P = .006). Short-term results compare favorably with much more intensive regimens that include tandem transplantation, but long-term follow-up is needed to fully assess the benefits of a reduced-intensity approach.[25,26] For patients who did not proceed to transplantation, the corresponding survival at 2 years was 91% compared to 80%, while the median progression-free survival was 22 months compared to 19.3 months.[26] This is a clear example of “less is more” since a reduction in dexamethasone from 480 to 160 mg per cycle not only led to equal efficacy, but also significantly lower toxicity including a lower incidence of thromboembolism and a reduction in early mortality.[26]

The thromboembolic risk of Len-dex is lower, and recent guidelines have addressed thromboprophylaxis in patients on IMiDs.[23] Although there have been some concerns that lenalidomide compromises progenitor cell collection,[27-29] a few cycles of therapy do not seem to interfere with mobilization of progenitor cells in preparation for ASCT.[27] The impact of Len-dex on progenitor cell collection seems to be eliminated when patients are mobilized with a combination of cyclophosphamide and growth factor rather than growth factor alone.[30] Moreover, with the availability of the CXCR4 inhibitor plerixafor (Mozobil), in our experience progenitor cell collection is not a problem. However, it seems prudent that whenever possible, patients on Len-dex should have progenitor cells collected not later than after four cycles of therapy.

BiRD
The combination of clarithromycin (Biaxin), lenalidomide, and dexamethasone (BiRD) has been tested in a phase II study involving 72 patients. Clarithromycin was given at 500 mg twice a day starting on day 2 of the first cycle, with lenalidomide at 25 mg on days 1 to 21 and dexamethasone at 40 mg on days 1 to 3, 8, 15, and 22 of cycle 1 and weekly for subsequent cycles. Therapy was repeated every 28 days. An objective response was seen in 90% of patients with 38.9% achieving a stringent CR (sCR), while another 34.7% achieved VGPR or better.[30] Although a PR was observed early on in most patients, the average time to achieve a VGPR was 5 months and the average time to sCR was almost 9 months. The combination did not impede progenitor cell collection or transplantation, even though the average time from initiation of therapy to progenitor cell collection was 353 days. The event-free survival for patients who continued on BiRD and did not undergo transplantation was 75.2% at 2 years.[30]

Bortezomib-Based Combinations
The introduction of bortezomib, a reversible inhibitor of the 26S proteasome, was a milestone in the therapy of multiple myeloma. Bortezomib blocks the degradation of the inhibitor of kappaB and as a consequence, indirectly inhibits the nuclear factor (NF)kappaB pathway that appears to be critical for myeloma cell growth and survival.[31,32] In addition, bortezomib interferes with the cell cycle by modulating the degradation of p21, p27, and other proteins that are critical for checkpoint control as well as activating p53 and caspases leading to cell death.

With its proven activity in the relapsed myeloma setting, even in heavily treated patients, it was only natural that the activity of bortezomib with dexamethasone be tested in the upfront setting. Harousseau et al enrolled 50 patients who received bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11 with dexamethasone at 40 mg on days 1 to 4, 9 to 12 for cycles 1 and 2, and days 1 to 4 only for cycles 3 and 4. After four cycles of therapy, the PR rate was 66%, with 21% CR and another 10% VGPR. After a single stem cell transplant, the respective CR and VGPR rates were 33% and 21%, respectively. Grade 2/3 neuropathy was observed in 14% of patients.[33]

Using a slightly different design, the Programa para el Tratamiento de Hemopatas Malignas (PETHEMA) group tested a regimen of alternating bortezomib and dexamethasone in 40 transplant-eligible patients.[34] Similar to the French study, the PR rate after four cycles of therapy was 65%. In this study, the kinetics of response to bortezomib vs dexamethasone could be evaluated. Interestingly, the largest decrease in tumor burden (as measured by the monoclonal protein) was observed after dexamethasone therapy and not after bortezomib. Both studies showed that bortezomib did not interfere with progenitor cell mobilization.

