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 second in a two-part series, summarizes the review’s insights into issues that need to be considered when choosing among relapse treatment options

Part 1 summarizes the review’s perspectives on the use of novel agents in the treatment of relapsed and refractory myeloma.  

According to the authors of the review, the goal at relapse is to select a treatment regimen that maximizes efficacy while minimizing toxicity for each myeloma patient.

The specific treatment regimen may vary for each patient depending on a variety of different factors.

“There is not a universal retreatment approach for all [relapsed and refractory] patients, but multiple retreatment approaches that depend on patient-related and disease-related factors,” said Dr. Mohamad Mohty of the University of Nantes in France and one of the study authors.

“Nowadays, the new challenge for clinicians in the choice of a retreatment for multiple myeloma is to find the best suitable treatment for the right patients and at the right moment. This task will become more and more difficult with the advent of so many drugs in the multiple myeloma pipeline,” added Dr. Mohty.

Disease-Related Factors

Disease-related factors include the duration of the patient’s remission and the timing of the patient’s relapse, as well as the aggressiveness of the disease.

The authors suggest that patients who are disease-free for at least 12 months and have not received treatment during this period of remission may receive the same initial therapy at relapse.

However, they advise that patients who relapse within 12 months, or while they are still receiving initial therapy, should receive a different therapy at relapse because it is likely that their disease has become resistant to the initial therapy.

They point out that stem cell transplantation is a feasible retreatment option in myeloma patients who are disease-free for a long period of time after their first stem cell transplant (at least two years in most cases). However, it is not recommended in myeloma patients who relapse within 18 months after their first stem cell transplant. Patients who relapse early should receive alternative treatments involving combinations of novel agents.

In addition, patients who are disease-free for a long period of time after receiving Velcade (bortezomib)-containing therapies may receive Velcade-containing therapies at relapse. Similarly, patients who respond well to thalidomide (Thalomid)-containing therapies may receive thalidomide- or Revlimid (lenalidomide)-containing therapies at relapse.

According to Dr. Sikander Ailawadhi of the USC Norris Cancer Hospital in Los Angeles, who was not involved in the current review, retreatment with a novel agent should be used only if the novel agent is given in a combination different from the initial combination.

“If the disease escapes initial treatment, then there has to be some amount of initial resistance [that the disease has] developed to it,” explained Dr. Ailawadhi.

“If a patient requires treatment again [after relapse], we will almost never go back to using exactly the same [initial] regimen. We want to use the same drug, but in a different combination so there is some novelty in the anti-cancer effect,” he said.

Patients who have high-risk features such as chromosomal abnormalities or extramedullary disease may also have a more resistant disease that requires different and more aggressive forms of treatment at relapse. For these patients, the French researchers recommend sophisticated combinations of novel agents, donor stem cell transplantation, or enrollment in clinical trials involving new, investigational drugs.

Patient-Related Factors

Patient-related factors include the presence of pre-existing toxicities from initial therapy, as well as patient characteristics such as age and kidney function.

For patients who experience kidney failure after initial therapy, the experts recommend treatment with Velcade-based therapies, which have been shown to have the best safety profile in patients with kidney failure. Modified doses of Revlimid-based therapies may also be feasible in these patients.

Patients who experience blood clots or heart problems after initial therapy should receive Velcade-based or Revlimid-based therapies.

Patients who experience peripheral neuropathy - a condition characterized by pain and tingling sensations in the extremities - after initial therapy should receive Revlimid-based therapies. Therapies containing thalidomide and Velcade should be avoided in these patients.

The authors of the review suggest that patients who are resistant to all novel agents participate in clinical trials involving new, investigational drugs such as the histone deacetylase inhibitors panobinostat, Istodax (romidepsin), and Zolina (vorinostat); antibody therapies such as elotuzumab; new proteasome inhibitors such as carfilzomib; or the new immunomodulatory agent pomalidomide.

Those who do not qualify for inclusion in clinical trials should receive treatment aimed at mitigating symptoms and maintaining quality of life while preventing, as much as possible, the spread of disease.

This may include treatment with alkylating agents such as cyclophosphamide (Cytoxan), a type of chemotherapy that prevents DNA replication in cancer cells, in combination with corticosteroids such as dexamethasone (Decadron) and prednisone.

Long-Term Effects Of Prolonged Treatment With Novel Agents

Currently, novel agents are also used in maintenance treatment strategies with the aim of further improving the efficacy of initial treatment with novel agents. However, according to the review authors, the long-term impact of prolonged treatment with novel agents is still unknown, and its benefits should be evaluated in light of its possible risks.

Thalidomide Maintenance

The authors of the review point out that, of the novel agents, thalidomide has been the most widely investigated in both transplant and non-transplant myeloma patients.

While thalidomide maintenance therapies have been shown to improve response rates and progression-free survival, they have not always translated into improved overall survival. In several studies, the overall survival was shorter in myeloma patients who received thalidomide maintenance therapy than in patients who did not. Therefore, researchers have speculated that prolonged exposure to thalidomide could result in the production of drug-resistant myeloma clones.

However, results of another study showed a survival benefit for patients who received thalidomide maintenance. These findings suggest that other factors may influence the final outcome of myeloma patients who receive prolonged treatment with thalidomide, such as the components of the initial therapy, the intensity of previous therapies, the sequence of drugs, and other patient-related factors.

Revlimid Maintenance

The review authors point out that studies investigating Revlimid maintenance therapy have shown promising results, although the long-term effects of Revlimid maintenance are still unknown.

A sub-analysis of a Phase 3 clinical trial showed that myeloma patients who continued Revlimid therapy had a longer overall survival times (51 months versus 35 months) than patients who discontinued Revlimid therapy.

Results of another Phase 3 clinical trial show that the myeloma patients who relapsed after continuous Revlimid therapy had similar outcomes as patients who relapsed after fixed-duration therapies, suggesting that Revlimid maintenance is not associated with more aggressive relapses.

In another study, researchers found that Revlimid maintenance could improve the very good partial response and complete response rates of elderly myeloma patients from 58 percent after induction therapy to 86 percent after maintenance therapy.

Although Revlimid maintenance may be effective in myeloma patients, there are concerns that it may significantly increase a patient's risk of developing secondary cancers (see related Beacon news). According to the review authors, this issue requires additional study to better understand the balance between the benefits and risks of Revlimid maintenance.

Velcade Maintenance

According to the review authors, several studies have indicated that Velcade maintenance improves quality of response and increases progression-free survival in myeloma patients. Moreover, the studies have shown that Velcade maintenance is well-tolerated without a large increase in toxicities such as peripheral neuropathy.

The authors also note, however, that Velcade maintenance has not yet been shown to improve overall survival in myeloma patients.

For more information, please see the review in the journal Leukemia (abstract).