Introduction

Myeloma is a heterogeneous group of plasma cell disorders. In recent years there have been rapid developments in myeloma both in the clinical arena and in our understanding of myeloma at the cellular and molecular level. The Salmon-Durie Staging System is increasingly replaced by the new International Staging System (ISS) using simple clinical parameters comprising 2-microglobulin and albumin levels to classify patients into low, intermediate and high risk groups. The application of micro-array and cytogenetic data has provided intriguing insights into the pathobiology of myeloma and has resulted in a new molecular classification proposed by Bergsagel and Shaughnessy.[1]

Current questions in the clinical management of myeloma include: one, the role of new agents during induction therapy, including Velcade® (bortezomib) and Revlimid® (lenalidomide); two, whether increased response rates after induction therapy translate into improved outcome after autologous stem cell transplantation (PBSCT); three, improving the outcome of PBSCT; four, the management of patients not suitable for PBSCT; and, five, the application of novel agents and the adoption of risk-related treatment strategies taking into account both new clinical and molecular data. This review of data presented at the American Society of Hematology meeting will address some of the above issues.

Front Line Therapy

Revlimid is a Thalomid® (thalidomide) analogue, which belongs to the group of immunomodulatory agents called (IMiDs). Revlimid has a different side-effect profile compared to Thalomid. Revlimid is not teratogenic and causes less peripheral neuropathy, but is more myelosuppressive and has more potent immunomodulatory effects. Both agents have been associated with increased risk of thrombo-embolism. Encouraging results have been reported in relapsed or refractory myeloma.[2],[3] ,[4]

Rajkumar et al presented the results of a phase II trial using the combination of Revlimid and Decadron® (dexamethasone) for newly diagnosed myeloma.[5] Revlimid was administered to 34 patients orally 25 mg daily on days 1-21 together with Decadron 40 mg days 1-4, 9-12 and 17-20 for 4 cycles. After 4 cycles the patients were allowed to go on to stem cell transplantation or continue with Revlimid and Decadron with a reduction in Decadron to 40 mg day 1-4 only per cycle. Aspirin was given as prophylaxis for deep venous thrombosis. The median age of the patients was 64 years (range: 32-78). Thirty-one of 34 patients (91%) had a partial response (>50% reduction in M-protein). Two patients (6%) attained a complete remission, while 11 patients had a very good partial response (>90% M-protein reduction). Nearly half of the patients had ≥ grade III non-hematologic toxicity comprising fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). One patient died due to infection, and one patient sustained a pulmonary embolism. These data suggest that Revlimid will be an important addition to the therapeutic armamentarium for myeloma, although the drug has significant toxicity. Revlimid has just been approved by the FDA for some forms of myelodysplastic syndrome, which allows for off label use in some myeloma patients.  Revlimid is being further evaluated in two cooperative phase 3 trials. In SWOG-S0232 Revlimid alone is compared to Revlimid and Decadron in a double blind placebo controlled fashion. ECOG-E4A03 randomizes patients to Revlimid with standard or low Decadron.

Wang et al reported the use of a combination of Velcade, Thalomid and Decadron (VTD) in 36 newly diagnosed patients with myeloma.[6] The application of this combination was first reported by Zangari et al and appears to be highly synergistic and effective in Thalomid- and Velcade-resistant myeloma.[7],[8] It has been reported recently by Richardson et al that Velcade can overcome poor prognostic features including deletion chromosome 13q14.[9] Velcade was given twice weekly at 3 different dose levels: 1.3, 1.5 and ≥ 1.6 mg/m2 in, respectively, 15, 11 and 10 patients. Thalomid doses were between 100 and 200 mg daily and Decadron was given IV 20mg/m2 on days 1-4, 9-12 and 17-21. Patients received low-molecular weight heparin to prevent thrombosis. Thirty-three patients obtained a partial response (92%), including 7 patients (19%) who achieved a CR. No more than 2 cycles were necessary in responding patients and no benefit was observed in escalating the Velcade dose beyond 1.3 mg/m2. Twenty-two patients went onto to receive PBSCT therapy. Side-effects include grade III neuropathy (n=3), DVT (n=2), and serious non-neutropenic infections (n=3). This data suggests a role for VTD either up front, as part of consolidation after PBSCT or as salvage therapy in myeloma.