In 2005, the Intergroupe Francophone du Myelome (IFM) started a trial where patients with newly diagnosed multiple myeloma were randomized to induction therapy with four cycles of VAD with or without two additional cycles of dexamethasone, cyclophosphamide, etoposide, and platinum (DCEP) or four cycles of bortezomib and dexamethasone (Vel/D) with or without DCEP. The patients proceeded to ASCT after consolidation, having collected progenitor cells between cycles 3 and 4. The incidence of neurologic symptoms was significantly higher in the Vel/D arm (36% vs 11%). The two additional cycles of consolidation with DCEP did not improve CR rates before ASCT. Although more patients on Vel/D achieved CR and near CR (nCR) before ASCT, there was no statistically significant difference in CR and nCR (28% vs 38%, P = .127) after transplant. However, VGPR or better responses occurred more frequently with Vel/D (66% vs 50%, P = .021).[35] Long-term follow-up results of patients enrolled in this trial are awaited.

More recently, bortezomib has been combined with additional agents to further improve response rates. In vitro studies suggest that bortezomib can synergize with other antimyeloma agents and can sensitize cells to drugs that alone have more limited activity.[36] The combination of bortezomib, thalidomide, and dexamethasone (BTD) is being studied by various groups.[37,38] Wang et al have treated 38 patients with BTD. Patients were started on thalidomide at 100 mg every evening and, if this dose was tolerated, increased to 200 mg after 1 week. Dexamethasone at 20 mg/m² was given for 4 days starting on days 1, 9, and 17, while bortezomib (1.3 mg/m²) was given on days 1, 4, 8, and 11. The regimen was repeated every 4 weeks for a maximum of three cycles.

BTD appears to be very effective, producing objective response rates of 87%. Moreover, 11 patients proceeded to transplant after one cycle, suggesting that the regimen enables rapid progression to progenitor cell collection and transplantation. If additional studies confirm the efficacy and safety of this combination, it may become an attractive option, especially in the setting of acute renal failure due to myeloma kidney, where rapid reduction in paraprotein production is important for salvage of renal function. The short duration of therapy is also attractive since it limits the risk of side effects from the agents used (some of which have similar adverse effects such as neuropathy).

The Gruppo Italiano per le Malattie Ematologiche dell’Adulto (GIMEMA) is currently performing a phase III trial comparing the combination of bortezomib, thalidomide, and dexamethasone (VTD) to TD prior to ASCT. Patients have received standard-dose bortezomib with dexamethasone at 40 mg on each day of and after bortezomib as well as thalidomide at 200 mg daily for 63 days. Patients randomized to TD receive thalidomide as in the other arm but with dexamethasone at 40 mg on days 1 to 4 and 9 to 12 of each 21-day cycle. Interim results show that CR or nCR was achieved in 38% of VTD-treated patients vs 7% of those receiving TD (P < .001). At least 60% of patients in the VTD arm achieved a VGPR or better, compared to 25% of those in the TD arm (P < .001). VTD was associated with a higher incidence of skin rash and neuropathy. Of the patients who proceeded to ASCT, the CR-plus-nCR rate increased to 57% with VTD, compared to 28% with TD. The respective VGPR rates were 77% and 54%.[38]

Oakervee et al evaluated the activity of bortezomib (PS-341), doxorubicin (Adriamycin), and dexamethasone (PAD) in 21 patients with newly diagnosed multiple myeloma.[39] The patients received standard-dose bortezomib with dexamethasone at 40 mg on days 1 to 4, 8 to 11, and 15 to 18 of cycle 1 and on days 1 to 4 of cycles 2 to 4. For anthracycline dosing, the patients were divided into three cohorts, receiving 0, 4.5, or 9 mg/m² of doxorubicin on days 1 to 4; 14 patients received dose level 3. The overall response rate was 95%, including 62% who achieved a VGPR or better. Painful peripheral neuropathy was reported in almost half of the patients, most of whom experienced the side effect after the second cycle of therapy.[39]

Richardson et al performed a phase I/II trial combining lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as initial therapy for myeloma. Patients received lenalidomide at 15 to 25 mg for 14 days and bortezomib at 1.0 to 1.3 mg/m² on days 1, 4, 8, and 11, with dexamethasone at 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for cycles 1 to 4 and 20 mg on the same days for cycles 5 to 8. Therapy was repeated every 21 days. The regimen appeared to be well tolerated, with low rates of thrombosis and neuropathy. An objective response (PR or better) was seen in 89% of patients, including 35% with at least a VGPR.[40]

