The huge number of presentations at the American Society of Hematology Meetings (ASH), December 4^th – 9^th 2003 in San Diego capped a truly momentous year for myeloma research and new drug development. Earlier this year, bortezomib (VELCADE^TM) was approved by the FDA for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression. Finally, a new drug approved specifically for myeloma! But this was just the most obvious evidence of the increased focus on myeloma, a disease deserving fundamental research as a basis for the search for better therapies.

At ASH, several sessions focused on myeloma and related diseases, including the so-called “Super Friday” sessions on December 5^th, Educational Sessions, IMF working group meetings, plus the formal oral and poster scientific presentations. Details of many of these sessions can be accessed electronically. The “Super Friday” session dealt with challenging cases, including (topic/discussant in parentheses): Initial Therapy (Dr. Vincent Rajkumar); Renal Failure (Dr. James Berenson); Role of Transplantation (Dr. Jean-Luc Harousseau); Refractory Myeloma (Dr. Paul Richarson); Novel Therapies (Dr. Donna Weber) and Neuropathy (Dr. Robert Kyle). The “MYELOMA EDUCATIONAL SESSION” covered Advances in Biology and Therapy of Multiple Myeloma. The IMF Myeloma Working Group addressed a number of topics, including the new International Staging System (ISS), as well as new criteria for Response Evaluation and Endpoint Definitions.

Although every abstract adds a new piece of information, it is helpful to summarize the major advances, which fell into several categories:

• Role of high-dose chemotherapy with transplantation.
• Novel therapies, including particularly bortezomib (VELCADE ^TM), thalidomide and analogs, arsenic trioxide, Doxil® (liposomal doxorubicin), Samarium and Holmium, and Atiprimod.
• Prognostic factors and staging, including molecular and cytogenetic studies.
• Laboratory-based studies of biology, e.g. stem cell analyses and signal transduction pathways, apoptosis, immunology and many other aspects.
• Clinical studies and diagnostic testing, including the role of FREELITE^TM, MRI, FDG/PET scanning and SNP analyses.

Transplant (Abstracts #135 - #138)

There was tremendous interest in the long-awaited results of the SWOG/ ECOG/ CALGB Intergroup randomized trial S9321 of high-dose therapy (HDT) versus frontline standard therapy using VBMCP (vincristine, BCNU, melphalan, cytoxan, and prednisone) (Abstract 135: presented by Dr. Bart Barlogie). And the answer was: In this particular study, there was no improvement in overall survival for frontline HDT with transplant! There was a slight improvement in progression-free survival with high-dose therapy (25 vs. 21 months: p=.05). Explanations offered and discussed for the lack of improvement in overall survival were:

Ø 52% (89 patients in total) in the standard treatment arm of the study received transplant at the time of relapse. Thus the study in reality compared early transplant with late transplant, for about half the patients.

Ø All the standard (VBMCP) treatment patients received high-dose cytoxan up front for stem cell mobilization and harvesting. This “anti-myeloma intensification” may account for the better outcome with VBMCP in this S9321 study versus prior protocols (median overall survival of 52 months versus 37 months in prior protocols without high-dose cytoxan for mobilization).

Ø The overall prognostic factors in this study were better than average. Since transplant appears to be helpful, particularly for higher-risk patients (e.g. MRC study), but less so for “normal” or good-risk patients, this may account in part for the lack of transplant benefit.

So what conclusions can be drawn from this Intergroup study? Unfortunately, not as many as had been hoped. There is support for the notion that “upfront” and “delayed” transplant have an equivalent impact upon overall survival, as already shown in a French randomized study by Fermand et al. But there is also support for the conclusion that upfront “intensification” with high-dose cytoxan and/or stem cell transplantation can improve overall outcome. It remains unclear from this study which patient groups benefit from “intensification.” The authors conclude that although the overall results with treatment in S9321 were better than in prior standard-dose protocols, the low CR (complete response) rate of 17% may explain the lack of added benefit with the upfront high-dose therapy.

The next Abstract, #136, also presented by Dr. Barlogie, emphasized the importance of achieving complete remission as an essential step toward achieving benefit from transplant, including extended survival. For the Total Therapy I and II patients treated in Little Rock , the achievement of complete remission is what translates into longer overall survival.

