PVd an effective option after lenalidomide-based MM therapy: OPTIMISMM trial

13 Dec 2021

Pomalidomide (POMALYST®) in combination with bortezomib and dexamethasone (PVd triplet therapy) was reimbursed October 1st, 2021 for the treatment of patients with relapsed or refractory (R/R) multiple myeloma (MM) who have received prior treatment with lenalidomide.1

Pharmaceutical Benefits Scheme (PBS) reimbursement of PVd comes in the wake of the OPTIMISMM study2 that showed superior efficacy with PVd triplet therapy compared to bortezomib and dexamethasone (Vd) in patients with R/R MM who were previously treated with lenalidomide, including those patients who were refractory to lenalidomide.2

Speaking to the limbic, Dr Anna Kalff, Consultant Haematologist at The Alfred Hospital, said that the expanded availability of POMALYST is a welcome addition to the therapeutic armamentarium, but PBS constraints limit choices for optimal sequencing.

Sequencing considerations in R/R MM

Treating R/R MM is a challenge, and treatment goals focus on attaining durable remissions whilst maintaining quality of life in an often frail, ageing population.2 Regardless of the treatment, patients become refractory, and the depth and duration of response decreases with each line of therapy.2

Current strategies involve combining compounds with different mechanisms of action, such as immunomodulators (IMiDs), proteasome inhibitors (PIs), glucocorticoids, alkylators and monoclonal antibodies (mAbs) in an effort to overcome intra-tumour heterogeneity and drug resistance while keeping the immune system engaged.2

Since its approval and reimbursement for maintenance therapy in early 2020, the IMiD lenalidomide has become central to induction regimens for MM patients.3 It’s currently recommended in triplet therapy (bortezomib, lenalidomide and dexamethasone; VRd) as standard of care for induction in patients prior to autologous stem cell transplant (ASCT) and as frontline therapy in transplant ineligible (TIE) patients.4

As lenalidomide has become increasingly established for first-line MM treatment, there is a growing pool of patients who eventually become refractory to this drug.2 Dr Kalff has many patients on lenalidomide combination regimens and is starting to face this problem. “In myeloma, you constantly have to think about the next strategy. Patients almost always relapse and go on to have multiple relapses, so you have to think about how you sequence treatments,” she said.

When patients relapse on VRd and are refractory to lenalidomide, treating clinicians have a large selection of potential agents and combinations from which to choose for future lines of therapy.3 Sequencing considerations include prior treatments, potential toxicities, duration of response to prior lines of therapy, the patient’s current health status, and the tempo of the patient’ relapse. Dr Kalff’s approach echoes the guidelines. “Whether it’s first relapse or second relapse, you have to take into consideration what they’ve had before: if they’ve had response on bortezomib or lenalidomide, if they’re refractory or have organ damage, how proliferative their disease is, and even patient preference: do they want to be based in hospital again or do they want an oral therapy?

With the recent PBS-availability of PVd , clinicians now have a choice of two reimbursed triplet therapies for their relapsed or refractory multiple myeloma patients: PVd or daratumumab, bortezomib, plus dexamethasone (DVd).

OPTIMISMM trial2 illustrates PVd benefits in patients previously exposed to lenalidomide

The OPTIMISMM trial was a randomised, open-label phase III trial conducted across 133 centres and 21 countries in 559 patients with R/R MM who were previously treated with lenalidomide, including patients who were refractory to lenalidomide.2

The trial showed that PVd therapy significantly improved progression-free survival (PFS) compared to bortezomib plus dexamethasone (Vd) in the overall intention-to-treat population who had received 1-3 prior lines (median 11.20 vs. 7.10 months respectively; HR 0.61, 95% CI 0.49–0.77; p<0.0001).  In patients who had received one prior line of therapy only (n=226), PVd significantly improved PFS compared to Vd (median 20.70 vs. 11.60 months respectively; HR 0.54, P=0.0027) and, importantly, in lenalidomide-refractory patients in the ITT population (median 9.53 vs. 5.59 months respectively; HR 0.65, 95% CI 0.50–0.84; p=0.0008). 2

A separate post hoc analysis evaluated the safety and efficacy of PVd versus Vd in patients at first relapse (i.e. after one prior line of therapy only) and according to lenalidomide-refractory status, prior exposure to bortezomib, and prior stem cell transplantation. The analysis confirmed the PFS benefit of PVd therapy compared to Vd in the lenalidomide-refractory population (17.8 vs. 9.5 months respectively; P=0.0276).5

The PFS findings in the lenalidomide-refractory patients – in both the ITT population (who had received 1–3 prior lines of therapy) and in the post hoc sub-population (after one prior line of therapy only) are particularly useful, since the data reflect the impact of therapy in the type of patients increasingly seen in clinical practice today. “The OPTIMISMM data are really good for patients who have progressed on lenalidomide, and it’s great that we have that,” said Dr Kalff.

A total of 86 deaths were recorded in each treatment group during the treatment and follow-up periods, with no clinically significant difference in the causes of death noted between treatment arms,2 and the safety profile remained consistent with known adverse events for the study drugs.

The OPTIMISMM study authors concluded that the results provide evidence supporting the use of pomalidomide-based regimens immediately after lenalidomide, showing that there is no need for a class switch, and highlighting the importance of continued immunomodulation.2

PBS restrictions impact sequencing choices, says Dr Kalff

Dr Kalff says that treatment of multiple myeloma has become a “balancing act” between optimal sequencing and preserving PBS eligibility to access treatments further down the line.

When it comes to sequencing in her own clinical practice, Dr Kalff expressed her frustration at current PBS restrictions that impact on what she can choose as her next line of therapy: “The PBS is very didactic in what you can and can’t do…If I use PVd second-line right now [with the current PBS restrictions], it means I can’t access daratumumab at second relapse, and I want to be able to use that [also] in my patients,” she said.

Since choosing the DVd regimen for second-line therapy still allows access to reimbursed PVd and other options, like carfilzomib, for subsequent lines of treatment, Dr Kalff believes that most clinicians will choose to use PVd third-line, despite its potential for good response in the second-line setting.

Dr Kalff recommended all clinicians consider the option of clinical trials for their patients. “Sometimes, the only way to access effective therapy is to enrol patients in clinical trials. I always encourage other clinicians to do the same for their patients, wherever possible,” she said.

Disclosure

This article was sponsored by Celgene Pty Ltd, a Bristol Myers Squibb company. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the POMALYST product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

  1. PBS.gov.au
  2. Richardson P et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;20: 781–794.
  3. Quach H & Prince MH on behalf of MSAG. Clinical Practice Guideline Multiple Myeloma. Updated October 2019.
  4. Quach H & Prince MH. MSAG Update: Bortezomib, lenalidomide, and dexamethasone (VRd) for initial treatment of multiple myeloma. July 2020.
  5. Dimopoulos M et al. Pomalidomide, bortezomib, and dexamethasone for multiple myeloma previously treated with lenalidomide (OPTIMISMM): outcomes by prior treatment at first relapse. Leukaemia 2021;35:1722–1731

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