The efficacy of the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in untreated multiple myeloma was recently determined in a phase II trial.[41] Patients received standard-dose bortezomib together with oral cyclophosphamide at 300 mg/m² on days 1, 8, 15, and 22 and dexamethasone at 40 mg on days 1 to 4, 9 to 12, and 17 to 20, with each cycle repeated every 28 days. Responses tended to be rapid (80% decline in M-protein within two cycles), with 88% of patients achieving at least a PR, including 61% with a VGPR or better. In patients who completed four cycles of therapy, a response VGPR increased to 71%, while the CR/nCR rate in patients who went on to ASCT was 70%.

Conclusions About Pretransplant Therapy
In the absence of a head-to-head comparison and long-term follow-up, it is hard to be dogmatic about the specific choice of induction therapy. In standard-risk patients, we prefer Len-dex, since the regimen is arguably more convenient, is well tolerated, and yields high response rates, including VGPR or better in over 40% of patients. To date, no study has shown that a deeper response before transplant translates into a better outcome in terms of a longer response duration or overall survival.[42] Although one can postulate that proceeding to transplant with less tumor burden may be desirable, to date no study has shown this to be the case.

Our own studies suggest that the impact of high-dose melphalan (Alkeran) dwarfs any effect of the pretransplant regimen.[16,43,44] Therefore, in as much as a deep response is important before transplant, Len-dex appears to be the safest and most convenient combination in patients with standard-risk disease who do not wish to enroll in a clinical trial. In high-risk patients (see next section) a different approach may be needed. Ultimately, the optimal induction regimen-either bortezomib- or lenalidomide-based (or including both)-can only be addressed in a randomized clinical trial.

Induction Therapy for High-Risk Myeloma

Patients with high-risk disease (defined in Table 1) have a guarded prognosis. In this setting, bortezomib-containing regimens appear to be particularly effective and may mitigate the negative prognostic impact of adverse cytogenetics such as del13.[33,34,45] Indeed, Harousseau et al reported an objective response rate of 67% in patients with del13 and at least a PR in all patients with t(4;14) or isolated del(17p).[33] Similarly, in the PETHEMA study, no difference in response rates was observed in patients with IgH translocations including t(4;14) and t(14;16).[34] CyBorD also appears to be a very active combination in high-risk myeloma, with response rates of 75% to 94%.[41] Moreover, VDT appears to overcome the adverse prognostic effect of del13 and t(4;14).[38] Thus, in high-risk patients, we prefer a bortezomib-containing induction regimen such as VDT or CyBorD.

Maintenance Therapy After ASCT

The introduction of high-dose therapy and ASCT led the way to a meaningful prolongation of survival in multiple myeloma.[46-48] However, patients normally relapse and require additional therapy. Several trials have attempted to determine whether maintenance therapy with novel agents after transplantation will improve both response rates and response duration.

In Total Therapy 2 (TT2), Barlogie et al randomized patients to a complex induction regimen using a combination of chemotherapy and novel agents.[49] Half of the patients were randomized to continuous thalidomide therapy from induction until disease progression or adverse drug events. Thalidomide increased the CR rates to 62% (vs 43% in the control arm, P < .001), with event-free survival rates at 5 years of 56% and 44%, respectively (P = .01). However, there was no impact on overall survival (65% at 5 years).[49] Survival from relapse was 1.1 years for patients who were on thalidomide vs 2.7 years for the controls (P = .001).

In a subsequent analysis, the Arkansas group reported that thalidomide was most beneficial in patients with high-risk myeloma as defined by cytogenetic abnormalities: Overall survival was 70% at 5 years for the thalidomide group compared to 51% for the controls (P = .01). Moreover, the CR duration was higher in patients on thalidomide (47% vs 25% at 5 years, P = .05).[50] The lack of impact of thalidomide maintenance on survival was also observed in the Medical Research Council’s Myeloma IX study.[51] Although thalidomide after transplant improved progression-free survival, overall survival after relapse in these patients was quite poor. In this study, thalidomide at induction and maintenance appeared to be detrimental in patients with 17p.[51]

