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Multiple Myeloma

What Your Doctor Should Know: Which Treatment Is Best for a Patient with Relapsed or Refractory Multiple Myeloma?

Many medications for multiple myeloma have been approved in recent years. That is great for patients, but it becomes even more important that doctors choose the best treatment for each patient.
February 2020 Vol 6 No 1
Meg Barbor, MPH

Keeping up with the many treatment options that have become available in the past decade for patients with multiple myeloma whose disease has relapsed (came back) or is refractory (not responding to treatment) can be a challenge even for the most informed doctors, suggested Jorge J. Castillo, MD, Clinical Director of the Bing Center for Waldenström’s Macroglobulinemia at Dana-Farber Cancer Institute in Boston, Massachusetts.

Jorge J. Castillo, MD

Dr. Castillo discussed this topic at the National Comprehensive Cancer Network (NCCN) 2019 Hematologic Malignancies annual meeting, explaining how to approach this challenge in the face of recent advances in multiple myeloma treatment.

“In myeloma, a higher variety of medications have been approved in recent years than in any other oncology malignancy. And that, in itself, is a good thing. But then it also gives us a number of headaches,” Dr. Castillo said.

The main headache, he said, is simply deciding which treatment options to use for which patient. The NCCN guidelines for multiple myeloma (which are used as a resource by physicians across the country for selecting cancer therapies) list 8 preferred treatment regimens, as well as more than 20 additional recommended regimens.

So the choice of treatment for patients with relapsed or refractory disease comes down to personalizing the treatment for each patient based on the patient’s specific nature of multiple myeloma, potential genetic abnormalities, as well as patient preferences, according to Dr. Castillo.

“In the relapsed and refractory setting, patient preference has become much more important,” Dr. Castillo said.

Factors Related to Treatment Selection

Deciding on the course of treatment for a patient with relapsed or refractory multiple myeloma often seems less scientific and more like a “wheel of fortune” game, Dr. Castillo said. He was advising oncologists how to hone this process, first by considering the factors that are related to the patient’s disease, such as:


  • The nature of the relapse: is the disease indolent (progressing slowly) or aggressive (progressing fast)?
  • Risk stratification of the disease—is it a high-, intermediate-, or low-risk disease?
  • Are there any genetic or genomic abnormalities associated with the disease?
  • The overall disease burden on the patient.

Patient-Related Factors

As Dr. Castillo said, the factors related to the individual patient must also be carefully weighed, especially regarding:

  • The patient preferences for intravenous versus oral therapy and the patient’s distance to the treatment center if intravenous treatment is used
  • Any associated medical conditions, such as renal insufficiency (kidney malfunctioning); almost 50% of all patients with multiple myeloma will have some degree of renal insufficiency.

In patients with relapsed or refractory multiple myeloma and renal insufficiency, Dr. Castillo recommends that doctors select from a range of medications, including chemotherapy with cyclophosphamide; proteasome inhibitors, such as Velcade (bortezomib), Kyprolis (carfilzomib), or Ninlaro (ixazomib); and dose-reduced immunomodulatory drugs, such as Revlimid (lenalidomide) or Pomalyst (pom­alidomide). These drugs are more likely to be effective and with fewer side effects than other drugs in patients with relapsed or refractory multiple myeloma.

Previous Therapy Used

The type of previous therapy the patient received is also a critical factor that should be considered when deciding what treatment to use for the individual patient. Oncologists should consider whether the disease progressed while the patient received a proteasome inhibitor (such as Velcade, Kyprolis, or Ninlaro) or an immunomodulatory drug (such as Revlimid), and if the disease progressed during maintenance therapy or not. Another factor is the depth and duration of the disease response to treatment in each patient.

Side Effects and Patient Conditions

The degree of side effects that patients have, and any associated medical conditions (or comorbidities) they have, should also be considered. Each drug is made up of different pharmacologic properties, so certain medications should be avoided in certain patients or situations.

In general, Dr. Castillo warned oncologists to avoid using ­Velcade and thalidomide in patients with preexisting neuropathy (numbness of hands/feet); avoid using Kyprolis in ­patients with cardiac problems and in elderly patients; avoid using the monoclonal antibody Darzalex (daratumumab) in patients with pulmonary problems, and Revlimid or other immunomodulatory drugs in patients who have blood clots.

Although these drugs are not prohibited (contraindicated) from being used in these situations, knowing which treatment may result in worse outcomes in certain patients can help oncologists to narrow down their selection options.

Dr. Castillo added that certain side-effects trends should also be used to guide treatment decisions. For example, neuropathy is often more common in patients using proteasome inhibitors; infections are more common with combinations that include Darzalex, and cardiac side effects are more common with Kyprolis.

However, certain side effects, such as diarrhea, occur across the board with most therapies.

For patients whose disease returned twice or more, using combinations with Pomalyst is a good choice, according to Dr. Castillo, but the doctor must be vigilant about the risk of neuropathy with it.

3-Drug Therapy After Relapse

A 2-drug combination treatment with Revlimid plus dexamethasone has extended survival and the time without disease progression in patients with relapsed or refractory multiple myeloma. However, in some patients, Dr. Castillo believes, a 3-drug (triplet) therapy is best. “Triplets are the way to go, not only for front-line disease, but also for relapsed disease,” Dr. Castillo said.

Many studies have explored the use of 3-drug therapy in patients with relapsed or refractory multiple myeloma who had minimal previous use of Revlimid. In these studies, adding Kyprolis to the combination of Revlimid plus dexamethasone showed promising results after the first time the disease came back, as did adding the oral proteasome inhibitor Ninlaro to that combination in patients with relapsed or refractory disease.

Adding Darzalex to a Revlimid plus dexamethasone combination has demonstrated significant extension of the time without disease progression, and the SLAMF7-directed immunostimulatory antibody Empliciti (elotuzumab), when added to the combination of Revlimid and dexamethasone in patients who had minimal previous exposure to Revlimid has also shown promising results.

However, Dr. Castillo warned that many of these findings come from clinical trials and don’t always apply to people outside of clinical trials, who would usually have had higher exposure to Revli­mid. In patients who had previously used Revlimid, adding Kyprolis to dexamethasone led to a “remarkable” time without disease progression compared with the combination of Velcade plus dexamethasone. In addition, evidence has shown that adding Darzalex to Velcade plus dexamethasone was superior to Velcade plus dexamethasone only.

Rules of Thumb

Dr. Castillo also listed the following general rules to help doctors when selecting which drug to use in patients with ­relapsed or refractory multiple myeloma:

  1. Consider non-Revlimid 3-drug combinations in patients whose disease progressed during maintenance therapy with Revlimid, but a Revlimid-based triplet is advised in patients who had a prolonged duration without disease progression after Revlimid-based initial therapy.
  2. Consider a triplet with different novel agents in patients with primary refractory disease.
  3. Always consider referring patients for transplant if an auto logous stem-cell transplant was not done during initial treatment.

According to Dr. Castillo, current research in multiple myeloma is focusing on new types of therapies, including CAR T-cell therapies, antibody-drug con­jugates, and bi-specific T-cell engagers; these emerging treatments should be on the radar of every oncologist.

Key Points

  • The NCCN guidelines for multiple myeloma list 8 preferred treatment regimens and more than 20 additional recommended regimens to choose from
  • So the choice of medication should be based on the specific nature of multiple myeloma and the patient preferences
  • For relapsed or refractory disease, using a proteasome inhibitor and a low-dose immunomodulatory drug is effective and carries fewer side effects than other options
  • A 3-drug combination is now recommended for initial treatment and for patients with relapsed disease
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Last modified: April 14, 2020

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