Step 9: Do you need a change in treatment?

It’s important to assess possible relapse very carefully, and for the physician and the patient to discuss available options. One lab test on its own could be flawed, so it’s important to double-check. The continued presence of CRAB features will in part determine if new treatment is needed. If new treatment is needed, a prior successful therapy could work again and may be a viable option. 

The two types of relapse


Also called “M-Spike-only” relapse. In this type of relapse, the patient will have a 25% increase in the M-Spike in the blood and/or urine (compared to the low point or best response level). The M-Spike must increase by at least 500mg/dl in the serum and/or 200mg/24hrs in the urine. This is the technical definition of relapse used in clinical trials.

Clinical relapse

In this type of relapse, new myeloma has emerged that is producing (or starting to produce) medical problems for the patient. The same CRAB criteria are used to evaluate the disease state as are used at initial treatment. When CRAB criteria emerge, new treatment is required or the current regimen needs to be enhanced (e.g., increased dosage, addition of steroids and/or a new drug to the therapy).

Testing at relapse

It is very important to determine if relapse is occurring. If there is an unexpected change in the M-Spike, the first thing to do is to REPEAT THE TEST to make sure the result is correct and not a lab error. If you experience sudden acute pain, swelling, fever, or anything else unusual or unexpected, call your physician immediately and schedule a checkup. The specific testing required depends upon the exact circumstances. Typically, a full set of lab tests will be performed, and imaging or a bone marrow test may also be needed. Genetic testing with FISH and/or cytogenetics will often be done to assess or re-assess the risk status. Kidney, heart, lung, or other testing (including biopsy) may also be needed.

Options at relapse

A frequent problem in myeloma is the relapse that occurs following one- to three-year remission. Relapse requires re-induction therapy. 

If relapse occurs after a remission of six months to one year, the first strategy to consider is to reuse the therapy that produced the remission in the first place. If remission has lasted fewer than six months, additional therapy may be required. This is also the case if relapse occurs after a second or third use of the original induction therapy. Adding a third drug to a patient's regimen is an important consideration in this setting.

Velcade (bortezomib) for relapsing myeloma

Velcade plays a crucial role as a platform on which to base combination therapies for relapse. In August 2014, Velcade was approved in the US for the retreatment of adult patients with myeloma who had previously responded to Velcade therapy, yet relapsed at least six months following such therapy. The best combinations for Velcade therapy at relapse are explained in further detail in the booklet Understanding VELCADE (bortezomib for injection).

Kyprolis (carfilzomib) for relapsing myeloma

Kyprolis has been evaluated alone and as a backbone drug in combination therapy trials for relapse therapy. It has demonstrated safety and efficacy in a variety of combinations. For example, the ASPIRE trial proved that Kyprolis in combination with Revlimid (lenalidomide) + dexamethasone was more effective than Revlimid + dexamethasone alone. In addition, the ENDEAVOR  trial demonstrated that patients who had had one to three prior therapies fared better on Kyprolis + dexamethasone as compared to similar patients who were treated with Velcade + dexamethasone. However, the ENDEAVOR trial still requires final results to determine whether the higher-than-approved dose of Kyprolis it used, as well as other factors of this trial, influenced results. Another trial, a phase I Kyprolis + pomalidomide + dexamethaosone trial in relapsed/refractory myeloma showed that this combination is well tolerated and highly active, with a 50% response rate (partial response or better) in highly pretreated patients. Because the combinations with Kyprolis are vast and complex, it is recommended to learn more with the booklet Understanding Kyprolis (carfilzomib) for injection

Pomalyst (pomalidomide) for relapsing myeloma

Pomalyst has also demonstrated its value in the relapse setting in multiple combination therapy trials. Encouraging recent news indicated that patients with early relapsed/refractory myeloma who have high-risk deletions 17p and/or t(4;14) show improved progression-free survival and overall survival with Pomalyst + low-dose dexamethasone. Pomalyst may also be used in combinations with a number of other myeloma drugs, and it is recommended to review the booklet Understanding Pomalyst (pomalidomide capsules)

2015 drug approvals and new options for patients with relapsed disease

The 2015 approvals of Farydak (panobinostat), Darzalex (daratumumab), Ninlaro (ixazomib), and Empliciti (elotuzumab) provide new options for treatment of patients with relapsed disease. The optimal sequencing and combination of therapies remains to be sorted out.

  • Darzalex is the only new therapy to demonstrate single-agent activity. It may be administered alone to patients who have received at least three prior therapies, including a proteasome inhibitor and an immunomodulatory agent or are double-refractory. Recent results of the CASTOR and POLLUX trials may explain the approved indications of this drug in the future. It is recommended to learn more with the booklet Understanding Darzalex (daratumumab for injection)
  • For patients who have had at least two prior regimens, Farydak is approved in combination with Velcade (bortezomib) and dexamethasone, incuding bortezomib and an immunomodulatroy drug (IMiD). 
  • For patients who have had one prior therapy, Ninlaro and Empliciti are approved in combination with lenalidomide and dexamethasone. Learn more with the booklets Understanding Ninlaro (ixazomib) capsules and Understanding Empliciti (elotuzumab)

Other intervention options at relapse

  • If relapse is associated with the development of one or two bone lesions, radiation to the site(s) of bone involvement may be a satisfactory way to manage the relapse.
  • If overall relapse occurs, dexamethasone may be useful as a single agent to help control the overall disease. Learn more with the booklet Understanding Dexamethasone and Other Steroids.
  • For patients who relapse after bone marrow transplantation, a second high-dose therapy with transplant may be considered, although the benefits of this protocol remain unclear.
  • Treatment in the context of clinical trials may be an option with patients with relapsed myeloma, which can be researched at Step 10.
  • Finally, supportive care is crucial for all stages of myeloma care and can be explored further at Step 4.