Two published studies have shown an improvement in survival with thalidomide maintenance after transplantation.[52,53] Attal et al randomized 597 patients to no maintenance (arm A), pamidronate (arm B), and thalidomide with pamidronate (arm C), starting 2 months after tandem transplantation (IFM 99 02).[52] The CR rates were 55%, 57%, and 67% for arms A, B, and C, respectively (P = .03), and the 3 year event-free survival rates were 36%, 37%, and 52% for the same arms (P < .009). At 4 years from diagnosis, overall survival was 77%, 74%, and 87% (P < .04) for each arm. However, the investigators report that the overall survival differences are no longer significant with longer-follow-up.

More recently Abdelkefi et al reported their experience with 195 multiple myeloma patients initially treated with TD followed by randomization to either tandem transplantation or a single transplant followed by maintenance thalidomide (100 mg daily) starting 90 days after transplant and continued for 6 months.[53] The two arms had similar CR/VGPR rates (40% and 41%) after the first transplant, and these increased to 54% and 68% at 6 months after the second transplant or 6 months of thalidomide therapy (P = .04). The patients on the thalidomide arm had a higher 3-year progression-free survival (85% vs 57%, P = .02) and overall survival (85% vs 65%, P = .04). Thalidomide benefited patients with less than an optimal response (ie, less than VGPR).

The Australian Leukemia and Lymphoma Group (ALLG) evaluated the impact of alternate-day prednisolone (AP) vs thalidomide and AP after a single transplant starting 6 weeks after high-dose therapy.[54] Patients enrolled in the thalidomide arm remained on the drug for up to a year while AP was continued until progression. The progression-free survival rate at 2 years was 73% vs 36% in favor of thalidomide (P = .0003), although to date no difference in survival has been reported. Studies on the impact of bortezomib maintenance after transplant are ongoing,[55] whereas the impact of maintenance therapy with lenalidomide has yet to be evaluated.

Based on the above studies, one can perhaps conclude that patients with high-risk disease may benefit from thalidomide maintenance after transplantation. Patients with standard-risk disease who achieve less than an optimal response to transplant may also benefit from thalidomide administered for a short period of time (“consolidation” rather than true maintenance). Until further studies are completed, other patients should be observed without any form of consolidation or maintenance. The role of lenalidomide in place of thalidomide is not clear. Immunomodulatory drugs and bortezomib can effectively salvage patients with standard-risk disease when they relapse after transplantation. However, routine use of these agents after transplant increases the risk of resistance-hence, the shorter survival of patients in the thalidomide arm after relapse/progression. Moreover, maintenance therapy is associated with a risk of toxicity, and cost considerations also need to be taken into account.

Induction Therapy in Non–Transplant-Eligible Patients With Standard-Risk Disease

By itself, age is not a contraindication for stem cell transplantation. Patients up to 75 years old in otherwise good health (ie, no significant cardiac, pulmonary, hepatic, or renal disease), can undergo ASCT safely.[56] Ludwig et al compared standard melphalan and prednisone (MP) with TD (thalidomide at 200 mg daily with dexamethasone at 40 mg on days 1–4 and 15–18 on even cycles and 1–4 on odd cycles).[57] Despite higher response rates in the TD arm (VGPR or better, 26% vs 13%, P = .0066; PR, 68% vs 50%, P = .0023), time to disease progression was similar in both arms (16.7 vs 20.7 months, P = .2) but overall survival was inferior in the TD group (41.5 vs 49.4 months, P = .024). Moreover, TD was associated with significantly more toxicity (grade 2–3 neuropathy, 25% vs 8%).

