Novel agents in myeloma: an exciting saga

New agents are changing the way we treat this patient population.

An exciting page in the annals of cancer therapy has been unfolding recently with the development of novel agents for the treatment of multiple myeloma. Less than a decade ago, myeloma therapy was in the doldrums, and it had been that way for years. Other than bisphosphonates, basic therapy consisted of alkylating agents in all their various guises, although oral melphalan, and to a lesser degree, cyclophosphamide, were the mainstays of treatment.

Morton Coleman

Combining alkylating agents into a triple-therapy combination had been considered a step forward by some, but only represented more intense therapy. Steroids, particularly high-dose dexamethasone, were helpful, but the contribution of vincristine and doxorubicin in the classic VAD regimen was marginal.

For younger patients, autologous transplantation, employing mostly high-dose alkylating agents, was and still remains the gold standard therapy. However, its effect compared to conventional chemotherapy is modest and does not represent curative therapy. Furthermore, it is not applicable to the elderly, a large cohort of patients who predominate in this disease. Median survival for active myeloma a decade ago ranged from three to five years.

In the late 1990s, an assemblage including a determined and insistent wife of a patient with heavily-treated myeloma, a receptive and innovative group of physicians in Arkansas and a biotech company came together to provide the first major breakthrough in years. Thalidomide (Thalomid, Celgene), the infamous drug used as a sedative in pregnant women, which was responsible for shortened or truncated limbs in newborns, was tried in myeloma for its putative anti-angiogenic properties based on the observation that the more aggressive or advanced the myeloma, the greater the vascularity. As is almost universal in cancer therapy, end-stage, refractory, or previously-treated patients were the initial recipients of this novel therapy.

Indeed, almost all of the patients had received extensive treatment and had limited marrow reserve. Despite these severe drawbacks, thalidomide produced responses in approximately one-third of patients, although some of the responses were minor (the myeloma immunoglobulin levels declined by less than one-half). Thalidomide, however, was particularly useful here because it is minimally myelosuppressive.

Subsequently several groups observed that the addition of steroids greatly augmented the therapeutic effect of thalidomide in previously treated patients, enhancing both the quality and amount of the responses. Successful responses occurred in more than one-half of the patients.

In our program at Cornell, we gave only low-dose thalidomide, dexamethasone weekly and added clarithromycin. Responses approached 90%.

Whether the enhanced response in our program reflected differences in patient selection (one of many problems in comparing phase-2 results), the effect of clarithromycin on the myeloma or the metabolism of the other two drugs, or the use of weekly dexamethasone is unclear.

However, “low-dose” (weekly) dexamethasone has been proven superior to the “classical” Barlogie method of spaced four continuous days of high-dose dexamethasone. Although steroids combined with thalidomide greatly augmented the response, there is no such thing in life as a free lunch. The steroids also ratcheted up the toxicity.

Indeed, the major impediment to long-term use of thalidomide has been neuropathy, which invariably occurs in almost all individuals receiving the combination. The neuropathy does not resolve easily, even with cessation of the drugs. In addition, we, and subsequently others, observed that the combination was associated with an extraordinarily high incidence of thrombosis and sudden death.

Reasoning that thalidomide may produce vascular injury if it is truly anti-angiogenic, we inaugurated low-dose aspirin, and it proved successful, notwithstanding the reported lack of efficacy of aspirin in “slow flow” venous thrombosis, a frequently reported phenomenon with thalidomide-dexamethasone. Heparin and warfarin have also been effective, but low-dose warfarin may not be adequate.

As a natural sequence in testing, the Mayo Clinic headed up a cooperative group study comparing thalidomide plus dexamethasone and dexamethasone alone in a randomized trial of newly-diagnosed patients destined for autologous transplantation. The combination is, in some ways, ideal since neither medicine in the combination was myelosuppressive. The combination indeed proved superior to dexamethasone alone, producing statistically superior responses (70% vs. 50%). But the cost was greater toxicity, primarily thrombotic events. Unfortunately, antithrombotic measures were not employed in the study.

Lenalidomide

Following the remarkable success of thalidomide, two novel agents, bortezomib (Velcade, Millennium Pharmaceuticals) and lenalidomide (Revlimid, Celgene), followed in relatively rapid succession.

Lenalidomide, an immunomodulatory drug reportedly more potent than thalidomide, was introduced in 2006. Again, treatment was first tried in previously treated patients. As with thalidomide, approximately one-third of patients responded. In two concurrent randomized studies, one spearheaded in North America by a group at the M.D. Anderson Cancer Center and one conducted by groups in Australia, Europe and Israel, lenalidomide and dexamethasone were compared with dexamethasone alone in previously treated patients.

The combination of dexamethasone and lenalidomide was superior and produced responses in approximately one-half of patients, similar to the results with thalidomide. Once data of the combination’s efficacy were established in previously treated patients, newly-diagnosed patients were studied. Responses in at least 90% of the patients were produced.

In addition, up to 40% of patients had nearly a complete reduction of the myeloma spike. This depended on several factors: the nuances of the combination, such as the addition of clarithromycin or the addition of weekly dexamethasone; or response criteria used, such as strict complete remissions, complete remissions, near complete response, or very good partial responses — greater than a 90% reduction in immunoglobulin. This response represented a significant achievement since responses of this magnitude were rarely seen with conventional chemotherapy and were equal to or superior to transplantation.