This presentation was followed by another that also failed to show improved overall survival with stem cell transplant versus standard-dose chemotherapy (in this case, standard therapy with alternating VBMCP and VBAD [vincristine, BCNU, Adriamycin, and dexamethasone]). The long-term results from the Spanish study group (Abstract # 137: Dr. Joan Bladé) were presented and included details of a higher CR rate in the transplanted group (30% versus 11%: p=0.0002). However, there was no improvement in disease-free or overall survival with the high-dose therapy. In this case, the results were influenced by the fact that randomization to receive high-dose therapy did not occur until after the initial induction chemotherapy was administered and response was observed. Randomization was therefore not on what is called an “intent to treat basis.” This excluded poorer-risk patients, which impacts the outcome of the study.

So where does all this leave us right now? Clearly, the decisive role for transplant as a part of frontline therapy is coming into question. Implications from Dr. Barlogie’s presentations and prior French (IFM) and UK (MRC) data indicate that transplant is particularly helpful for some poorer risk patients (e.g. high pretreatment serum b₂ microglobulin, such as > 8 or > 10 mg/dl) and/or patients failing to have complete remission prior to the procedure. But it is also true that good-risk patients achieving CR can do unusually well with autotransplant. It seems reasonable to attempt to achieve complete remission, whether that be with a single and/or a tandem (double) autologous transplant procedure. However, this shifts the focus of attention to achieving complete remission as an endpoint in the effort to achieve longer survival. As discussed below, several exciting new drug combinations can produce complete remissions (e.g. thalidomide plus melphalan/prednisone; several VELCADEä combinations). The relative efficacy of autotransplant will now have to be assessed either combined with, or compared to, these novel therapy combinations. The new question is therefore: Does complete remission achieved by single or double autotransplant, thalidomide/dexamethasone combinations, or VELCADEä combinations translate into an equivalent remission and/or survival benefit?

In Abstract #138 (IFM 9903 and 9904: Dr. Philippe Moreau) the disappointing interim results (based upon 24 months of follow-up) combining single autotransplantation with mini allogeneic transplant were presented. The “single auto/mini allo” combination was not superior to double autologous transplant and carried a substantial added risk of complications. It seems the IFM will prefer the double auto approach for future studies. It is worth noting that double transplant, which produces complete remission in patients who were not in complete remission with a single autotransplant, confers added benefit.

Three posters dealt with autotransplantation (Abstracts #1630, #1651, #3656). Dr. Bhawna Sirohi (#1630) presented the results from the Royal Marsden in the UK , evaluating long-term survivors, including 13 patients in first complete remission for over 10 years. Predictors for long survival were: complete remission with pre-transplant induction, which is pertinent to the above discussions; younger age (< 55 years); and a trend for lower serum ß₂ microglobulin (median 2.6 mg/dl) and normal serum Albumin (i.e. I.S.S. Stage I patients).

The Boston results with high-dose melphalan for amyloidosis (Abstract # 1651) were presented. Durable remissions and improvement in quality of life were reported for 312/700 (56%) of amyloid patients treated between 1994 and 2002.

A novel approach to transplant was reported from the Mayo Clinic (Abstract # 3656: Dr. Angela Dispenzieri) utilizing high-dose 153-Samarium EDTMP [Quadramet^TM], a bone-targeting radiopharmaceutical combined with high-dose melphalan. Note that this is different than Holmium. The addition of the high-dose Samarium in a study of 46 patients showed promising results. The radiopharmaceutical was safe and well tolerated, and very good responses were observed (29% complete remission; 18% very good partial remission; 49% partial remission). Further studies are planned.

Novel Therapies

It is hard to encompass all the nuances of the numerous novel therapy presentations. The bortezomib (VELCADE^TM) presentations are summarized as part of a separate ASH 2003 review. The local group in Los Angeles was particularly pleased with the excellent early results using VELCADE™ as a frontline therapy (Abstract # 1650).

The primary oral session on novel therapies covered Abstracts #507 - #510. The longer- term follow-up results were presented from IFM study 95-01 involving 489 patients treated with melphalan/prednisone-based or dexamethasone-based regimens. Interestingly, the best outcome, including quality of life, was simply with melphalan/prednisone, which remained the “gold standard” for the IFM group in this setting of newly diagnosed patients 65-75 years of age. However, the greatest attention focused on Abstract #509, presented by Dr. Antonio Palumbo for the Torino- based myeloma group. In this study, 56 patients with newly diagnosed myeloma were treated with melphalan/prednisone combined with thalidomide 100 mg per day. This protocol was generally well tolerated and produced results substantially better than usually observed with melphalan/prednisone alone. At the time of presentation, the overall response rate was an amazing 94%, including 47% having very good partial remission or better.