Palumbo et al randomized elderly patients to either MP or MP with thalidomide (MPT). MP was given every 4 weeks for a total of six cycles, whereas thalidomide (100 mg daily) was maintained until relapse or progression.[58] Patients in the MPT arm had higher response rates (PR or better, 76% vs 47.6%; CR plus nCR, 27.9% vs 7.2%, respectively). These higher response rates translated into longer time to progression (21.8 vs 14.5 months, P = .004), but overall survival was not different: 45 months for MPT and 47.6 for MP (P = .79).[59] As expected, toxicity (thromboembolism, neuropathy, and infection) was significantly higher in the MPT arm.[58]

The IFM compared MP with MPT or reduced-intensity autologous transplant (melphalan, 100 mg/m2) in patients older than 65 years with newly diagnosed myeloma (IFM 99-06).[60] Again MPT was associated with higher response rates compared to MP (VGPR or better, 47% vs 7%, P < .0001). Interestingly, the reduced-intensity transplant led to response rates similar to those with MPT and clearly superior to MP, but transplantation did not give a superior event-free or overall survival compared to MPT (overall survival, 38.3 and 51.6 months, respectively). These results clearly contrast with those of Palumbo et al. Indeed, it seems that in the IFM trial, the MP arm had a significantly inferior overall survival compared to the Italian study (33.2 vs 47.6 months) despite a higher proportion of elderly patients (> 70 years) in the latter.[59,60]

In a separate study, the IFM randomized patients over 75 years old to MP or MPT every 6 weeks for a total of 12 cycles. Patients in the MPT arm had a median overall survival of 45.3 months, compared to 27.7 months for the MP-plus-placebo arm (P = .03). VGPR or better responses were observed in 22% and 7%, respectively (P < .001). Many patients in the MP arm received thalidomide after relapse. However, survival after progression was the same in both groups (9.8 vs 9.3 months). Therefore, in this study, thalidomide did not prolong survival after relapse or progression.[61]

Given the favorable safety profile of lenalidomide compared to thalidomide, Palumbo et al conducted a phase I/II study of MP with lenalidomide (MPR) in 54 patients with newly diagnosed myeloma.[62] The median age was 71 years and the maximum tolerated dose of lenalidomide was 10 mg (days 1–21) with melphalan at 0.18 mg/kg (days 1–4) and prednisone at 2 mg/kg (days 1–4). Cycles were repeated every 28 days. Aspirin alone was used for thromboprophylaxis. The combination was well tolerated, with patients experiencing mainly hematologic toxicity (neutropenia and thrombocytopenia). A VGPR or better response was seen in 47.6% of patients, including 24.8% with CR. Survival at 1 year was 100% and event-free survival was 92%. Although the number of patients was small, MPR seemed to have a similar impact on event-free survival in patients with del13 and t(4;14).[62] Based on these data, an international study comparing MP with MPR has been initiated, while the Eastern Cooperative Oncology Group (ECOG) is conducting a study comparing MPT with MPR.

In the VISTA trial (Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone), 682 patients were randomized to nine cycles of therapy with either MP or MPV (MP plus bortezomib, 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycles 1–4 and days 1, 8, 22, and 29 of cycles 5–9).[63] A PR was observed in 71% of patients receiving MPV compared to 35% with MP. CR rates were 30% and 4%, respectively. Patients who achieved a CR with MPV had a response duration of about 24 months. The median time to progression was 24 months with MPV, compared to 16.6 months with MP (P < .001). With a median follow up 16.3 months, 13% of patients on MPV and 22% of patients on MP have died (P = .008). Grade 2 or worse neuropathy was reported in almost 30% of the patients on MPV, although the severity of this problem reportedly decreased with time. Thus, MPV gives superior results compared to MP, albeit with some added toxicity and frequent visits, especially for the first four cycles.

In a subsequent follow-up analysis, the VISTA investigators showed that even in the nontransplant setting, achieving a CR led to a superior time to progression in patients on MPV, and this impact was seen regardless of the time to achieving a CR. In other words, patients who achieved CR after the first four cycles had a benefit similar to that of patients who achieved CR within the first four cycles of therapy. Therefore, this study implies that patients should continue with therapy until a maximum or best response is achieved.[64]

The GIMEMA group has reported on the use of four cycles of PAD followed by progenitor cell mobilization with cyclophosphamide at 3 g/m² and granulocyte colony-stimulating factor (G-CSF, Neupogen). Subsequently, the patients received melphalan at 100 mg/m² and autologous stem cell transplantation.[65] A PR was observed in 97.1% of patients, with 61.8% achieving a VGPR or better. After transplantation, the VGPR-or-better rate was 80%, including 30% CRs. As expected the main toxicities were hematologic effects (grade 3/4 thrombocytopenia in 13.5%, neutropenia in 8.1%) and neuropathy (21.6%). The long-term impact of this therapeutic program on survival is unknown, but it seems that such therapy can be tolerated by selected elderly patients.