Data suggest that these major responses may translate into enhanced survival. Remarkably, thrombosis was less problematic with the prophylactic use of antithrombotic agents. However, thrombosis was seen when the antithrombotic agent and lenalidomide were discontinued simultaneously. Apparently, damage to the endothelium is more long-standing than the antithrombotic effects of aspirin, for instance, which usually abates in about 10 days.

Bortezomib

Bortezomib, another novel agent, entered the market in 2003 with a mechanism of action thought to be entirely different from the immunomodulatory drugs. Putatively, bortezomib inhibits proteosome activity, allowing inhibition of NF-kappa B, a substance with many nefarious activities once it enters the nucleus. Other mechanisms, though, may be operative. Nevertheless, responses in previously-treated patients hovered around one-third, which was similar to the results with thalidomide and lenalidomide.

Adding steroids clearly enhanced the efficacy of bortezomib. When used in newly-diagnosed patients and augmented with steroids, responses similar to the immunomodulatory drugs were obtained. Nearly 90% of patients responded, again with major response. In a large randomized study headed by the Dana-Farber Cancer Institute, bortezomib was clearly superior and showed an actual enhancement in survival when tested against dexamethasone.

Bortezomib, like thalidomide, produces neuropathy, although the neuropathy is clearly different from that resulting from thalidomide and is more rapidly reversible. Like lenalidomide, there is some myelosuppression, primarily thrombocytopenia, but generally less than with lenalidomide. The immunomodulatory drugs are taken orally; bortezomib is given intravenously. Bortezomib does not need to be given on a continuous basis once a major response has occurred and has been sustained.

Novel agent combinations

Given the different mechanisms of action, the novel agents have been combined, but because of overlapping toxicity, doses may require attenuation. For instance, thalidomide has been combined with bortezomib, but the combination results in overlapping neurologic toxicity. Bortezomib and lenalidomide are also being combined but with some overlapping hematologic toxicity.

A thalidomide and lenalidomide combination represents another possible combination due to the relative lack of overlapping toxicity. Whether such a combination will have an additive or synergistic effect remains to be seen, since there are insufficient data to indicate that resistance to one will not impart resistance to the other.

However, the preliminary responses to combinations of the immunomodulatory drugs with bortezomib in previously treated patients look remarkably impressive. Now that doses are finalized, it will only be a matter of time before the combinations are tested in newly-diagnosed patients.

New chemotherapy agents

A group in Los Angeles and several European groups have combined novel agents with chemotherapy and showed enhanced efficacy to chemotherapy alone. The Italians have shown that thalidomide combined with melphalan was clearly superior to melphalan alone.

The French have shown in elderly patients with newly-diagnosed myeloma that thalidomide and melphalan combined were superior to melphalan alone or to reduced-intensity autologous transplantation. Meanwhile, a group formerly at the Cleveland Clinic showed that pegylated liposomal doxorubicin was effective in myeloma, despite what appears to be marginal activity of standard doxorubicin.

A group in North Carolina, having done pioneering work with bortezomib, noted excellent results when combining bortezomib with liposomal doxorubicin. In the August issue of Hem/Onc Today, an article reported a study presented at the 2007 ASCO Annual Meeting, in which researchers compared bortezomib and liposomal doxorubicin with bortezomib alone in previously treated patients. The findings were subsequently published in the Journal of Clinical Oncology (2007;25:3892-3901). The combination was superior in just about every parameter measured. It is now apparent that combinations of novel agents with steroids and/or chemotherapy are superior to a novel agent, steroids, or chemotherapy alone and probably represent true synergism.

Issues to consider

A question often posed is which novel agent is superior and which should be used initially? The data would suggest they are all of relatively equal efficacy and that the selection of the particular agent should be based on the necessities presented by the patient. Does the patient have a thrombotic tendency, renal failure, a karyotypic chromosome 13 abnormality, an access problem, neuropathy or limited marrow reserve? In each of these cases, one novel agent over the other would be selected.

The critical issue currently is the role novel agents will play in transplantation. Will they make transplantation more effective, or will they turn myeloma into a chronic disease, obviating the need for transplantation? Most importantly, have they improved the overall survival of patients with myeloma? Although some data are available and some are currently being culled, the answer appears to be a resounding yes.

Only several handfuls of institutions, countries and studies have been mentioned in this editorial, but there have been many other institutions throughout the world and many other pertinent studies that have contributed to our better understanding of these remarkable new agents. There are now a bewildering array of trials combining and using novel agents with steroids and chemotherapy, and many other new agents are rapidly coming down the pike. It is an exciting time to be engaged in myeloma therapy.

For more information:

• Morton Coleman, MD, director of the Center for Myeloma and Lymphoma at Weill Cornell Medical College, is an editorial board member of Hem/Onc Today’s Hematology Malignancies section.
• Coleman, M, Leonard J, Lyons L, et al. BLT-D (clarithromycin, low-dose thalidomide and dexamethasone) for the treatment of myeloma and Waldenstrom’s macroglobulin. Leuk Lymphoma. 2002;43:1777-1782.