A group of French myeloma specialists recently published a review of treatment strategies for multiple myeloma patients who have relapsed or become resistant to previous therapies.

This Beacon article, the first in a two-part series, summarizes the review's perspectives on the use of novel agents in the treatment of relapsed and refractory myeloma.  

A second Beacon article will look at the review's insights into issues that need to be considered when choosing among relapse treatment options.

The authors of the recent review begin their discussion by noting how use of the novel agents thalidomide ^[1] (Thalomid), Velcade ^[2] (bortezomib), and Revlimid ^[3] (lenalidomide) has changed over time.

“In the last decade, several powerful novel agents have been registered for the treatment of multiple myeloma and several new strategies are being tested in clinical trials,” said Dr. Mohamad Mohty of the University of Nantes in France and one of the study authors.

Recently, these new strategies have led to the increased use of novel agents in the upfront treatment of myeloma, whereas previously they had been used mostly to treat relapsed myeloma.

“In this context, many questions are being raised, such as the best first line treatment, the best sequence of drugs and the best retreatment approach,” said Dr. Mohty.

These are the questions that motivated the French specialists to write their review.

The Goals For Treatment At Relapse

It is generally accepted that treatment with novel agents brings about high-quality responses in newly diagnosed multiple myeloma patients.

Moreover, patients who achieve high-quality responses during initial therapy tend to have longer overall survival than patients who achieve low-quality responses

“Regimens that are giving a better depth of response are likely to translate into better survival if we are able to follow patients long enough,” said Dr. Sikander Ailawadhi of the USC Norris Cancer Hospital in Los Angeles, who was not involved in the current review.

Therefore, the French researchers argue that the goal of initial ("induction") therapy should be to induce the best possible response in newly diagnosed myeloma patients.

This raises an obvious question: Does the same line of reasoning apply when making treatment decisions for relapsed and refractory myeloma patients?

More specifically, should "depth of response" also be the key goal in relapsed patients?

The authors of the current review admit that the answer to this question is controversial.

One could argue, for example, that duration of response -- rather than depth of response -- should be the key consideration when treating relapsed myeloma patients.

The French researchers believe, however, that recent research supports that view that depth of response should also be the key factor when choosing a treatment for relapsed and refractory patients.

They write that "for patients with a good performance status who can tolerate aggressive treatments, the ultimate goal at induction as well as at relapse should be to achieve the deepest possible response in order to improve survival."

However, the French researchers acknowledge that patients’ quality of life should also be considered when determining appropriate treatment strategies at relapse.

In this regard, a treatment regimen which may yield a deep response may not be ideal if the patient’s quality of life is comprised in the process.

“At the present time, it has become possible to obtain high response rates and prolongation of survival with powerful drugs. However, this success should not be achieved at the cost of an impairment of quality of life due to the side effects of some drugs,” said Dr. Mohty.

“Therefore, it is highly important to include the quality of life issues when choosing a retreatment approach…indeed, the choice of retreatment should take into account several factors in order to avoid cumulative toxicity on the nervous system, bone marrow, or other organs,” he added.

Treatment With Novel Agents At Relapse

With novel agents being used so frequently in the treatment of newly diagnosed myeloma patients, it no longer is possible to discuss the efficacy of these agents in relapsed patients without taking into account the previous treatments patients have received.

This is a major reason the authors of the current review typically use the word retreatment when referring to the use of novel agents to treat relapsed and refractory myeloma patients.

Retreatment With Thalidomide and Revlimid

Thalidomide and Revlimid belong to the class of drugs known as immunomodulatory agents.  These drugs work by encouraging a patient’s immune system to destroy myeloma cells.

Currently, most of the clinical trial results describing the efficacy of Revlimid as a "retreatment" are for myeloma patients who have relapsed after thalidomide therapy.

A sub-analysis of two previous Phase 3 clinical trials, for example, shows that retreatment with Revlimid is more effective in myeloma patients who have not had previous thalidomide exposure than in patients who have had thalidomide exposure.

Specifically, patients who did not have previous thalidomide exposure had higher overall response rates, including complete response rates, and longer progression-free survival times compared to patients who had previous thalidomide exposure.

However, patients who had previous thalidomide exposure still achieved better outcomes with Revlimid plus dexamethasone ^[4] (Decadron) compared to patients who received dexamethasone alone.