Therefore, it appears that an “MP+” regimen is now the better option for elderly patients with newly diagnosed myeloma. Typically, we prefer MPT in standard-risk patients, and VMP in high-risk patients, but whether MP is combined with thalidomide, lenalidomide, or bortezomib depends more on convenience, expense, and comorbidities. In addition to MP+ regimens, for frail patients we have increasingly used Len-dex as a less toxic alternative. Results of ongoing randomized trials will shed light on the best choice of initial therapy in elderly patients.

Therapy of Relapsed Disease

With the availability of so many novel agents, it would be the rare patient who is not exposed to these agents when the disease relapses. Thalidomide, lenalidomide, and bor­tezomib alone or in combination with dexamethasone all have significant activity in the relapse setting.[6,66,67] In the APEX trial (Assessment of Proteasome Inhibition for Extending Remissions), bortezomib was compared with dexamethasone in patients who had received one to three prior regimens. Bortezomib was associated with higher response rates and an improved 1-year overall survival (80% vs 66%, P = .003). Despite significant crossover from the dexamethasone arm to the bortezomib arm, with longer follow-up, survival among bortezomib-treated patients remained superior (29.8 vs 23.7 months, P = .027).[68]

Two phase III randomized, double-blind trials have been conducted to compare lenalidomide/dexamethasone with placebo/dexamethasone (MM-009 and MM-010).[69,70] The results from these two studies were essentially identical. The response rates were higher with Len-Dex (60% vs ~20%, P < .001), with the time to progression being 11.2 months, compared with 4.7 months for placebo/dexamethasone. Overall survival has not been reached in the MM-010 trial but in MM-009 was 29.6 months for Len-Dex compared to ~20.4 months for the control arm. Lenalidomide was more effective if used initially after relapse, but responses were seen regardless of whether patients had prior stem cell transplantation. Moreover, lenalidomide was also effective in patients with prior exposure to thalidomide.[71]

Similar to the recent observations that lenalidomide/low-dose dexamethasone gives superior results (response rates, time to progression, and overall survival) in the newly diagnosed setting, it appears that this is also the case in relapsed disease. Combinations of lenalidomide and dexamethasone with liposomal doxorubicin (Doxil), cyclophosphamide, vincristine, or bortezomib are being tested.[72,73] Ideally, patients with relapsed disease should be enrolled in clinical trials evaluating the impact of combination therapy or the use of novel agents.

In summary, patients with multiple myeloma now have many therapeutic options with agents that are very active alone or in combination. The novel agents have non–cross-reactive toxicities and therapy can be tailored for the individual patient. The impact of three or four drug combinations that incorporate the novel agents together with chemotherapy and steroids is as yet unclear, and the results of ongoing studies are awaited in earnest. Perhaps in the not too distant future, myeloma can be cured.

References:

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516-2520, 2008.
2. Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23:6333-6338, 2005.
3. Kuehl WM, Bergsagel PL: Multiple myeloma: Evolving genetic events and host interactions. Nat Rev 2:175-187, 2002.
4. Dispenzieri A, Rajkumar SV, Gertz MA, et al: Treatment of newly diagnosed multiple myeloma based on mayo stratification of myeloma and risk-adapted therapy (mSMART): Consensus statement. Mayo Clin Proc 82:323-341, 2007.
5. Stewart AK, Bergsagel PL, Greipp PR, et al: A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy. Leukemia 21:529-534, 2007.
6. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
7. D’Amato RJ, Lentzsch S, Anderson KC, et al: Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 28:597-601, 2001.
8. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003.
9. Shaughnessy J, Barlogie B: Chromosome 13 deletion in myeloma. Curr Top Microbiol Immunol 246:199-203, 1999.
10. Fonseca R, Barlogie B, Bataille R, et al: Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res 64:1546-1558, 2004.
11. Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55-65, 1999.
12. Dingli D, Nowakowski GS, Dispenzieri A, et al: Flow cytometric detection of circulating myeloma cells before transplantation in patients with multiple myeloma: A simple risk stratification system. Blood 107:3384-3388, 2006.
13. Harousseau JL: Induction therapy in multiple myeloma. ASH Education Book 2008, pp 306-312. Hematology/the Education Program of the American Society of Hematology Education Program Book, 2008.
14. Dingli D, Nowakowski GS, Dispenzieri A, et al: Cyclophosphamide mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma. Clin Lymphoma Myeloma 6:384-388, 2006.
15. Tricot GJ: What is the significance of molecular remission in multiple myeloma? Clin Adv Hematol Oncol 5:91-95, 2007.
16. Dingli D, Pacheco JM, Nowakowski GS, et al: Relationship between depth of response and outcome in multiple myeloma. J Clin Oncol 25:4933-4937, 2007.
17. Bergsagel PL: A kinder, gentler way: Control of the proliferative tumor compartment, not cosmetic complete response, should be the goal of myeloma therapy. Leukemia 22:673-675, 2008.
18. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al: Making progress in treating multiple myeloma with total therapies: Issue of complete remission and more. Leukemia 22:1633-1636, 2008.
19. Cavo M, Zamagni E, Tosi P, et al: Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 106:35-39, 2005.
20. Rajkumar SV, Rosinol L, Hussein M, et al: Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 26:2171-2177, 2008.
21. Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al: Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 93:124-127, 2008.
22. Rajkumar SV, Blood E, Vesole D, et al: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431-436, 2006.
23. Palumbo A, Rajkumar SV, Dimopoulos MA, et al: Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 22:414-423, 2008.
24. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106:4050-4053, 2005.
25. Barlogie B, Anaissie E, van Rhee F, et al: Incorporating bortezomib into upfront treatment for multiple myeloma: Early results of Total Therapy 3. Br J Haematol 138:176-185, 2007.
26. Rajkumar S, Jacobus S, Collander N, et al: Randomized trial of lenalidomide plus hig-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome (abstract 8504). J Clin Oncol 26(15S):455s, 2008.
27. Kumar S, Dispenzieri A, Lacy MQ, et al: Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 21:2035-2042, 2007.
28. Mazumder A, Kaufman J, Niesvizky R, et al: Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients (letter). Leukemia 22:1280-1282 (incl author reply), 2008.
29. Paripati H, Stewart AK, Cabou S, et al: Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia 22:1282-1284, 2008.
30. Mark T, Stern J, Furst JR, et al: Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Biol Blood Marrow Transplant 14:795-798, 2008.
31. Mitsiades N, Mitsiades CS, Poulaki V, et al: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374-14379, 2002.
32. Mitsiades N, Mitsiades CS, Poulaki V, et al: Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: Therapeutic applications. Blood 99:4079-4086, 2002.
33. Harousseau JL, Attal M, Leleu X, et al: Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Results of an IFM phase II study. Haematologica 91:1498-1505, 2006.
34. Rosinol L, Oriol A, Mateos MV, et al: Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: Efficacy and clinical implications of tumor response kinetics. J Clin Oncol 25:4452-4458, 2007.
35. Harousseau JL, Mathiot C, Attal M, et al: Velcade/dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): Updated results of the IFM 2005/01 trial (abstract 450). Blood 110, 2007.
36. Mitsiades N, Mitsiades CS, Richardson PG, et al: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications. Blood 101:2377-2380, 2003.
37. Wang M, Giralt S, Delasalle K, et al: Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology 12:235-239, 2007.
38. Cavo M, Patriarca F, Tocchetti M, et al: Bortezomib (Velcade)-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM) (abstract 73). Blood 110, 2007.
39. Oakervee HE, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755-762, 2005.