It appears that the addition or combination of novel agents such Revlimid, Thalomid and Velcade when combined with Decadron substantially increase response rates both in relapsed and newly diagnosed myeloma, albeit at the cost of increased toxicity. It is not yet certain if the upfront use of these agents followed by PBSCT results in improved event free survival (EFS) or overall survival (OS) (vide infra)

PBSCT

Convincing evidence has emerged that the combination of Thalomid and Decadron is superior to VAD as induction therapy for myeloma.[10] Two large studies raised questions how to best use Thalomid in the context of PBSCT. The joint Dutch/German HOVON/GMMG-HD3 phase III trial assessed the effect of Thalomid during induction therapy and maintenance therapy post PBSCT.[11] Patients were first randomized to receive three cycles of VAD or TAD, replacing vincristine with 200 mg or 400 mg of Thalomid. This followed by stem cell collection and single or tandem high dose Alkeran®-based (melphalan) PBSCT. Maintenance therapy was interferon- in the standard and Thalomid 50 mg in the Thalomid arm. Four hundred and six patients are thus far evaluable. TAD was superior to VAD in achieving a CR/PR. However, the benefit of Thalomid was lost after PBSCT.

Table 1: Response to VAD and TAD

	After VAD Response (%)	After TAD Response (%)	p-value
PR	60	73	<0.001
CR	3	7	0.11
PR/CR	63	80	0.001
	After VAD/PBSCT Response (%)	After TAD/PBSCT Response (%)
PR	75	72	0.8
CR	13	19	0.3
PR/CR	88	91	0.4

 

The Arkansas group examined in a randomized trial (Total Therapy 2) whether Thalomid could improve the outcome of PBSCT.[12]   Six hundred and sixty-eight patients were randomized to receive Thalomid (n=323) or no Thalomid (n=345) throughout the treatment regimen. Total Therapy 2 (TT2) comprised a) 4 cycles of induction chemotherapy (VAD, DCEP, CAD and DCEP), b) Alkeran 200 mg/m2 tandem PBSCT, c) 4 cycles D-PACE consolidation and d) interferon- maintenance with added Decadron pulsing during the first year. Randomization to Thalomid increased the CR rate from 41 to 59% (p<0.0001) and the 5-yr EFS survival rate from 54 to 42% (p=0.017, median follow-up:37 months). However, the 5-year OS was not different in botharms (67 vs. 62%, p= 0.9). The major benefit of Thalomid was restricted to patients who lacked metaphase cytogenetic abnormalities. Three genetic parameters dominated EFS and OS: metaphase cytogenetic abnormalities, amplification of chromosome 1q21 (FISH) and deletion of chromosome 13q14 (FISH). There was an additive effect of the number of poor prognostic features.< /p>

Table 2: Effect of the Number of Adverse Genetic Factors on EFS and OS

Number of Genetic Risk Factors	5-Year EFS (%)	5-Year OS(%)
No Genetic Adverse Factors	65 (56-73)	80 (73-87)
1 Abnormality	37 (24-50)	52 (38-65)
At Least 2 Abnormalities	18 (1-30)	44 (26-52)

The discrepancy between increased EFS, but no increased OS in the Thalomid arm could be explained by a shorter post relapse survival. This could be traced to an increased incidence of amplification of the cell cycle control check point gene CKS1-B located at chromosome 1q21 at relapse in the Thalomid arm despite comparable characteristics at enrollment in both arms. Explanations could include escape of proliferative myeloma clones during Thalomid induced growth suppression or differential sensitivity of molecularly defined myeloma subtypes to Thalomid. It is of interest to note that the final analysis of the French IFM9902 study also found improved 4-yr EFS with Thalomid maintenance, but no difference in OS compared to patients randomized   (n=593) to no maintenance or pamidronate.[13]