Based on these results, the authors of the current review conclude that retreatment with Revlimid can be effective in myeloma patients who have previously received thalidomide, but it is more effective in patients who have not previously been treated with thalidomide.

Retreatment With Velcade

The French researchers next turn their attention to retreatment with Velcade.

They note that there are several studies that have shown that retreatment with Velcade is safe and effective in myeloma patients with previous Velcade exposure.

In fact, results of a Phase 3 clinical trial showed that Velcade is as effective as thalidomide or Revlimid in treating myeloma patients with previous Velcade exposure.

In addition, several studies have shown an overall response rate of up to 50 percent in myeloma patients retreated with Velcade if they had previous Velcade exposure.

Retreatment with Velcade also has been shown not to increase toxicity in patients with previous Velcade exposure. A Phase 2 clinical trial found that 40 percent of myeloma patients who were retreated with Velcade experienced peripheral neuropathy, but most cases were moderate and did not suggest cumulative toxicity.

Reduced-dose or subcutaneous forms of Velcade likewise can limit toxicity during retreatment with the drug (see related Beacon ^[5] news).

Thus, the authors of the current review believe that "re-using [Velcade] in later lines [of therapy] is feasible and can result in responses in a considerable proportion of patients."

Response To Previous Therapy With Novel Agents: Does It Matter?

When considering treatment options for myeloma patients who have received several previous therapies, one area of controversy, the review authors write, is whether efficacy of retreatment is influenced by a patient's response to previous therapy.

Substantial attention has been devoted, in particular, to whether a patient's response to previous treatment with thalidomide influences response to Revlimid when it is given as relapse therapy.

The French researchers report that there are conflicting results on this point.

Results of one recent study, for example, indicate that Revlimid is equally effective in heavily pre-treated myeloma patients regardless of whether they were resistant to, or responded well to, previous thalidomide therapy.

When treated with Revlimid, thalidomide-resistant and thalidomide-sensitive myeloma patients had similar overall response rates (56 percent versus 62 percent), progression-free survival times (10 months versus 12 months), and overall survival times (17 months versus 18.5 months).

Results of another study, however, show that treatment with Revlimid is more effective in patients who respond well to thalidomide therapy than patients who are resistant to thalidomide therapy.

Thalidomide-sensitive patients had a higher overall response rate (65 percent versus 50 percent) and longer progression-free survival (9.3 months versus 7 months) than thalidomide-resistant patients.

Furthermore, results of another study suggest that the presence of thalidomide-resistant disease may generally predict for poor outcomes in myeloma patients.

In that study, thalidomide-resistant patients had a lower response rate, shorter progression-free and shorter overall survival compared to thalidomide-sensitive patients when the patients were treated with Revlimid-based therapies.

Moreover, the addition of Velcade to these Revlimid-based therapies could not overcome the poor prognosis of thalidomide-resistant patients.

Even here, however, the story is not clear cut.

Results of another study showed that thalidomide resistance affected progression-free survival and overall survival only in myeloma patients who also had been treated with Velcade.  This result led some researchers to wonder whether prior treatment with Velcade might generally make treatment at relapse more challenging.

Stem Cell Transplantation As A Treatment Option

The French researchers close out the first part of their review with a discussion of stem cell treatments and their role as relapse therapy.

According to the review authors, stem cell transplantation can be an effective treatment option for relapsed myeloma in patients who have not previously had a transplant.

Results of one key study show that myeloma patients who receive a stem cell transplant at relapse have similar overall survival outcomes as patients who receive a stem cell transplant at diagnosis. However, patients who received an early stem cell transplant have longer progression-free survival and a longer period of time without symptoms, treatments, and treatment-related toxicities.

The French researchers also note that stem cell transplantation may be an effective option at relapse in myeloma patients who previously received a stem cell transplant as long as the first transplant yielded a disease-free period at least 1.5 to 2 years long.

Several clinical trials have shown that a longer disease-free period after initial transplant is associated with improved progression-free and overall survival in patients undergoing a second transplant.

The value of a third stem transplant seems less certain.  The review authors note that a study looking at the potential benefit of a third transplant found that it "did not contribute to long-term disease control."

For more information, please see the review in the journal Leukemia ^[6] (abstract).