40. Richardson P, Jagannath S, Raje N, et al: Lenalidomide, bortezomib and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): Preliminary results of a phase 1/2 study (abstract 187). Blood 110, 2007.
41. Reeder CB, Reece DE, Kukreti V, et al: Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia Feb 19, 2009 (epub ahead of print).
42. Kumar SK, Dingli D, Dispenzieri A, et al: Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous sct. Bone Marrow Transplant 41:1013-1019, 2008.
43. Dingli D, Pacheco JM, Dispenzieri A, et al: Serum m-spike and transplant outcome in patients with multiple myeloma. Cancer Sci 98:1035-1040, 2007.
44. Dingli D, Pacheco JM, Dispenzieri A, et al: In vivo and in silico studies on single versus multiple transplants for multiple myeloma. Cancer Sci 98:734-739, 2007.
45. Jagannath S, Richardson PG, Sonneveld P, et al: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 21:151-157, 2007.
46. McElwain TJ, Powles RL: High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 2:822-824, 1983.
47. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996.
48. Barlogie B: Hemopoietic stem cell transplant for multiple myeloma (MM). Leukemia 7:1095, 1993.
49. Barlogie B, Tricot G, Anaissie E, et al: Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 354:1021-1030, 2006.
50. Barlogie B, Pineda-Roman M, van Rhee F, et al: Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 112:3115-3121, 2008.
51. Morgan GJ, Jackson GH, Davies FE, et al: Maintenance thalidomide may improve progression free but not overall survival; results from the Myeloma IX Maintenance Randomisation (abstract 656). Blood 112, 2008.
52. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289-3294, 2006.
53. Abdelkefi A, Ladeb S, Torjman L, et al: Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: Results of a multicenter randomized clinical trial. Blood 111:1805-1810, 2008.
54. Spencer A, Prince M, Roberts AW, et al: First analysis of the Australasian Leukemia and Lymphoma Group (ALLG) trial of thalidomide and alternate day prednisolone following autologous stem cell transplantation (ASCT) for patients with multiple myeloma (ALLG MM6) (abstract 58). Blood 108, 2006.
55. Schiller GJ, Liao M, Sohn JP, et al: Phase I/II trial of bortezomib maintenance following autologous peripheral blood progenitor cell transplantation as treatment for intermediate- and advanced-stage multiple myeloma (abstract 176). Biol Blood Marrow Transplant 14, 2008.
56. Gertz MA, Ansell SM, Dingli D, et al: Autologous stem cell transplant in 716 patients with multiple myeloma: Low treatment-related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative. Mayo Clin Proc 83:1131-1138, 2008.
57. Ludwig H, Hajek R, Tothova E, et al: Thalidomide-dexamethasone compared to melphalan-prednisolone in elderly patients with multiple myeloma. Blood Oct 27, 2008 (epub ahead of print).
58. Palumbo A, Bringhen S, Caravita T, et al: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367:825-831, 2006.
59. Palumbo A, Bringhen S, Liberati AM, et al: Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: Updated results of a randomized controlled trial. Blood 112:3107-3114, 2008.
60. Facon T, Mary JY, Hulin C, et al: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet 370:1209-1218, 2007.
61. Hulin C, Facon T, Rodon P, et al: Melphala-prednisone-thalidomide (mp-t) demonstrates a significant survival advantage in elderly patients > 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double blind, placebo-controlled tial, IFM 01/01 (abstract 75). Blood 110, 2007.
62. Palumbo A, Falco P, Corradini P, et al: Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: A report from the GIMEMA-Italian Multiple Myeloma Network. J Clin Oncol 25:4459-4465, 2007.
63. San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906-917, 2008.
64. Harousseau JL, Palumbo A, Richardson P, et al: Superior outcomes associated with complete response: Analysis of the phase III VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone (abstract 2778). Blood 112, 2008.
65. Palumbo A, Avonto I, Patriarca F, et al: Bortezomib, pegylated-piposoma-doxorubicin and dexamethasone followed by melphalan 100mg/m2 in elderly newly diagnosed patients: An interim analysis (abstract 448). Blood 110, 2007.
66. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al: Phase i trial of the proteasome inhibitor ps-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002.
67. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005.
68. Richardson PG, Sonneveld P, Schuster M, et al: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the apex trial. Blood 110:3557-3560, 2007.
69. Weber DM, Chen C, Niesvizky R, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133-2142, 2007.
70. Dimopoulos M, Spencer A, Attal M, et al: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123-2132, 2007.
71. Wang M, Dimopoulos MA, Chen C, et al: Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 112:4445-4451, 2008.
72. Morgan GJ, Schey SA, Wu P, et al: Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br J Haematol 137:268-269, 2007.
73. Baz R, Walker E, Karam MA, et al: Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: Safety and efficacy. Ann Oncol 17:1766-1771, 2006.