These studies underlined the feasibility, safety and efficacy of high dose Alkeran-based PBSCT. However, taken together these studies raise unanswered questions regarding the optimal application of Thalomid. It is not yet certain that Thalomid is required during induction therapy when combined with a single or double PBSCT. Perhaps the use of Thalomid pre- and post PBSCT should be confined to those with no adverse prognosticators. These studies cast doubt on the use of Thalomid in patients with adverse features. Based on the IFM data, Thalomid should probably only be used post-transplantation in patients failing to achieve a > 90% reduction in M-protein after tandem transplants and only for a limited time (no more than 2 years). Such an approach will prevent excessive toxicity associated with prolonged use and may prevent resistance to Thalomid. It is clear that Thalomid also deserves further study in combination with novel agents, e.g. Velcade, to overcome Thalomid resistance.

In Total Therapy 3 (TT3) Velcade has therefore been incorporated during the induction, consolidation and maintenance phase of the regimen and the number of induction cycles was reduced to 2 comprising both VDTPACE thus allowing rapid reaching rapid completion of the tandem transplant phase, which is followed by 2 courses of VDTPACE, 1 year maintenance with VTD and 2 years with Thalomid and Decadron.[14]  As of April 2005, 162 patients were enrolled and these were compared to 314 comparable TTII patients who were enrolled on the Thalomid arm. First and second transplant on TT3 were completed faster, at medians of 3 and 5 months, compared to 5 and 10 months, respectively, in the TTII group. The probability of achieving ≥ near-CR (n-CR: only immunofixation positive) at 12 months was 81% with TT3 and 64% in TT2 (p=.001). Treatment-related mortality at 12 months was 4% with TT3 and 6% with TT2 (p=.3, the incorporation of Velcade upfront therefore appears to be more effective in inducing ≥ n-CR, but was associated with an increase in toxicity, especially in patients > 65 years. It is too early to assess OS and EFS and to determine if this approach impacts the outcome of patients with high risk features.

Management of Patients Not Suitable for PBSCT

Alkeran and prednisone (MP) has been the mainstay for therapy in patients not eligible for PBSCT for many years. Addition of Thalomid to MP improves the response rate, but is has hitherto not been known if this translates into improved outcome.[15] Palumbo et al presented data from a multi-center Italian phase III trial in which 255 newly diagnosed patients older than age 65 were randomized to receive Alkeran (4mg/m2 for 7 days), prednisone (40mg/m2 for 7 days) and Thalomid 100 mg /day continuously (MPT) for six 4-weekly cycles. The control arm comprised Alkeran and prednisone alone. The overall response rate in the MPT arm was superior to MP (76 vs. 48%, p<0.0001) and near CR rates were 28 and 7%, respectively (p<0.0001). MPT increased the median time to progression by 19 months (33 vs. 14 months respectively, p<0.001). OS at 2 years in patients who completed the 6 cycles was superior in the MPT arm (90 vs. 71%; hazards ratio 0.39, p<0.01). More grade III/IV adverse events occurred in patients treated with MPT (49 vs. 25%). This was due to increase in thrombo-embolism (12% vs. 2%), peripheral neuropathy (10% vs. 1%) and infections (10% vs. 1%). Overall the outcome in the MPT arm was better, but careful, management of side-effects is required to improve toxicity. Similar observations were made in the French IFM99-06 study were MPT was also superior in terms of response rates and progression free survival and OS.[16] Other exploratory studies combining MP with Revlimid or Velcade in elderly patients were reported with encouraging response rates.[17],[18]