At this point the numbers in this Italian study are small and the follow-up very short. Since time to first progression is a critical endpoint in assessing therapeutic benefit, some further time is required to truly assess these exciting results. The myeloma community will be “staying tuned” to hear the assessment in 2004. Likewise for an innovative study from the Greek Myeloma Study Group (Abstract #510: Dr. Meletios Dimopoulos) evaluating pulsed thalidomide therapy combined with cytoxan and dexamethasone. This study of 43 patients showed significant anti-myeloma activity in previously treated myeloma and was associated with less frequent occurrence of peripheral neuropathy and deep venous thrombosis complications than with continuous thalidomide therapy protocols. Again this regimen deserves further evaluation.

On a separate topic (Abstract #508: Dr. Morie Gertz), the results with rituximab as treatment for Waldenstrom’s Macroglobulinemia were presented. This was an ECOG phase II pilot study. Rituximab demonstrated significant activity, producing 52.2% objective plus minor responses in both previously untreated and relapsing Waldenstrom’s.

Other abstracts dealing with novel therapies which were of particular interest included Abstracts #252, #825 - #832, #1639, #1650, #1653, #1654, #2544, #3456, and #3492. Just to highlight a few aspects, there were follow-up data related to the several thalidomide analogs: Revimid (#825), Actimid (#829 and #3456), and ENMD-0995 [Entremed] (#1654). These new analogs are moving through clinical trial development with promising results. The pivotal trials with the “lead compound,” Revimid, are ongoing and will undoubtedly produce results for submission to the F.D.A.

As discussed elsewhere, there were numerous presentations related to bortezomib (VELCADE^TM). Perhaps most interesting were the continued very promising results with the three-drug combination of VELCADE™, thalidomide, plus dexamethasone, which is very active in patients with refractory myeloma (Abstract #830). A small point was the observation that bone alkaline phosphatase (from osteoblasts) increased in the serum with successful VELCADE™ therapy (Abstract #2544), indicating possible reactivation of osteoblasts. There were several presentations involving arsenic trioxide (e.g. Abstract #827) and Doxil^® (e.g. Abstracts #831 and #1653).

The numerous presentations of drugs at the preclinical stage were, as always, hard to evaluate, but the number was impressive and very encouraging. It is important to note that results in the laboratory with myeloma cell cultures do not necessarily translate into patient results, but may do so.

One interesting follow-up was a prospective, sequential, randomized trial (Abstract #832: Dr. Ruben Niesvizky) from Weill Medical College evaluating the role of Biaxin^TM combined with low-dose thalidomide and dexamethasone. This study is showing clear evidence in a randomized study that Biaxin™ can augment the response with dexamethasone alone and/or with thalidomide.

Prognostic Factors and Staging

Abstracts #662, #664, #1634, #1638, #3491 and #3492 dealt with prognostic factors and staging. The new International Staging System (I.S.S.) for myeloma was presented (Abstract #664: Dr. Philip Greipp for the IMF Myeloma Working Group).

International Staging System (I.S.S.) for Multiple Myeloma

Footnote: ß₂M = serum ß₂ microglobulin in mg/dl

ALB = serum albumin in g/dl

This staging system is the result of detailed statistical analysis of over 11,000 myeloma patients from around the world treated with standard or high-dose therapy. The system is very simple to use and worked well for all patient subgroups. It is proposed for widespread use, particularly in the clinical trial setting. The Greek Myeloma Study Group (Abstract #3492) presented data indicating that the new staging system works well for their dataset. The MD Anderson group (Abstract #3491) also presented supportive data analysis, although for some reason in their analyses, the use of serum Albumin for their patients identified only a small subset of patients, versus 31% in the original I.S.S. data set. They also emphasized the added discrimination of levels of serum ß₂ microglobulin greater than 5.5 mg/dl (i.e. >8, >10, or higher). This trend is also seen in the I.S.S. dataset, but identifies relatively small high-risk groups. Overall, it is very exciting to have available a new, simple, widely applicable staging system. The full implementation of this system will take time and is discussed elsewhere.

In Abstract #662, Dr. John Shaughnessy and colleagues provided insights into the future of myeloma prognostic factor classification and staging. Using the sophisticated myeloma cell gene expression profiling techniques developed at the Arkansas center, a model for prognostic classification using three genes was presented. The patterns of gene expression were highly predictive. Since this technology is not currently broadly applicable, this is not proposed as a practical staging system. The information is rather used in reverse fashion to indicate the biologic importance of these genes in myeloma pathogenesis and behavior.