Novel Agents

There is a multiplicity of interacting regulatory pathways involved in controlling myeloma cell growth, which makes it difficult to visualize that a single drug can interrupt myeloma growth. This is reflected in the current pre-clinical work where candidate compounds are tested in combination with Decadron, Adriamycin and Velcade. There is currently particular interest in finding novel drugs, which may synergize with Velcade. Combination therapy is now also introduced at an earlier stage in clinical trials. A number of novel compounds are currently tested in the clinic or about to enter clinical trial. CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis, including VEGFR, PDGFR, FGFR, C-KIT, and FLT-3.[19] CHIR-258 induces in vitro anti-proliferative activity and apoptosis of (t4;14) FGFR3 mutant myeloma cell lines and primary myeloma cells. Xin et al reported that CHIR-258 also induces tumor regression and apoptosis in a mouse model of (t4;14) myeloma. CHIR-258 has recently entered into phase I clinical trial.  The heat shock protein 90 (hsp90) inhibitor KOS-953 has been studied in phase I clinical trial both as single agent and in combination with Velcade.[20],[21] KOS-953 is a new formulation of geldanamycin. Hsp90 is a molecular "chaperone" which maintains the stability of numerous "client proteins" implicated in tumor growth and metastasis. Inhibition of Hsp90 results in the degradation of the client proteins.  Hsp-90 has the ability to target multiple signaling pathways in cancer. KOS-953 showed activity in 41% (9/22) patients who had 4 or more lines of prior therapy.  In a second phase I trial KOS-953 and Velcade are combined.21 Velcade can potentially synergize with KOS-953 since it upregulates hsp-90. Fifteen heavily pretreated patients have thus far been enrolled in this, which employs dose escalation of both drugs. Anti-tumor responses in terms of stabilization of disease have thus far been observed in 4 of 15 patients. Perifosine, which is about to enter clinical trial, belongs to a new class of anti-tumor drugs which targets cell membranes and inhibits Akt activation and induces apoptosis.[22] Recently, a second system, the aggresome for cells to discard ubiquinated proteins by autophagic clearance has been described. This is an alternative system to the proteasome. Histone deacetylase 6 plays a central role in the aggresome and can be inhibited by tubacin. Combination of tubacin with Velcade is effective in pre-clinical models and is attractive to overcome Velcade resistance in myeloma.[23] Finally, a number of antibodies were reported for the therapy of myeloma, including an anti-CD40 antibody.[24] Revlimid may synergize with these antibodies by enhancing antibody dependent cellular cytotoxicity.[25]

Incorporating Cytogenetic and Molecular Data Into Therapy.

In recent years, a large volume of cytogenetic and molecular data has been gathered in myeloma. This has led to the identification of genes involved in pathogenesis and potential therapeutic pathways. In addition, it has been possible to build a detailed picture of myeloma resulting in classifications, which may prove both clinically useful in terms of prognosis and identification of candidate pathways and genes for targeted therapeutics. However, the wholy grail of individualized therapy for myeloma patients has thus far been elusive. Recently, two molecular/cytogenetic classifications have been proposed for myeloma, which divide myeloma into 7or 8 subgroups respectively.1,[26] Both classifications agree in terms of identifying patients who will do poorly with current treatment approaches. Patients who have spiked expression of FGFR3 and/or MMSET t(4;14), MAF t(14;16), MAF-B (t(14;20) fare especially poorly both with conservative therapy and high dose therapy. Gene expression profiling (GEP) identifies these abnormalities in approximately 25% of patients. These patients are candidates to explore novel therapeutics or perhaps full myelo-ablative therapy in young patients. The application of GEP before therapy and/or shortly afterwards may provide a way forward for the early identification of patients destined to fail specific therapies. Kumar et al analyzed 30 samples by GEP from the ECOGE100 trial and the Mayo clinic and identified 25 genes which predict response to Thalomid and Decadron.[27] Burington et al showed in 97 samples from TT2 patients that the predictive power of GEP could be improved by comparing the baseline gene expression profile at baseline with the profile 48 hours after therapy had started. In multivariate analysis this prediction was so powerful that metaphase cytogenetics was no longer an independent prognosticator of EFS.[28] This approach is now systematically applied to all TT3 patients with an aim to identify very early in therapy patients who will have a poor prognosis. Although the goal of individualized therapy has not yet been achieved, it is realistic to expect that we will be able to design in the near future clinical studies, which offer different therapies according to the cytogenetic and molecular profile of patients.

Acknowledgements

I thank Drs.Barlogie, Tricot and Shaughnessy for their helpful comments

References

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[1] Bergsagel PL, MW, Zhan F, Jeffrey Sawyer, et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(6): 296-303.