Abstract #1634 was an analysis of UK (Medical Research Council [MRC]) data from 2,745 patients with respect to the prognostic significance of different types of myeloma. The major conclusion was that Bence-Jones or light chain only myeloma patients fared less well with long-term follow-up versus the IgG and IgA types. Likewise, for IgD myeloma, summarized in Abstract #1638. Patients with IgD myeloma and Bence-Jones myeloma have very similar disease patterns.

Laboratory-based Studies of Biology

There were numerous presentations on this topic, but some of special interest were #1609, #1612 - #1614, #2511, #3461 and #3467.

There was a particular focus on the impact of myeloma upon bone cell functions. Several abstracts addressed the impact upon osteoblast functions, which are inhibited as disease transitions from MGUS (Abstract #1614) to more active myeloma (Abstract #1609, #1612, #1613 and #3461). In Abstract #1614 from the Hammersmith Hospital in London , the interesting point is made that osteoclast activity is increased in MGUS patients, but is compensated for by increased osteoblast activity and renewed bone formation. Conversely, in active myeloma, osteoblast function is inhibited by various mechanisms, including directly (Abstract #1609), via RANKL, IL-6, and IL-11 (Abstract #1612), and via IL-3 (Abstract #1613). Abstract #3461 emphasizes the role of bone morphologic protein-2 (BMP-2) and Wnt antagonists upon osteoblast inhibition. The osteoblast is a new target for planned therapeutic interventions.

Abstract #2511 from ECOG evaluates the impact of polymorphisms of cytokine genes upon overall patient outcome in phase III trial E9486. Of particular interest, patients with high-producer TNF-alpha phenotype have the poorest survival. This analysis is part of a pilot project for the ongoing IMF genetic project called Bank on a Cure® discussed in detail elsewhere.

The final abstract in this section (#3467) is the basis for a separate article, entitled “In Search of the Myeloma Stem Cell.” (Also in “Myeloma Minute” and “Myeloma Today.”)

Clinical Studies and Diagnostic Testing

Again, there were numerous presentations, but several of note were Abstracts #1630, #1656, #2545, #2546, #2547, #3481, #3489, and #3493.

Two studies dealt with Zometa® as treatment for myeloma bone disease (Abstracts #1630 and #2545). In Abtract #1630, by Dr. Iuliano and colleagues from Cantazaro , Italy , the radiopharmaceutical Samarium-153 EDTMP was combined with Zometa® as treatment of elderly myeloma patients with progressive, painful bone disease. The combination proved to be remarkably effective with reduction in myeloma M-component in some cases. This very interesting observation in eight symptomatic refractory patients will undoubtedly form the basis for further studies. In the other abstract, #2545 from the Cleveland Clinic (Dr. Tahir Latif), it was reassuring to see that with careful monitoring there was no increased frequency of renal toxicity with Zometa® versus Aredia® (pamidronate). However, caution was clearly indicated with elevated baseline serum creatinine levels. Other renal risk factors also need to be proactively assessed.

Three abstracts dealt with the role of imaging. Abstract #2546 highlighted the importance of MRI of the spine in identifying asymptomatic patients at high risk for disease progression. Abstract #3493 from France confirmed the utility of whole body FDG/PET imaging, especially to rule out (or in) any additional myeloma lesions in patients presenting with apparently localized disease (e.g. solitary plasmacytoma). Since FDG/PET detects both bone and extramedullary disease, Abstract #1656, which identified frequent extramedullary disease as a pattern of progression following thalidomide-based therapies, was of particular relevance. Monitoring with FDG/PET is therefore particularly important in this setting.

Abstracts #2547 and #3481 dealt with the important role of the serum FREELITE™ test for disease monitoring. Changes in FREELITE™ are very helpful for evaluating efficacy of high-dose therapy (Abstract #2547: Arthur Bradwell, Birmingham , UK ) and the potential transition from MGUS to active myeloma (Abstract #3481: Dr. Rajkumar, Mayo Clinic). In the latter study, the presence of monoclonal serum free light chains by FREELITE^TM predicted risk of progression from MGUS to active myeloma. A final interesting study related to MGUS was Abstract #3489, indicating a higher than expected incidence of secondary cancers among patients with MGUS.

From this rapid review of ASH 2003, the avalanche of data is clear. This overview of the meeting’s highlights reveals the amazing progress being made in myeloma research and the great hopes we all share for new and better therapies in the near future.